THERAPEUTIC AND DIAGNOSTIC METHODS FOR TREATING CANCER WITH ANTI-FcRH5 / ANTI-CD3 BISPECIFIC ANTIBODIES

Abstract

The invention provides therapeutic and diagnostic methods for the treatment of cancer, such as multiple myeloma (MM), with anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibodies.

Description

[0001] THERAPEUTIC AND DIAGNOSTIC METHODS FOR TREATING CANCER WITH ANTI- FcRH5 / ANTI-CD3 BISPECIFIC ANTIBODIES

[0002] SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on November 6, 2024, is named 50474-340WO2_Sequence_Listing_11_6_24 and is 41 ,629 bytes in size.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to therapeutic and diagnostic methods for treating subjects having multiple myeloma (MM) with an anti-fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3) bispecific antibody.

[0006] BACKGROUND

[0007] Cancer remains one of the most deadly threats to human health. In the U.S., cancer affects more than 1 .7 million new patients each year and is the second leading cause of death after heart disease, accounting for approximately one in four deaths.

[0008] Hematologic cancers, in particular, are the second leading cause of cancer-related deaths. Hematologic cancers include multiple myeloma (MM), a neoplasm characterized by the proliferation and accumulation of malignant plasma cells. Worldwide, approximately 110,000 people are diagnosed with MM annually. MM remains incurable despite advances in treatment, with an estimated median survival of 8-10 years for standard-risk myeloma and 2-3 years for high-risk disease, despite receipt of an autologous stem-cell transplant. Despite the significant improvement in patient survival over the past 20 years, only 10-15% of patients achieve or exceed expected survival compared with the matched general population. Increased survival has been achieved with the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and monoclonal antibodies. Nevertheless, most patients (if not all) eventually relapse, and the outcome of patients with MM after they become refractory, or ineligible to receive a proteasome inhibitor or an I MiD, is quite poor, with survival less than 1 year.

[0009] Therefore, the treatment of relapsed or refractory (R / R) MM, in particular, continues to constitute a significant unmet medical need. For such patients, alternative or secondary treatment modalities, such as bispecific antibody-based immunotherapies (e.g., anti-FcRH5 / anti-CD3 bispecific antibodies), may be particularly efficacious. However, there is an unmet need in the field for identifying R / R MM subjects that are most likely to respond to such treatments.

[0010] SUMMARY OF THE INVENTION

[0011] In one aspect, the disclosure features a method of treating a subject having a multiple myeloma (MM) including administering to the subject a bispecific antibody that binds to Fc receptor- homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), wherein prior to administering the bispecific antibody, (a) a sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 3, as compared to a reference level, (b) a sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 4, as compared to a reference level, and / or (c) the subject has been determined to have a lower number in one or more of the features set forth in Table 5, as compared to a reference level.

[0012] In some aspects, the sample from the subject has been determined to have (a) a decreased level of one or more cell types set forth in Table 6, as compared to a reference level, and / or (b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 7, as compared to a reference level.

[0013] In some aspects, the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 8 as compared to a reference level, and optionally or alternatively, the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 9 as compared to a reference level.

[0014] In another aspect, the disclosure features a method of treating a subject having an MM, wherein the method includes a step of: (I) optionally, determining (a) a level of one or more cell types set forth in Table 3 and / or Table 4 in a sample form the subject, and / or (b) one or more of the features of the subject set forth in Table 5; (II) identifying the subject as one who would benefit from a treatment including a bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level; (b) the sample from the subject has an increased level of the one or more cell types set forth in Table 4, as compared to a reference level; and / or (c) the subject has a lower number in one or more of the features set forth in Table 5, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3; and (III) administering to the subject the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0015] In some aspects, the method includes: (I) determining a level of one or more cell types set forth in Table 6 and / or Table 7 in a sample from the subject; and (II) identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level, and / or (b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0016] In some aspects, the method includes: (I) determining a level of one or more cell types set forth in Table 8 and / or Table 9 in a sample from the subject; and (II) identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a decreased level of one or more cell types set forth in Table 8, as compared to the reference level, and / or (b) the sample from the subject has an increased level of one or more cell types set forth in Table 9, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0017] In yet another aspect, the disclosure features a method of identifying a subject having an MM as one who would benefit from a treatment including a bispecific antibody that binds to FcRH5 and CD3, the method including: (I) determining: (a) a level of one or more cell types set forth in Table 3 and / or Table 4 in a sample from the subject, and / or (b) one or more of the features set forth in Table 5 of the subject; and (II) identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level; (b) the sample from the subject has an increased level of the one or more cell types set forth in Table 4, as compared to a reference level; and / or (c) the subject has a lower number in one or more of the features set forth in Table 5, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0018] In some aspects, the method includes: (I) determining a level of one or more cell types set forth in Table 6 and / or Table 7 in a sample from the subject; and (II) identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level, and / or (b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0019] In some aspects, the method includes: (I) determining a level of one or more cell types set forth in Table 8 and / or Table 9 in a sample from the subject; and (II) identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3, wherein: (a) the sample from the subject has a decreased level of one or more cell types set forth in Table 8, as compared to the reference level, and / or (b) the sample from the subject has an increased level of one or more cell types set forth in Table 9, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0020] In yet another aspect, the disclosure features a method of classifying an MM in a subject, the method including: (I) determining a level of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject, and (II) assigning the subject’s MM to one of the following immune profiles based on the level of the CD8+ T cells, Treg cells, and CD8+ TN cells: (a) an activated immune profile; (b) an inactivated immune profile; or (c) a suppressed immune profile, thereby classifying the MM in the subject. In some aspects, the activated immune profile comprises: (a) an increased level of CD8+ T cells; (b) a decreased level of Treg cells; and (c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level. In some aspects, the inactivated immune profile comprises: (a) a decreased level of CD8+ T cells; (b) an increased level of Treg cells; and (c) an increased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level. In some aspects, the suppressed immune profile comprises: (a) an increased level of CD8+ T cells; (b) an increased level of Treg cells; and (c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level. In some aspects, the immune profile is assigned by a similarity network fusion (SNF) algorithm / analysis. In some aspects, the MM is classified as having an activated immune profile or an inactivated immune profile, which identifies the subject having the MM as one who would benefit from a treatment including a bispecific antibody that binds to FcRH5 and CD3. In some aspects, the MM is classified as having a suppressed immune profile, which identifies the subject having the MM as one who would not benefit from a treatment including a bispecific antibody that binds to FcRH5 and CD3.

[0021] In some aspects, the method further includes administering to the subject the treatment including the bispecific antibody that binds to FcRH5 and CD3.

[0022] In some aspects of any one of the methods described herein, the sample from the subject is a bone marrow sample.

[0023] In some aspects of any one of the methods described herein, the sample from the subject is a blood sample.

[0024] In some aspects, the sample from the subject is a baseline sample.

[0025] In some aspects of any one of the methods described herein, determining the level of the one or more cell types includes flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof. In some aspects, determining the level of the one or more cell types includes FC.

[0026] In some aspects of any one of the methods described herein, the reference level is a mean Z- score of the one or more cell types in a population of subjects having the MM. In some aspects, the reference level is a median Z-score of the one or more cell types in a population of subjects having the MM. In some aspects, the reference level is an assigned reference level set forth in Table 14.

[0027] In some aspects of any one of the methods described herein, the reference number is a mean of the one or more features set forth in Table 5 in a population of subjects of having the MM. In some aspects, the reference number is a median of the one or more features set forth in Table 5 in a population of subjects of having the MM. In some aspects, the reference number is an assigned reference number set forth in Table 15.

[0028] In some aspects of any one of the methods described herein, the benefit from the treatment includes a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof. In some aspects, the benefit from the treatment includes a relative increase in OS. In some aspects, the benefit from the treatment includes a relative increase in ORR. In some aspects of any one of the methods described herein, the MM is a relapsed or refractory (R / R) MM.

[0029] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 includes an anti-FcRH5 arm having a first binding domain including the following six hypervariable regions (HVRs): (a) an HVR-H1 including the amino acid sequence of RFGVH (SEQ ID NO: 1 ); (b) an HVR-H2 including the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2); (c) an HVR-H3 including the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3); (d) an HVR-L1 including the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4); (e) an HVR-L2 including the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and (f) an HVR-L3 including the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6). In some aspects, the bispecific antibody that binds to FcRH5 and CD3 includes an anti-FcRH5 arm having a first binding domain including (a) a heavy chain variable (VH) domain including an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain including an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b). In some aspects, the first binding domain includes a VH domain including an amino acid sequence of SEQ ID NO: 7 and a VL domain including an amino acid sequence of SEQ ID NO: 8. In some aspects, wherein the bispecific antibody that binds to FcRH5 and CD3 includes an anti-CD3 arm having a second binding domain including the following six HVRs: (a) an HVR-H1 including the amino acid sequence of SYYIH (SEQ ID NO: 9); (b) an HVR-H2 including the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10); (c) an HVR-H3 including the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 ); (d) an HVR-L1 including the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12); (e) an HVR-L2 including the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and (f) an HVR-L3 including the amino acid sequence of KQSFILRT (SEQ ID NO: 14). In some aspects, the bispecific antibody that binds to FcRH5 and CD3 includes an anti-CD3 arm having a second binding domain including (a) a VH domain including an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain including an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b). In some aspects, the second binding domain includes a VH domain having an amino acid sequence of SEQ ID NO: 15 and a VL domain including an amino acid sequence of SEQ ID NO: 16. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 includes an anti-FcRH5 arm having a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti- CD3 arm including a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein: (a) H1 includes the amino acid sequence of SEQ ID NO: 35; (b) L1 includes the amino acid sequence of SEQ ID NO: 36; (c) H2 includes the amino acid sequence of SEQ ID NO: 37; and (d) L2 includes the amino acid sequence of SEQ ID NO: 38.

[0030] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 includes an aglycosylation site mutation. In some aspects, the aglycosylation site mutation reduces effector function of the bispecific antibody. In some aspects, the aglycosylation site mutation is a substitution mutation. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 includes a substitution mutation in the Fc region that reduces effector function. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment that binds FcRH5 and CD3. In some aspects, the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody. In some aspects, the IgG antibody is an IgGi antibody.

[0031] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 includes one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 1) domain, a first CH2 (CH2j) domain, a first CH3 (CH3y) domain, a second CH1 (CH12) domain, second CH2 (CH22) domain, and a second CH3 (CH32) domain. In some aspects, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some aspects, the CH3y and CH32domains each include a protuberance or cavity, and wherein the protuberance or cavity in the CH3y domain is positionable in the cavity or protuberance, respectively, in the CH32domain. In some aspects, the CH3y and CH32domains meet at an interface between the protuberance and cavity. In some aspects, the CH2j and CH22domains each include a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH22domain. In some aspects, the CH2j and CH22domains meet at an interface between said protuberance and cavity. In some aspects, the anti-FcRH5 arm includes the protuberance and the anti-CD3 arm includes the cavity. In some aspects, a CH3 domain of the anti-FcRH5 arm includes a protuberance including a T366W amino acid substitution mutation (EU numbering) and a CH3 domain of the anti-CD3 arm includes a cavity including T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

[0032] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

[0033] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a monotherapy.

[0034] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a combination therapy. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject concurrently with one or more additional therapeutic agents. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject prior to the administration of one or more additional therapeutic agents. In some aspects, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject subsequent to the administration of one or more additional therapeutic agents. In some aspects, the one or more additional therapeutic agents include an effective amount of tocilizumab. In some aspects, tocilizumab is administered to the subject by intravenous infusion. In some aspects, (a) the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg; (b) the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg / kg; or (c) the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg / kg. In some aspects, tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody that binds to FcRH5 and CD3. In some aspects, the one or more additional therapeutic agents includes an effective amount of a corticosteroid, an analgesic and antipyretic, an antihistamine, an anti-myeloma agent, a PD-1 axis binding antagonist, an anti-CD38 therapeutic agent, an immunomodulatory (IMiD) agent, a cereblon E3 ligase modulatory drug (CELMoD), a proteosome inhibitor (PI), a CAR-T therapy, an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

[0035] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject by intravenous infusion.

[0036] In some aspects of any of the methods described herein, the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject subcutaneously.

[0037] In some aspects of any of the methods described herein, the subject has a cytokine release syndrome (CRS) event, and the method further includes treating the symptoms of the CRS event while suspending treatment with the bispecific antibody that binds to FcRH5 and CD3. In some aspects, the method further includes administering to the subject an effective amount of tocilizumab to treat the CRS event. In some aspects, tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg. In some aspects, the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, and the method further including administering to the subject one or more additional doses of tocilizumab to manage the CRS event. In some aspects, the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

[0038] In some aspects, the one or more additional therapeutic agents include an effective amount of a corticosteroid. In some aspects, the corticosteroid is administered intravenously to the subject. In some aspects, the corticosteroid is methylprednisolone. In some aspects, methylprednisolone is administered at a dose of about 80 mg. In some aspects, the corticosteroid is dexamethasone. In some aspects, dexamethasone is administered at a dose of about 20 mg. In some aspects, the one or more additional therapeutic agents include an effective amount of acetaminophen or paracetamol. In some aspects, acetaminophen or paracetamol is administered at a dose of between about 500 mg to about 1000 mg. In some aspects, acetaminophen or paracetamol is administered orally to the subject. In some aspects, the one or more additional therapeutic agents include an effective amount of diphenhydramine. In some aspects, diphenhydramine is administered at a dose of between about 25 mg to about 50 mg. In some aspects, diphenhydramine is administered orally to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] FIG. 1 is a schematic illustrating the omic and non-omic data types that were compiled and integrated into a single similarity network using Similarity Network Fusion analysis (SNF).

[0040] FIGS. 2A-2E are illustrative examples of the steps of SNF. FIG. 2A is a representation of mRNA expression and DNA methylation data sets for the same cohort of patients. FIG. 2B illustrates patient-by-patient similarity matrices for each data type. FIG. 2C shows patient-by-patient similarity networks, equivalent to the patient-by-patient data. Patients are represented by nodes and patients’ pairwise similarities are represented by edges. FIG. 2D illustrates a network fusion by SNF, which iteratively updates each of the networks with information from the other networks, making them more similar with each step. FIG. 2E illustrates the iterative network fusion results in convergence to the final fused network. Edge color indicates which data type has contributed to the given similarity.

[0041] FIG. 3A is a schematic illustrating the data layers that were integrated using SNF.

[0042] FIG. 3B is a heatmap showing clinical data (e.g., features of the subject) and Z-scores of cell types isolated from bone marrow (BM) and / or blood. As determined by SNF, three clusters (“Cluster 1 ,” “Cluster 2,” and “Cluster 3”) were identified.

[0043] FIG. 4 is a set of bar graphs showing the response of Cluster 1 , Cluster 2, and Cluster 3 according to the International Myeloma Working Group (IMWG) criteria. NR: no response; R: response; sCR: stringent complete response; CR: complete response; VGPR: very good partial response; PR: partial response; MR: minimal response: SD: stable disease; PD: progressive disease.

[0044] FIG. 5 is a set of Kaplan-Meier curves showing the probability of progression-free survival (PFS; left) or overall survival (OS; right) of subjects in Cluster 1 (subjects that responded to cevostamab treatment and had an activated immune profile), Cluster 2 (subjects that responded to cevostamab treatment and had an inactivated immune profile), and Cluster 3 (subjects that responded to cevostamab treatment and had suppressed immune profile) over time (days). Clusters were identified by similarity network fusion (SNF). Each curve is shown with a table below showing the number of subjects at risk over time.

[0045] FIG. 6 is a set of Kaplan-Meier curves showing the probability of PFS (left) or OS (right) of responders to cevostamab treatment (Clusters 1 and 2) or non-responders to cevostamab treatment (Cluster 3). Clusters were identified by SNF. Each curve is shown with a table below showing the number of subjects at risk over time as stratified by response cluster or non-response cluster.

[0046] FIG. 7A is a set of bar graphs showing the percentage (left) and total number (right) of best overall response of responders to cevostamab treatment (Clusters 1 and 2) or non-responders to cevostamab treatment (Cluster 3). SCR: stringent complete response; CR: complete response; VGPR: very good partial response; PR: partial response; MR: minimal response: SD: stable disease; PD: progressive disease.

[0047] FIG. 7B is a set of bar graphs showing the clinical response, according to the IMWG criteria, of responders to cevostamab treatment (Clusters 1 and 2) or non-responders to cevostamab treatment (Cluster 3).

[0048] FIG. 8A is a heatmap of the clinical data layers of Cluster 1 , Cluster 2, and Cluster 3. FIG. 8B is a set of box and whisker plots showing the number of lines of prior therapy (left), the levels of cellular ferritin (middle), and the levels of soluble B-cell maturation agent (sBCMA; right) of subjects in Clusters 1 , 2, and 3.

[0049] FIG. 9 is a heatmap showing clinical data and Z-scores of cell types isolated from BM as grouped by Clusters 1 , 2, and 3. Clinical data layers include a whether or not the subject had a response® or no response (NR) to cevostamab treatment, what the best overall response was (e.g., SCR: stringent complete response; CR: complete response; VGPR: very good partial response; PR: partial response; MR: minimal response: SD: stable disease; PD: progressive disease), whether the subject had prior lines of therapy (e.g., BCMA, ADC, or CART therapy), and whether the subject was a triple class or pentarefractory subject. Cell types determined include the percent of CD8+ TN cells, Treg cells, CD8+ TCM cells, CD3- non-lymphocytes, CD4+PD1 +OX40- T cells, CD4-PD1 + T cells, CD4+DR+PD1 + T cells, CD4+GzB+ T cells, CD8+GzB- T cells, CD8+GzB+ TEM T cells, CD8+GzB+ TEMRA T cells, CD8+DR+GzB+ TEMRA T cells, CD8+DR+ T cells, CD8+DR+ TEMRA T cells, CD8+DR+PD1 + T cells, CD8+PD1 +GzB+ T cells, and CD8+DR+PD1 + TEM cells.

[0050] FIG. 10A is a set of box and whisker plots showing the levels of cell types isolated from BM, as grouped by Clusters 1 , 2, and 3. The represented cell types are cluster of differentiation 8 (CD8)- positive (CD8+) T cells, CD8+ naive T cells (CD8Tn), CD8+ central memory T cells (CD8Tcm), CD8+ effector memory T cells (CD8Tem), and CD8+ terminally differentiated effector memory T cells (CD8Temra).

[0051] FIG. 10B is a set of box and whisker plots showing the levels of cell types isolated from BM as grouped by Clusters 1 , 2, and 3. The represented cell types are regulatory T cells (Treg), CD8+ and granzyme B (GzB)-positive effector memory T cells (CD8TemGzB), and CD8-positive and GzB- positive terminally differentiated effector memory T cells (CD8TemraGzB).

[0052] FIG. 11 is a heatmap showing clinical data and Z-scores of cell types isolated from blood as grouped by Clusters 1 , 2, and 3.

[0053] FIG. 12A is a set of box and whisker plots showing the level of cell types isolated from the blood as grouped by Clusters 1 , 2, and 3. The represented cell types are CD8-positive cells, which are further stratified by naive T cells (Tn), central memory T cells (Tern), effector memory T cells (Tern), and terminally differentiated effector memory T cells (Temra).

[0054] FIG. 12B is a set of box and whisker plots showing the level of cell types isolated from the blood as grouped by Clusters 1 , 2, and 3. The represented cell types are CD4-positive cells, which are further stratified by naive T cells (Tn), central memory T cells (Tern), effector memory T cells (Tern), and terminally differentiated effector memory T cells (Temra).

[0055] FIG. 13 is a set of box and whisker plots showing the level of cell types as grouped by Clusters 1 , 2, and 3. The plot on the left shows the level of regulatory T cells (Treg). The plot in the middle shows the level of CD8-positive, programmed cell death protein 1 (PDI )-positive (PD1 +), T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT)-positive (TIGIT+), and T cell immunoglobulin and mucin-domain containing-3 (TIM3)- positive cells (TIM3+). The plot on the right shows the level of PD1 +, TIGIT+, and TIM3+ cells. FIG. 14A is a heatmap showing the clinical data and Z-scores of cell types, as grouped by Clusters 1 , 2, and 3, in subjects that received <5 prior lines of therapy.

[0056] FIG. 14B is a heatmap showing the clinical data and Z-scores of cell types, as grouped by Clusters 1 , 2, and 3, in subjects that received >5 prior lines of therapy.

[0057] FIG. 15A is a heatmap showing the clinical data and Z-scores of cell types, as grouped by Clusters 1 , 2, and 3, in subjects that received <3 prior lines of therapy.

[0058] FIG. 15B is a heatmap showing the clinical data and Z-scores of cell types, as grouped by Clusters 1 , 2, and 3, in subjects that received >3 prior lines of therapy.

[0059] FIG. 16 is a set of box and whisker plots showing the levels of cell types isolated from BM as grouped by Clusters 1 , 2, and 3. The represented cell types are cluster of differentiation 4 (CD4)- positive and GzB-positive cells (CD4GzB); CD4-positive, human leukocyte antigen - DR isotype (DR)- positive, and GzB-positive cells (CD4DR+GzB+); CD8-positive and GzB-positive effector memory T cells (CD8TemGzB); and CD8-positive, GzB-positive terminally differentiated effector memory T cells (Cd8TemraGzB).

[0060] FIG. 17A is a Kaplan-Meier curve showing the probability of PFS over time (days) in subjects treated for multiple myeloma (MM) with a bispecific antibody that binds to FcRH5 and CD3, wherein the subjects either received a post BCMA treatment (blue) or did not (red). Below the curve is a chart showing the number of subjects at risk over time as stratified by treatment group.

[0061] FIG. 17B is a Kaplan-Meier curve showing the probability of PFS over time (days) in subjects treated for MM with a bispecific antibody that binds to FcRH5 and CD3, wherein the subjects either received a prior anti-BCMA antibody treatment (blue) or did not (red). Below the curve is a chart showing the number of subjects at risk over time as stratified by treatment group.

[0062] FIG. 17C is a Kaplan-Meier curve showing the probability of PFS over time (days) in subjects treated for MM with a bispecific antibody that binds to FcRH5 and CD3, wherein the subjects either received a prior anti-BCMA bispecific antibody treatment (blue) or did not (red). Below the curve is a chart showing the number of subjects at risk over time as stratified by treatment group.

[0063] FIG. 18A is a Kaplan-Meier curve showing the probability of PFS over time (days) in subjects treated for MM with a bispecific antibody that binds to FcRH5 and CD3, wherein the subjects either received a prior anti-BCMA antibody and a prior chimeric antigen receptor T-cell (CART) therapy (blue) or did not (red). Below the curve is a chart showing the number of subjects at risk over time as stratified by treatment group.

[0064] FIG. 18B is a Kaplan-Meier curve showing the probability of PFS over time (days) in subjects treated for MM with a bispecific antibody that binds to FcRH5 and CD3, wherein the subjects either received a prior anti-BCMA antibody drug conjugate (ADC) treatment (blue) or did not (red). Below the curve is a chart showing the number of subjects at risk over time as stratified by treatment group.

[0065] FIG. 18C is a Kaplan-Meier curve showing the probability of PFS over time (days) in subjects treated for MM with a bispecific antibody that binds to FcRH5 and CD3, wherein the subjects either received a prior anti-BCMA bispecific antibody treatment (blue) or did not (red). Below the curve is a chart showing the number of subjects at risk over time as stratified by treatment group. FIG. 19 is a set of box and whisker plots showing the soluble levels of sBCMA (left) and interferon (IFN) (right) in blood samples as grouped by Clusters 1 , 2, and 3.

[0066] FIG. 20 is a set of box and whisker plots showing the levels of regulatory T cells (Treg) (left), CD4-positive naive T cells (CD4Tn) (middle), and CD8-positive naive T cells (CD8Tn) (right) in blood samples as grouped by Clusters 1 , 2, and 3.

[0067] FIG. 21 is a set of box and whisker plots showing the levels of regulatory T cells (Treg) (left), CD4-positive naive T cells (CD4Tn) (middle), and CD8-positive naive T cells (CD8Tn) (right) in BM samples as grouped by Clusters 1 , 2, and 3.

[0068] FIG. 22A is a set of box and whisker plots showing the level of CD8-positive cells (left) and CD4-positive cells (right) in BM samples as grouped by Clusters 1 , 2, and 3.

[0069] FIG. 22B is a set of box and whisker plots showing the level of CD8-positive cells (left) and CD4-positive cells (right) in blood samples as grouped by Clusters 1 , 2, and 3.

[0070] FIG. 23 is a heatmap showing the clinical data (e.g., features of the subject) and Z-scores of the number of previous treatments as grouped by Clusters 1 , 2, and 3.

[0071] FIG. 24A is a heatmap showing the clinical data (e.g., features of the subject) and Z-scores of cell types isolated from the BM as grouped by Clusters 1 , 2, and 3.

[0072] FIG. 24B is a heatmap showing the clinical data (e.g., features of the subject) and Z-scores of cell types isolated from the blood as grouped by Clusters 1 , 2, and 3.

[0073] DETAILED DESCRIPTION OF THE INVENTION

[0074] I. DEFINITIONS

[0075] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter perse.

[0076] It is understood that aspects of the invention described herein include “comprising,” “consisting,” and “consisting essentially of” aspects.

[0077] The term “FcRH5” or “fragment crystallizable receptor-like 5,” as used herein, refers to any native FcRH5 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, and encompasses “full-length,” unprocessed FcRH5, as well as any form of FcRH5 that results from processing in the cell. The term also encompasses naturally occurring variants of FcRH5, including, for example, splice variants or allelic variants. FcRH5 includes, for example, human FcRH5 protein (UniProtKB / Swiss-Prot ID: Q96RD9.3), which is 977 amino acids in length.

[0078] The terms “a bispecific antibody that binds to Fc receptor-homolog 5 (FcRH5) and cluster of differentiation 3 (CD3),” “a bispecific anti-FcRH5 / anti-CD3 antibody,” and “an anti-FcRH5 / anti-CD3 bispecific antibody” refer to an antibody that is capable of binding FcRH5 and CD3 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting FcRH5 and CD3. In one embodiment, the extent of binding of a bispecific antibody that binds to FcRH5 and CD3 to an unrelated, non-FcRH5 protein and / or non-CD3 protein is less than about 10% of the binding of the antibody to FcRH5 and / or CD3 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, a bispecific antibody that binds to FcRH5 and CD3 has a dissociation constant (KD) to FcRH5 and / or CD3 of < 1 pM, < 250 nM, < 100 nM, < 15 nM, < 10 nM, < 6 nM, < 4 nM, < 2 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10-8M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain embodiments, a bispecific antibody that binds to FcRH5 and CD3 binds to (i) an epitope of FcRH5 that is conserved among FcRH5 from different species, and (ii) an epitope of CD3 that is conserved among CD3 from different species. In one embodiment, a bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

[0079] The term “cluster of differentiation 3” or “CD3,” as used herein, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3e, CD3y, CD3a, and CD3p chains. The term encompasses “full-length,” unprocessed CD3 (e.g., unprocessed or unmodified CD3e or CD3y), as well as any form of CD3 that results from processing in the cell. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, human CD3e protein (NCBI RefSeq No. NP_000724), which is 207 amino acids in length, and human CD3y protein (NCBI RefSeq No. NP_000064), which is 182 amino acids in length.

[0080] “Cevostamab,” also referred to as BFCR4350A or RO7187797, is an Fc-engineered, humanized, full-length non-glycosylated IgG 1 kappa T-cell-dependent bispecific antibody (TDB) that binds FcRH5 and CD3 and comprises an anti-FcRH5 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 35 and the light chain polypeptide sequence of SEQ ID NO: 36 and an anti- CD3 arm comprising the heavy chain polypeptide sequence of SEQ ID NO: 37 and the light chain polypeptide sequence of SEQ ID NO: 38. Cevostamab comprises a threonine to tryptophan amino acid substitution at position 366 on the heavy chain of the anti-FcRH5 arm (T366W) using EU numbering of Fc region amino acid residues and three amino acid substitutions (tyrosine to valine at position 407, threonine to serine at position 366, and leucine to alanine at position 368) on the heavy chain of the anti-CD3 arm (Y407V, T366S, and L368A) using EU numbering of Fc region amino acid residues to drive heterodimerization of the two arms (half-antibodies). Cevostamab also comprises an amino acid substitution (asparagine to glycine) at position 297 on each heavy chain (N297G) using EU numbering of Fc region amino acid residues, which results in a non-glycosylated antibody that has minimal binding to Fc (Fey) receptors and, consequently, prevents Fc-effector function. Cevostamab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 84, Vol. 34, No. 3, published 2020 (see page 701 ).

[0081] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fabs) so long as they exhibit the desired antigen-binding activity.

[0082] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary aspects for measuring binding affinity are described in the following.

[0083] An “affinity matured” antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.

[0084] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.

[0085] An “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to bis-Fabs; Fv; Fab; Fab, Fab’-SH; F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, ScFab); and multispecific antibodies formed from antibody fragments.

[0086] A “single-domain antibody” refers to an antibody fragment comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain aspects, a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Patent No. 6,248,516 B1 ). Examples of single-domain antibodies include but are not limited to a VHH.

[0087] A “Fab” fragment is an antigen-binding fragment generated by papain digestion of antibodies and consists of an entire L chain along with the variable region domain of the H chain (VH), and the first constant domain of one heavy chain (CH1 ). Papain digestion of antibodies produces two identical Fab fragments. Pepsin treatment of an antibody yields a single large F(ab’)2 fragment which roughly corresponds to two disulfide linked Fab fragments having divalent antigen-binding activity and is still capable of cross-linking antigen. Fab’ fragments differ from Fab fragments by having an additional few residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab’-SH is the designation herein for Fab’ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab’)2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0088] “Fv” consists of a dimer of one heavy- and one light-chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although often at a lower affinity than the entire binding site.

[0089] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all Lys447 residues removed, antibody populations with no Lys447 residues removed, and antibody populations having a mixture of antibodies with and without the Lys447 residue.

[0090] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG 1 Fc region (non-A and A allotypes); native sequence human lgG2 Fc region; native sequence human lgG3 Fc region; and native sequence human lgG4 Fc region as well as naturally occurring variants thereof.

[0091] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or to the Fc region of a parent polypeptide, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region or in the Fc region of the parent polypeptide. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region and / or with an Fc region of a parent polypeptide, preferably at least about 90% homology therewith, or preferably at least about 95% homology therewith.

[0092] “Hinge region” is generally defined as stretching from about residue 216 to 230 of an IgG (EU numbering), from about residue 226 to 243 of an IgG (Kabat numbering), or from about residue 1 to 15 of an IgG (IMGT unique numbering).

[0093] “Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one that binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain (see review M. in Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991 ); Capel et al., Immunomethods 4:25-34 (1994); and de Haas etal., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)).

[0094] The term “knob-in-hole” or “KnH” technology as mentioned herein refers to the technology directing the pairing of two polypeptides together in vitro or in vivo by introducing a protuberance (knob) into one polypeptide and a cavity (hole) into the other polypeptide at an interface in which they interact. For example, KnHs have been introduced in the Fc:Fc interaction interfaces, CL:CH1 interfaces or VH / VL interfaces of antibodies (e.g., US2007 / 0178552, WO 96 / 027011 , WO 98 / 050431 and Zhu et al. (1997) Protein Science 6:781 -788). This is especially useful in driving the pairing of two different heavy chains together during the manufacture of multispecific antibodies. For example, multispecific antibodies having KnH in their Fc regions can further comprise single variable domains linked to each Fc region, or further comprise different heavy chain variable domains that pair with identical, similar, or different light chain variable domains. KnH technology can also be used to pair two different receptor extracellular domains together or any other polypeptide sequences that comprise different target recognition sequences.

[0095] “Framework” or “FR” refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the HVR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -H1 (L1 )-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0096] The “CH1 region” or “CH1 domain” comprises the stretch of residues from about residue 118 to residue 215 of an IgG (EU numbering), from about residue 114 to 223 of an IgG (Kabat numbering), or from about residue 1 .4 to residue 121 of an IgG (IMGT unique numbering) (Lefranc M-P, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0097] The “CH2 domain” of a human IgG Fc region usually extends from about residues 244 to about 360 of an IgG (Kabat numbering), from about residues 231 to about 340 of an IgG (EU numbering), or from about residues 1 .6 to about 125 of an IgG (IGMT unique numbering). The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain. Burton, Molec. Immunol.22: 161 -206 (1985).

[0098] The “CH3 domain” comprises the stretch of residues C-terminal to a CH2 domain in an Fc region (i.e., from about amino acid residue 361 to about amino acid residue 478 of an IgG (Kabat numbering), from about amino acid residue 341 to about amino acid residue 447 of an IgG (EU numbering), or from about amino acid residue 1 .4 to about amino acid residue 130 of an IgG (IGMT unique numbering)).

[0099] The “CL domain” or “constant light domain” comprises the stretch of residues C-terminal to a light-chain variable domain (VL). The light chain of an antibody may be a kappa (K) (“CK”) or lambda (A) (“CA”) light chain region. The CK region generally extends from about residue 108 to residue 214 of an IgG (Kabat or EU numbering) or from about residue 1 .4 to residue 126 of an IgG (IMGT unique numbering). The CA residue generally extends from about residue 107a to residue 215 (Kabat numbering) or from about residue 1.5 to residue 127 (IMGT unique numbering) (Lefranc M-P, Giudicelli V, Duroux P, Jabado-Michaloud J, Folch G, Aouinti S, Carillon E, Duvergey H, Houles A, Paysan-Lafosse T, Hadi-Saljoqi S, Sasorith S, Lefranc G, Kossida S. IMGT®, the international ImMunoGeneTics information system® 25 years on. Nucleic Acids Res. 2015 Jan;43(Database issue):D413-22).

[0100] The light chain (LC) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, having heavy chains designated a, 5, y, £, and p, respectively. The y and a classes are further divided into subclasses on the basis of relatively minor differences in CH sequence and function, e.g., humans express the following subclasses: IgG 1 , lgG2, lgG3, lgG4, lgA1 , and lgA2.

[0101] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0102] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, IgGs, lgG4, IgAi, and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 5, E, y, and p, respectively.

[0103] A “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter. J. Mol. Biol. 227:381 ,1991 ; Marks et al. J. Mol. Biol. 222:581 , 1991 . Also available for the preparation of human monoclonal antibodies are methods described in Cole et al. Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al. J. Immunol., 147(1 ):86-95, 1991 . See also van Dijk and van de Winkel. Curr. Opin. Pharmacol. 5:368-74, 2001 . Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li et al. Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006 regarding human antibodies generated via a human B-cell hybridoma technology.

[0104] A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain aspects, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. In certain aspects in which all or substantially all of the FRs of a humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues (e.g., one or more Vernier position residues of FRs) from non-human FR(s). A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0105] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al. Kuby Immunology, 6thed. W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991 .

[0106] The term “hypervariable region” or “HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence (“complementarity determining regions” or “CDRs”). Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). Exemplary CDRs herein include:

[0107] (a) CDRs occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26-32 (H1 ), 53- 55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917, 1987);

[0108] (b) CDRs occurring at amino acid residues 24-34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35b (H1 ), 50-65 (H2), and 95-102 (H3) (Kabat et al. Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD (1991 )); and

[0109] (c) antigen contacts occurring at amino acid residues 27c-36 (L1 ), 46-55 (L2), 89-96 (L3), 30- 35b (H1 ), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745, 1996).

[0110] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. supra.

[0111] “Single-chain Fv” also abbreviated as “sFv” or “scFv” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. Preferably, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun, The Pharmacology of Monoclonal Antibodies, vol. 1 13, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994); Malmborg et al., J. Immunol. Methods 183:7-13, 1995.

[0112] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phagedisplay methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.

[0113] The term “multispecific antibody” is used in the broadest sense and specifically covers an antibody that has polyepitopic specificity. In one aspect, the multispecific antibody binds to two different targets and is a “bispecific antibody.” Such multispecific antibodies include, but are not limited to, an antibody comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), where the VH / VL unit has polyepitopic specificity, antibodies having two or more VL and VH domains with each VH / VL unit binding to a different epitope, antibodies having two or more single variable domains with each single variable domain binding to a different epitope, full-length antibodies, antibody fragments such as Fab, Fv, dsFv, scFv, diabodies, bispecific diabodies and triabodies, antibody fragments that have been linked covalently or non-covalently. “Polyepitopic specificity” refers to the ability to specifically bind to two or more different epitopes on the same or different target(s). “Monospecific” refers to the ability to bind only one antigen. In one aspect, the monospecific biepitopic antibody binds two different epitopes on the same target / antigen. In one aspect, the monospecific polyepitopic antibody binds to multiple different epitopes of the same target / antigen. According to one aspect, the multispecific antibody is an IgG antibody that binds to each epitope with an affinity of 5 pM to 0.001 pM, 3 pM to 0.001 pM, 1 pM to 0.001 pM, 0.5 pM to 0.001 pM, or 0.1 pM to 0.001 pM.

[0114] “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures. For example, native IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light chains and two identical heavy chains that are disulfide- bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.

[0115] As used herein, the term “immunoadhesin” designates molecules which combine the binding specificity of a heterologous protein (an “adhesin”) with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with a desired binding specificity, which amino acid sequence is other than the antigen recognition and binding site of an antibody (i.e., is “heterologous” compared to a constant region of an antibody), and an immunoglobulin constant domain sequence {e.g., CH2 and / or CH3 sequence of an IgG). The adhesin and immunoglobulin constant domains may optionally be separated by an amino acid spacer. Exemplary adhesin sequences include contiguous amino acid sequences that comprise a portion of a receptor or a ligand that binds to a protein of interest. Adhesin sequences can also be sequences that bind a protein of interest, but are not receptor or ligand sequences {e.g., adhesin sequences in peptibodies). Such polypeptide sequences can be selected or identified by various methods, include phage display techniques and high throughput sorting methods. The immunoglobulin constant domain sequence in the immunoadhesin can be obtained from any immunoglobulin, such as IgG 1 , lgG2, lgG3, or lgG4 subtypes, IgA (including lgA1 and lgA2), IgE, IgD, or IgM.

[0116] As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of cancer, such as a multiple myeloma (MM, e.g., a relapsed or refractory (R / R) MM). Examples of chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech / OSI Pharm.); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3- chloro-4-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’-Chloro-4’-fluoroanilino)-7-methoxy-6-(3- morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)- quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1 -methyl-piperidin-4-yl)- pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1 - phenylethyl)amino]-1 H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1 - phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6- quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6- quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); and dual EGFR / HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3- chloro-4-[(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4- quinazolinamine)); a tyrosine kinase inhibitor (e.g., an EGFR inhibitor; a small molecule HER2 tyrosine kinase inhibitor such as TAK165 (Takeda); CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 (ISIS Pharmaceuticals) which inhibit Raf-1 signaling; non-HER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787 / ZK222584, Novartis / Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis / Schering AG); pan-HER inhibitors such as Cl- 1033 (Pfizer); Affinitac (ISIS 3521 ; Isis / Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI- 1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis / Schering AG); INC-1 C11 (Imclone); and rapamycin (sirolimus, RAPAMUNE®)); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1 and calicheamicin w1 ); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzi nostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0117] Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY1 17018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; (ix) growth inhibitory agents including vincas (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

[0118] The term “cytotoxic agent” as used herein refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At211, 1131, 1125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof such as nucleolytic enzymes; antibiotics; toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof; and the various antitumor or anticancer agents disclosed below.

[0119] A “disorder” is any condition that would benefit from treatment including, but not limited to, chronic and acute disorders or diseases including those pathological conditions which predispose a mammal to the disorder in question. In one aspect, the disorder is a cancer, e.g., a multiple myeloma (MM).

[0120] The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation. In one aspect, the cell proliferative disorder is cancer. In one aspect, the cell proliferative disorder is a tumor.

[0121] “Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein.

[0122] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Aspects of cancer include solid tumor cancers and non-solid tumor cancers. Examples of cancer include, but are not limited to, B cell proliferative disorders, such as multiple myeloma (MM), which may be relapsed or refractory MM. The MM may be, e.g., typical MM (e.g., immunoglobulin G (IgG) MM, IgA MM, IgD MM, IgE MM, or IgM MM), light chain MM (LCMM) (e.g., lambda light chain MM or kappa light chain MM), or non-secretory MM. The MM may have one or more cytogenetic features (e.g., high-risk cytogenic features), e.g., t(4;14), t(11 ;14), t(14;16), and / or del(17p), as described in Table 1 and in the International Myeloma Working Group (IMWG) criteria provided in Sonneveld et al., Blood, 127(24): 2955-2962, 2016, and / or 1 q21 , as described in Chang et al., Bone Marrow Transplantation, 45: 117- 121 , 2010. Cytogenic features may be detected, e.g., using fluorescent in situ hybridization (FISH).

[0123] Table 1. Cytogenic features of MM

[0124] The term “B cell proliferative disorder” or “B cell malignancy” refers to a disorder that is associated with some degree of abnormal B cell proliferation and includes, for example, a lymphoma, leukemia, myeloma, and myelodysplastic syndrome. In one embodiment, the B cell proliferative disorder is a myeloma, such as multiple myeloma (MM).

[0125] “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell- mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

[0126] “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) that are bound to their cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed.

[0127] “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a form of cytotoxicity in which secreted Ig bound onto Fc receptors (FcRs) present on certain cytotoxic cells {e.g., Natural Killer (NK) cells, neutrophils, and macrophages) enable these cytotoxic effector cells to bind specifically to an antigen-bearing target cell and subsequently kill the target cell with cytotoxic agents. The antibodies “arm” the cytotoxic cells and are absolutely required for such killing. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII, and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet. Anna. Rev. Immunol. 9:457-92, 1991 . To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in U.S. Patent No. 5,500,362 or 5,821 ,337 can be performed. Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest can be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. USA. 95:652-656, 1998.

[0128] “Complex” or “complexed” as used herein refers to the association of two or more molecules that interact with each other through bonds and / or forces {e.g., Van der Waals, hydrophobic, hydrophilic forces) that are not peptide bonds. In one aspect, the complex is heteromultimeric. It should be understood that the term “protein complex” or “polypeptide complex” as used herein includes complexes that have a non-protein entity conjugated to a protein in the protein complex (e.g., including, but not limited to, chemical molecules such as a toxin or a detection agent).

[0129] As used herein, “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and / or postpone development of the disease or disorder (e.g., a cell proliferative disorder, e.g., cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0130] An “effective amount” of a compound, for example, an anti-FcRH5 / anti-CD3 T-cell-dependent bispecific antibody (TDB) described herein or a composition (e.g., pharmaceutical composition) thereof, is at least the minimum amount required to achieve the desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting ( / .e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit ( / .e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and / or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0131] As used herein, “overall survival” or “OS” refers to the percentage of individuals in a group who are likely to be alive after a particular duration of time. As used herein, “objective response rate” or “ORR” refers to the sum of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) rates as determined using the International Myeloma Working Group response criteria (Table 13; Kumar et al., Lancet. Oncol., 17:e328-346, 2019).

[0132] The term “epitope” refers to the particular site on an antigen molecule to which an antibody binds. In some aspects, the particular site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting. In some aspects, the particular site on an antigen molecule to which an antibody binds is determined by crystallography.

[0133] A “growth inhibitory agent” when used herein refers to a compound or composition which inhibits growth of a cell either in vitro or in vivo. In one aspect, growth inhibitory agent is growth inhibitory antibody that prevents or reduces proliferation of a cell expressing an antigen to which the antibody binds. In another aspect, the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase. Aspects of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include the vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 also spill over into S-phase arrest, for example, DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1 , entitled “Cell cycle regulation, oncogenes, and antineoplastic drugs” by Murakami et al. (W.B. Saunders, Philadelphia, 1995), e.g., p. 13. The taxanes (paclitaxel and docetaxel) are anticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, which results in the inhibition of mitosis in cells.

[0134] An “immunoconjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a cytotoxic agent.

[0135] The term “immunomodulatory agent” refers to a class of molecules that modifies the immune system response or the functioning of the immune system. Immunomodulatory agents include, but are not limited to, PD-1 axis binding antagonists, thalidomide (a-N-phthalimido-glutarimide) and its analogues, OTEZLA® (apremilast), REVLIMID® (lenalidomide) and POMALYST® (pomalidomide), and pharmaceutically acceptable salts or acids thereof.

[0136] A “subject” or an “individual” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and nonhuman primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the subject or individual is a human.

[0137] An “isolated” protein or peptide is one which has been separated from a component of its natural environment. In some aspects, a protein or peptide is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0138] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0139] The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and / or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

[0140] The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and / or B7-1 . In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and / or B7-1 . In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1 and / or B7-1 . In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD- L1 binding antagonist binds to PD-L1 . In some instances, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1 105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP-002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB231 1 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some aspects, the anti-PD- L1 antibody is atezolizumab, MDX-1 105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1 105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS-003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab.

[0141] The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and / or PD-L2. PD-1 (programmed death 1 ) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.” An exemplary human PD-1 is shown in UniProtKB / Swiss-Prot Accession No. Q15116. In some instances, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one instance, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-1 binding antagonist binds to PD-1 . In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI- 0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21 . In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108. In another specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006.

[0142] The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.” An exemplary human PD-L2 is shown in UniProtKB / Swiss-Prot Accession No. Q9BQ51 . In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD- L2 to PD-1 . Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to PD-L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

[0143] The term “protein,” as used herein, refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the cell. The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.

[0144] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or may be compiled from the source code. The ALIGN-2 program should be compiled for use on a UNIX operating system, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

[0145] In situations where ALIGN-2 is employed for amino acid sequence comparisons, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X / Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in that program’s alignment of A and B, and where Y is the total number of amino acid residues in B. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained as described in the immediately preceding paragraph using the ALIGN-2 computer program.

[0146] The term “pharmaceutical formulation” refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0147] A “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0148] By “radiation therapy” is meant the use of directed gamma rays or beta rays to induce sufficient damage to a cell so as to limit its ability to function normally or to destroy the cell altogether. It will be appreciated that there will be many ways known in the art to determine the dosage and duration of treatment. Typical treatments are given as a one-time administration and typical dosages range from 10 to 200 units (Grays) per day.

[0149] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some aspects, antibodies described herein (e.g., an anti-FcRH5 / anti-CD3 bispecific antibody) are used to delay development of a disease or to slow the progression of a disease.

[0150] By “reduce” or “inhibit” is meant the ability to cause an overall decrease, for example, of 20% or greater, of 50% or greater, or of 75%, 85%, 90%, 95%, or greater. In certain aspects, reduce or inhibit can refer to the effector function of an antibody that is mediated by the antibody Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibodydependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

[0151] According to the invention, the term "vaccine" relates to a pharmaceutical preparation (pharmaceutical composition) or product that upon administration induces an immune response, in particular a cellular immune response, which recognizes and attacks a pathogen or a diseased cell such as a cancer cell. A vaccine may be used for the prevention or treatment of a disease. A vaccine may be a cancer vaccine. A “cancer vaccine” as used herein is a composition that stimulates an immune response in a subject against a cancer. Cancer vaccines typically consist of a source of cancer-associated material or cells (antigen) that may be autologous (from self) or allogenic (from others) to the subject, along with other components (e.g., adjuvants) to further stimulate and boost the immune response against the antigen. Cancer vaccines can result in stimulating the immune system of the subject to produce antibodies to one or several specific antigens, and / or to produce killer T cells to attack cancer cells that have those antigens.

[0152] As used herein, “administering” is meant a method of giving a dosage of a compound (e.g., an anti-FcRH5 / anti-CD3 bispecific antibody) to a subject. In some aspects, the compositions utilized in the methods herein are administered intravenously. The compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions. The method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).

[0153] “CD38” as used herein refers to a CD38 glycoprotein found on the surface of many immune cells, including CD4+, CD8+, B lymphocytes, and natural killer (NK) cells, and includes any native CD38 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. CD38 is expressed at a higher level and more uniformly on myeloma cells as compared to normal lymphoid and myeloid cells. The term encompasses “full-length,” unprocessed CD38, as well as any form of CD38 that results from processing in the cell. The term also encompasses naturally occurring variants of CD38, e.g., splice variants or allelic variants. CD38 is also referred to in the art as cluster of differentiation 38, ADP- ribosyl cyclase 1 , cADPr hydrolase 1 , and cyclic ADP-ribose hydrolase 1 . CD38 is encoded by the CD38 gene. The nucleic acid sequence of an exemplary human CD38 is shown under NCBI Reference Sequence: NM_001775.4 or in SEQ ID NO: 33. The amino acid sequence of an exemplary human CD38 protein encoded by CD38 is shown under UniProt Accession No. P28907 or in SEQ ID NO: 34.

[0154] The term “anti-CD38 antibody” encompasses all antibodies that bind CD38 with sufficient affinity such that the antibody is useful as a therapeutic agent in targeting a cell expressing the antigen, and does not significantly cross-react with other proteins such as a negative control protein in the assays described below. For example, an anti-CD38 antibody may bind to CD38 on the surface of a MM cell and mediate cell lysis through the activation of complement-dependent cytotoxicity, ADCC, antibody-dependent cellular phagocytosis (ADCP), and apoptosis mediated by Fc cross-linking, leading to the depletion of malignant cells and reduction of the overall cancer burden. An anti-CD38 antibody may also modulate CD38 enzyme activity through inhibition of ribosyl cyclase enzyme activity and stimulation of the cyclic adenosine diphosphate ribose (cADPR) hydrolase activity of CD38. In certain aspects, an anti-CD38 antibody that binds to CD38 has a dissociation constant (KD) of < 1 pM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 108M or less, e.g., from 10-8M to 10-13M, e.g., from 10-9M to 10-13M). In certain aspects, the anti-CD38 antibody may bind to both human CD38 and chimpanzee CD38. Anti-CD38 antibodies also include anti-CD38 antagonist antibodies. Bispecific antibodies wherein one arm of the antibody binds CD38 are also contemplated. Also encompassed by this definition of anti-CD38 antibody are functional fragments of the preceding antibodies. Examples of antibodies which bind CD38 include: daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 ); “MOR202” (U.S. Patent No: 8,263,746); and isatuximab (SAR-650984).

[0155] As used herein, the term “relative increase” refers to an increase in the survival (e.g., as measured by progression-free survival (PFS) or overall survival (OS)) of a subject having MM and whose baseline sample has been determined to have a decreased level of one or more cell types set forth in Table 3, an increased level of one or more cell types set forth in Table 4, a lower number in one or more of the features set forth in Table 5, a decreased level of one or more cell types set forth in Table 6, an increased level of one or more cell types set forth in Table 7, a decreased level of one or more cell types set forth in Table 8, or an increased level of one or more cell types set forth in Table 9 relative to a subject having an MM and whose baseline sample has been determined to have an increased level of one or more cell types set forth in Table 3, a decreased level of one or more cell types set forth in Table 4, a higher number in one or more of the features set forth in Table 5, an increased level of one or more cell types set forth in Table 6, a decreased level of one or more cell types set forth in Table 7, an increased level of one or more cell types set forth in Table 8, or a decreased level of one or more cell types set forth in Table 9.

[0156] As used herein, the term “reference level” refers to a mean or median level (e.g., percentage, fold change, Z-score, and the like), mode, quartile level, or pre-assigned value / level of a given cell type in a population of subjects have an MM. Exemplary reference levels for a plurality of cell types described herein (e.g., cell types in Table 1 , Table 2, Table 3, Table 4, Table 6, Table 7, Table 8, or Table 9) are provided in Table 14.

[0157] As used herein, the term “reference number” refers to a mean or median number, mode, quartile, or pre-assigned value of a given feature set forth in Table 5 in a population of subjects having an MM. Exemplary reference numbers for a given feature described herein (e.g., features in Table 5) are provided in Table 15.

[0158] As used herein, the term “a population of subjects have an MM” refers to an MM patient population that is at least 10 subjects in size (e.g., at least 10, at least 15, at least 20, at least 25, at least 50, at least 75, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 228, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500, at least 525, at least 550, at least 575, at least 600, at least 625, at least 650, at least 675, at least 700, at least 725, at least 750, at least 775, at least 800, at least 825, at least 850, at least 875, at least 900, at least 925, at least 950, at least 975, at least 1000, or more in size). For example, a population of subjects having an MM can refer to an MM patient population that is 228 subjects in size.

[0159] II. THERAPEUTIC METHODS

[0160] The present invention provides methods useful for treating subjects having MM who would benefit from treatment with a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3).

[0161] As described below, (i) measuring or determining a level of one or more cell types set forth in Table 3, Table 4, Table 6, Table 7, Table 8, and / or Table 9 in a sample from the subject or (ii) a number in one or more of the features of the subject set forth in Table 5 can be useful for identifying subjects having MM who would benefit from treatment with a bispecific antibody that binds to fragment crystallizable receptor-like 5 (FcRH5) / anti-cluster of differentiation 3 (CD3).

[0162] The methods described herein may require determining a level of a T cell (e.g., a CD4+ or CD8+ T cell), a T naive (TN) cell, a T central memory (TCM) cell, T effector memory (TEM) cell, a terminally differentiated effector memory (TEMRA) cell, a natural Killer (NK) cell, a natural killer T cell (NKT cell), a T regulatory (Treg) cell, a white blood cell (WBC), a non-lymphoid cell (e.g., a CD3- cell), or any combination thereof.

[0163] A TN cell is a mature T cell in circulation that has never encountered nor responded to its cognate antigen, thereby distinguishing said T cell from effector and memory T cell subtypes. Upon activation, naive CD8+ T cells may differentiate into cytotoxic T cells, and naive CD4+ T cells may differentiate into T helper cells (e.g., TH1 or TH2 cells). A TCM cell is a memory T cell largely restricted to lymphoid organs and the blood that provides immunosurveillance due to its high sensitivity and rapid response to its cognate antigen exposure. A TEM cell is a memory T cell largely found in peripheral circulation and tissues rather than lymphoid organs. TEM cells are long lasting and may quickly proliferate into large numbers upon re-exposure to its cognate antigen. A TEMRA cell plays an important role in humoral and cellular rejection. TEMRA cells generally have a shortened lifespan and carries higher levels of cytotoxic and exhausted genes compared to other effector or memory cells. A NK cell is a large, granular lymphocyte that mediates innate immunity to tumors and pathogens, as well as mediates antibody-dependent cell-mediated cytotoxicity (ADCC). A Treg cell dampens or suppresses an immune response by secreting anti-inflammatory cytokines. Its role in immune suppression maintains peripheral tolerance and aids in preventing autoimmune or inflammatory diseases or conditions. Exemplary positive and negative markers useful for identifying these cell types are described in Table 2. Table 2. Exemplary Cell Markers for Cell Identification

[0164] TN = T naive; TCM = T central memory; TEM = T effector memory; TEMRA = terminally differentiated effector memory; Treg = T regulatory; NK = natural killer; NKT = natural killer T cells; CD8 = cluster of differentiation 8; CD4 = cluster of differentiation 4; CD16 = Cluster of differentiation 16; CD19 = Cluster of differentiation 19; CD56 = Cluster of differentiation 56; CD45RA = Cluster of differentiation RA45; CD45RO = Cluster of differentiation 45RO; GzB= Granzyme B; CCR7 = c-c chemokine receptor type 7

[0165] Cell types associated with increased resistance to cevostamab

[0166] In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 3 in the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 3 has been previously determined in the subject.

[0167] In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20,

[0168] 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47,

[0169] 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74,

[0170] 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101 %, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 1 10%, about 1 1 1 %, about 1 12%, about 1 13%, about 1 14%, about 1 15%, about 1 16%, about 1 17%, about 1 18%, about 1 19%, about 120%, about 121 %, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131 %, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151 %, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161 %, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about

[0171] 170%, about 171 %, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181 %, about 182%, about 183%, about 184%, about

[0172] 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191 %, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about

[0173] 200%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0174] Table 3. Cell Types Associated with Increased Resistance to Cevostamab

[0175] CD = cluster of differentiation; DR = human leukocyte antigen - DR isotype; Ki67 = antigen Kiel 67; PD1 = programmed cell death protein 1 ; GzB = Granzyme B; TIGIT = T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin-domain containing-3; TN cells = naive T cells; TCM cells = central memory T cells; TEM cells = effector memory T cells; TEMRA cells = terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells

[0176] Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20,

[0177] 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47,

[0178] 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74,

[0179] 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0180] Cell types associated with increased sensitivity to cevostamab

[0181] In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 4 in the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 4 has been previously determined in the subject.

[0182] In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, are more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111 %, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121 %, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about 170%, about 171%, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181%, about 182%, about 183%, about 184%, about 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191%, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about 200%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0183] Table 4. Cell Types Associated with Increased Sensitivity to Cevostamab

[0184] CD = cluster of differentiation; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells; NK cells = natural killer cells

[0185] Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, are generally more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0186] Subject features associated with increased resistance to cevostamab

[0187] In some aspects of the invention, the methods described herein require determining one or more features set forth in Table 5 in the subject. In some aspects of the invention, the methods described herein require that one or more of the features set forth in Table 5 has been previously determined in the subject.

[0188] In general, MM subjects having a higher number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be higher by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). Table 5. Subject Features Associated with Resistance to Cevostamab

[0189] Pl= proteasome inhibitor; IMID= immunomodulatory drugs; BCMA= B cell maturation antigen; CD= cluster of differentiation; CAR-T= chimeric antigen receptor T cell

[0190] Conversely, MM subjects having a lower number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be lowered by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0191] Cell types in bone marrow that are associated with increased resistance to cevostamab In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 6 in the bone marrow of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 6 has been previously determined in the bone marrow of the subject.

[0192] In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 54%, about 40% to about 60%, or about 54% to about 80%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 83% (e.g., about 28% to about 55%, about 42% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 51 %, about 38% to about 58%, or about 51 % to about 77%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51 %, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 40% (e.g., about 13% to about 27%, about 20% to about 30%, or about 27% to about 40%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 89% (e.g., about 30% to about 59%, about 45% to about 67%, or about 59% to about 89%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 70% (e.g., about 23% to about 47%, about 35% to about 53%, or about 47% to about 70%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91 % (e.g., about 30% to about 61 %, about 46% to about 68%, or about 61 % to about 91 %), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 35% to about 104% (e.g., about 35% to about 70%, about 52% to about 78%, or about 70% to about 104%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 45%, about 34% to about 51 %, or about 45% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 51 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31 % (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 35%, about 26% to about 39%, or about 35% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 32% (e.g., about 1 1 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 56%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 41 % to about 124% (e.g., about 41 % to about 83%, about 62% to about 93%, or about 83% to about 124%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 38% to about 1 13% (e.g., about 38% to about 75%, about 56% to about 85%, or about 75% to about 1 13%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 37% to about 1 10% (e.g., about 37% to about 73%, about 55% to about 82%, or about 73% to about 1 10%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 36% to about 107% (e.g., about 36% to about 71 %, about 53% to about 80%, or about 71 % to about 107%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 21 %, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 9% to about 13%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 24% to about 72% (e.g., about 24% to about 48%, about 36% to about 54%, or about 48% to about 72%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 22%, about 17% to about 25%, or about 22% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11% to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21% to about 62% (e.g., about 21% to about 42%, about 31% to about 47%, or about 42% to about 62%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21 % to about 64% (e.g., about 21% to about 42%, about 32% to about 48%, or about 42% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31% (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21% to about 31%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 21% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 49%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91% (e.g., about 30% to about 61%, about 46% to about 69%, or about 61% to about 91%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 85% (e.g., about 28% to about 57%, about 43% to about 64%, or about 57% to about 85%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 16% to about 48% (e.g., about 16% to about 32%, about 24% to about 36%, or about 32% to about 48%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level.

[0193] Table 6. Cell Types in Bone Marrow that are Associated with Increased Resistance to Cevostamab

[0194] CD = cluster of differentiation; DR = human leukocyte antigen - DR isotype; Ki67 = antigen Kiel 67; PD1 = programmed cell death protein 1 ; GzB = Granzyme B; TIGIT = T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin-domain containing-3; TN cells = naive T cells; TCM cells = central memory T cells; TEM cells = effector memory T cells; TEMRA cells= terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells

[0195] Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25- CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11% to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 6% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 17% to about 50% (e.g., about 17% to about 33%, about 25% to about 37%, or about 33% to about 50%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 12% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 8%, about 6% to about 8%, or about 8% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level.

[0196] Cell types in bone marrow that are associated with increased sensitivity to cevostamab In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 7 in the bone marrow of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 7 has been previously determined in the bone marrow of the subject.

[0197] In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 7%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 11%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 11%, or about 10% to about 15%), as compared to a reference level.

[0198] Table 7. Cell Types in Bone Marrow that are Associated with Increased Sensitivity to Cevostamab

[0199] CD = cluster of differentiation; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells; NK cells = natural killer cells Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31% (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 28% to about 83% (e.g., about 28% to about 55%, about 41% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 20% to about 61% (e.g., about 20% to about 41%, about 31 % to about 46%, or about 41% to about 61%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 21% to about 64% (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 16% to about 47% (e.g., about 16% to about 31 %, about 23% to about 35%, or about 31 % to about 47%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 19% to about 57% (e.g., about 19% to about 38%, about 29% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%), as compared to a reference level.

[0200] Cell types in blood that are associated with increased resistance to cevostamab

[0201] In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 8 in the blood (e.g., whole blood, serum, or plasma) of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 8 has been previously determined in the blood of the subject.

[0202] In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, or all 80) cell types set forth in Table 8 in a blood sample (e.g., a baseline blood sample), as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 29%, about 22% to about 32%, or about 29% to about 43%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 38%, or about 34% to about 51%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 24% to about 73% (e.g., about 24% to about 49%, about 37% to about 55%, or about 49% to about 73%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 79% (e.g., about 26% to about 53%, about 39% to about 59%, or about 53% to about 79%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 14% to about 41 % (e.g., about 14% to about 27%, about 21 % to about 31 %, or about 27% to about 41%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., blood) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 11 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ T cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., blood) from the subject is increased by about 12% to about 35% (e.g., about 12% to about 23%, about 17% to about 26%, or about 23% to about 35%), as compared to a reference level. In some embodiments, a level of CD4+PDL1 + T cells in a sample (e.g., blood) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., blood) from the subject is increased by about 11 % to about 34% (e.g., about 11 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., blood) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 52%, about 39% to about 58%, or about 52% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 25% to about 74% (e.g., about 25% to about 49%, about 37% to about 55%, or about 49% to about 74%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 34% to about 102% (e.g., about 34% to about 68%, about 51 % to about 76%, or about 68% to about 102%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., blood) from the subject is increased by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 19% to about 57% (e.g., about 19% to about 38%, about 28% to about 43%, or about 38% to about 57%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 53% (e.g., about 18% to about 35%, about 27% to about 40%, or about 35% to about 53%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 53% (e.g., about 18% to about 35%, about 27% to about 40%, or about 35% to about 53%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 14% to about 41 % (e.g., about 14% to about 27%, about 20% to about 31 %, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51 %, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 21 % to about 63% (e.g., about 21 % to about 42%, about 31 % to about 47%, or about 42% to about 63%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 21 % to about 63% (e.g., about 21 % to about 42%, about 32% to about 47%, or about 42% to about 63%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TN cells in a sample (e.g., blood) from the subject is increased by about 19% to about 58% (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 38% to about 1 14% (e.g., about 38% to about 76%, about 57% to about 85%, or about 76% to about 1 14%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 53% to about 160% (e.g., about 53% to about 107%, about 80% to about 120%, or about 107% to about 160%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 81 % (e.g., about 27% to about 54%, about 41 % to about 61 %, or about 54% to about 81 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 19% to about 58% (e.g., about 19% to about 39%, about 29% to about 44%, or about 39% to about 58%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., blood) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., blood) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 25% to about 74% (e.g., about 25% to about 49%, about 37% to about 56%, or about 49% to about 74%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., blood) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., blood) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 43%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., blood) from the subject is increased by about 20% to about 61 % (e.g., about 20% to about 41 %, about 31 % to about 46%, or about 41 % to about 61 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 40%, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 25% to about 38%, or about 34% to about 51 %), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 37%, about 27% to about 41 %, or about 37% to about 55%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., blood) from the subject is increased by about 16% to about 49% (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TCM cells in a sample (e.g., blood) from the subject is increased by about 14% to about 43% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 43%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., blood) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from the subject is increased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., blood) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEM cells in a sample (e.g., blood) from the subject is increased by about 16% to about 47% (e.g., about 16% to about 31 %, about 23% to about 35%, or about 31 % to about 47%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 5% to about 16% (e.g., about 5% to about 11%, about 8% to about 12%, or about 11% to about 16%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 23% to about 69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 48%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is increased by about 7% to about 21% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., blood) from the subject is increased by about 15% to about 46% (e.g., about 15% to about 31%, about 23% to about 35%, or about 31% to about 46%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 53%, about 40% to about 60%, or about 53% to about 80%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 39% to about 116% (e.g., about 39% to about 77%, about 58% to about 87%, or about 77% to about 116%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 27% to about 82% (e.g., about 27% to about 54%, about 41 % to about 61%, or about 54% to about 82%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TN cells in a sample (e.g., blood) from the subject is increased by about 23% to about 69% (e.g., about 23% to about 46%, about 34% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., blood) from the subject is increased by about 34% to about 103% (e.g., about 34% to about 69%, about 51% to about 77%, or about 69% to about 103%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., blood) from the subject is increased by about 11 % to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40+ TN cells in a sample (e.g., blood) from the subject is increased by about 12% to about 37% (e.g., about 12% to about 25%, about 18% to about 28%, or about 25% to about 37%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., blood) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21%, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., blood) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 25%, about 19% to about 29%, or about 25% to about 38%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., blood) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 3%, about 3% to about 4%, or about 3% to about 5%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 3%, about 2% to about 4%, or about 3% to about 5%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is increased by about 2% to about 5% (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 5%), as compared to a reference level.

[0203] Table 8. Cell Types in Blood that are Associated with Increased Resistance to Cevostamab

[0204] CD = cluster of differentiation; DR = human leukocyte antigen - DR isotype; Ki67 = antigen Kiel 67; PD1 = programmed cell death protein 1 ; GzB = Granzyme B; TIGIT = T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains; TIM3 = T cell immunoglobulin and mucin-domain containing-3; TN cells = naive T cells; TCM cells = central memory T cells; TEM cells = effector memory T cells; TEMRA cells = terminally differentiated effector memory T cells; Treg cells = regulatory T cells; NK cells = natural killer cells Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, or all 80) cell types set forth in Table 8 in a blood sample (e.g., a baseline blood sample), as compared to a reference level, are generally more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 32% (e.g., about 1 1 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 6% (e.g., about 2% to about 4%, about 3% to about 4%, or about 4% to about 6%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 - TIGIT+TIM3- T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PDL1 + T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 41 % (e.g., about 14% to about 27%, about 20% to about 30%, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 1 1 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 11 %, about 8% to about 12%, or about 11 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TN cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 23% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 21 % to about 64% (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 11% to about 32% (e.g., about 11% to about 22%, about 16% to about 24%, or about 22% to about 32%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 15%, about 12% to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TN cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of

[0205] CD8+DR+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +KI67+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD8+DR+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 8% to about 13%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 9% to about 13%, or about 11% to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEM cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 1% to about 3% (e.g., about 1% to about 2%, about 2% to about 2%, or about 2% to about 3%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEMRA cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., blood) from the subject is decreased by about 11% to about 32% (e.g., about 11% to about 21%, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 15% to about 46% (e.g., about 15% to about 31 %, about 23% to about 35%, or about 31 % to about 46%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 1 1 % to about 33% (e.g., about 1 1 % to about 22%, about 16% to about 24%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TN cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21 %, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 41 % (e.g., about 14% to about 27%, about 21 % to about 31 %, or about 27% to about 41 %), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 8%, about 6% to about 10%, or about 8% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +0X40+ TN cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., blood) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., blood) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., blood) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of white blood cells in a sample (e.g., blood) from the subject is decreased by about 1 % to about 3%, as compared to a reference level.

[0206] Cell types in blood that are associated with increased sensitivity to cevostamab In some aspects of the invention, the methods described herein require determining a level of one or more cell types set forth in Table 9 in the blood (e.g., whole blood, serum, or plasma) of the subject. In some aspects of the invention, the methods described herein require that a level of one or more cell types set forth in Table 9 has been previously determined in the blood of the subject.

[0207] In general, MM subjects having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types set forth in Table 9, as compared to a reference level, are more sensitive to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 6% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., blood) from the subject is increased by about 2% to about 6% (e.g., about 2% to about 4%, about 3% to about 5%, or about 4% to about 6%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., blood) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is increased by about 5% to about 16% (e.g., about 5% to about 11 %, about 8% to about 12%, or about 11 % to about 16%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 8% to about 13%, or about 11% to about 17%), as compared to a reference level.

[0208] Table 9. Cell Types in Blood that are Associated with Increased Sensitivity to Cevostamab _

[0209] CD = cluster of differentiation; NK T cells = natural killer T cells; TN cells = naive T cells; TCM cells = central memory T cells

[0210] Conversely, MM subjects having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, or all five) cell types set forth in Table 9, as compared to a reference level, are more resistant to treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., blood) from the subject is decreased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., blood) from the subject is decreased by about 23% to about 69% (e.g., about 23% to about 46%, about 35% to about 52%, or about 46% to about 69%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., blood) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., blood) from the subject is decreased by about 16% to about 49% (e.g., about 16% to about 33%, about 25% to about 37%, or about 33% to about 49%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is decreased by about 13% to about 40% (e.g., about 13% to about 26%, about 20% to about 30%, or about 26% to about 40%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., blood) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 32%, or about 28% to about 42%), as compared to a reference level.

[0211] A. Methods of treating

[0212] In some aspects, the invention provides a method of treating a subject having an MM. The method may include administering to the subject a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). Prior to the administering of the bispecific antibody, a sample from the subject may have been previously determined to have a decreased level of one or more cell types set forth in Table 3, Table 6, and / or Table 8, as compared to a reference level. Prior to the administering of the bispecific antibody, a sample from the subject may have been previously determined to have an increased level of one or more cell types set forth in Table 4, Table 7, and / or Table 9, as compared to a reference level. The sample from the subject may be from the subject’s bone marrow and / or blood. Prior to the administering of the bispecific antibody, the subject may have been previously determined to have lower number in one or more of the features set forth in Table 5, as compared to a reference number. In some aspects, the reference level is an assigned reference level set forth in Table 14. In some aspects, the reference number is an assigned reference number set forth in Table 15.

[0213] Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription- quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof, may be used to determine the level of one or more cell types in a sample (e.g., BM or blood).

[0214] Prior to the administering of the bispecific antibody, a sample from the subject’s bone marrow may have been previously determined to have a decreased level of one or more cell types set forth in Table 3 and / or Table 6, as compared to a reference level. Prior to the administering of the bispecific antibody, a sample from the subject’s bone marrow may have been previously determined to have an increased level of one or more cell types set forth in Table 4 and / or Table 7, as compared to a reference level.

[0215] Prior to the administering of the bispecific antibody, a sample from the subject’s blood (e.g., whole blood, plasma, or serum) may have been previously determined to have a decreased level of one or more cell types set forth in Table 3 and / or Table 8, as compared to a reference level. Prior to the administering of the bispecific antibody, a sample from the subject’s blood (e.g., whole blood, plasma, or serum) may have been previously determined to have an increased level of one or more cell types set forth in Table 4 and / or Table 9, as compared to a reference level.

[0216] In some aspects, the invention provides a method of treating a subject having an MM, wherein the method may optionally include a step of determining a level of one or more cell types set forth in Table 3 and / or Table 4 in a sample from the subject. The sample from the subject may be from the subject’s bone marrow and / or blood. In some aspects of the invention, the method may or may not include a step of determining one or more of the features set forth in Table 5.

[0217] The method of treating the subject having an MM may include a step of identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3 prior to administering the bispecific antibody. A subject may benefit from the treatment based on a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

[0218] A subject that has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level, an increased level of the one or more cell types set forth in Table 4, as compared to a reference level, and / or a lower number in one or more of the features set forth in Table 5, as compared to a reference number, may be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. The method of treating the subject having an MM may further include a step of administering to the identified subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0219] In some aspects of the invention, the sample is from the subject’s bone marrow and has a decreased level of one or more cell types set forth in Table 3 and / or Table 6, as compared to a reference level. In some aspects of the invention, the sample is from the subject’s bone marrow and has an increased level of one or more cell types set forth in Table 4 and / or Table 7, as compared to a reference level.

[0220] In some aspects of the invention, the sample is from the subject’s blood (e.g., whole blood, plasma, or serum) and has a decreased level of one or more cell types set forth in Table 3 and / or Table 8, as compared to a reference level. In some aspects of the invention, the sample is from the subject’s blood (e.g., whole blood, plasma, or serum) and has an increased level of one or more cell types set forth in Table 4 and / or Table 9, as compared to a reference level.

[0221] In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -85), 2 or more (e.g., 2-85), 3 or more (e.g., 3-85), 4 or more (e.g., 4-85), 5 or more (e.g., 5-85), 6 or more (e.g., 6-85), 7 or more (e.g., 7-85), 8 or more (e.g., 8- 85), 9 or more (e.g., 9-85), 10 or more (e.g., 10-85), 1 1 or more (e.g., 1 1 -85), 12 or more (e.g., 12-85), 13 or more (e.g., 13-85), 14 or more (e.g., 14-85), 15 or more (e.g., 15-85), 16 or more (e.g., 16-85),

[0222] 17 or more (e.g., 17-85), 18 or more (e.g., 18-85), 19 or more (e.g., 19-85), 20 or more (e.g., 20-85),

[0223] 21 or more (e.g., 21 -85), 22 or more (e.g., 22-85), 23 or more (e.g., 23-85), 24 or more (e.g., 24-85),

[0224] 25 or more (e.g., 25-85), 26 or more (e.g., 26-85), 27 or more (e.g., 27-85), 28 or more (e.g., 28-85),

[0225] 29 or more (e.g., 29-85), 30 or more (e.g., 30-85), 31 or more (e.g., 31 -85), 32 or more (e.g., 32-85),

[0226] 33 or more (e.g., 33-85), 34 or more (e.g., 34-85), 35 or more (e.g., 35-85), 36 or more (e.g., 36-85),

[0227] 37 or more (e.g., 37-85), 38 or more (e.g., 38-85), 39 or more (e.g., 39-85), 40 or more (e.g., 40-85),

[0228] 41 or more (e.g., 41 -85), 42 or more (e.g., 42-85), 43 or more (e.g., 43-85), 44 or more (e.g., 44-85),

[0229] 45 or more (e.g., 45-85), 46 or more (e.g., 46-85), 47 or more (e.g., 47-85), 48 or more (e.g., 48-85),

[0230] 49 or more (e.g., 49-85), 50 or more (e.g., 50-85), 51 or more (e.g., 51 -85), 52 or more (e.g., 52-85),

[0231] 53 or more (e.g., 53-85), 54 or more (e.g., 54-85), 55 or more (e.g., 55-85), 56 or more (e.g., 56-85),

[0232] 57 or more (e.g., 57-85), 58 or more (e.g., 58-85), 59 or more (e.g., 59-85), 60 or more (e.g., 60-85),

[0233] 61 or more (e.g., 61 -85), 62 or more (e.g., 62-85), 63 or more (e.g., 63-85), 64 or more (e.g., 64-85),

[0234] 65 or more (e.g., 65-85), 66 or more (e.g., 66-85), 67 or more (e.g., 67-85), 68 or more (e.g., 68-85),

[0235] 69 or more (e.g., 69-85), 70 or more (e.g., 70-85), 71 or more (e.g., 71 -85), 72 or more (e.g., 72-85),

[0236] 73 or more (e.g., 73-85), 74 or more (e.g., 74-85), 75 or more (e.g., 75-85), 76 or more (e.g., 76-85),

[0237] 77 or more (e.g., 77-85), 78 or more (e.g., 78-85), 79 or more (e.g., 79-85), 80 or more (e.g., 80-85),

[0238] 81 or more (e.g., 81 -85), 82 or more (e.g., 82-85), 83 or more (e.g., 83-85), 84 or more (e.g., 84-85), or 85 of the cell types set forth in Table 3.

[0239] In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -8), 2 or more (e.g., 2-8), 3 or more (e.g., 3-8), 4 or more (e.g., 4-8), 5 or more (e.g., 5-8), 6 or more (e.g., 6-8), 7 or more (e.g., 7-8), or 8 of the cell types set forth in Table 4.

[0240] In some aspects of the invention, the method may include the step of measuring or determining 1 or more (e.g., 1 -15), 2 or more (e.g., 2-15), 3 or more (e.g., 3-15), 4 or more (e.g., 4- 15), 5 or more (e.g., 5-15), 6 or more (e.g., 6-15), 7 or more (e.g., 7-15), 8 or more (e.g., 8-15), 9 or more (e.g., 9-15), 10 or more (e.g., 10-15), 1 1 or more (e.g., 1 1 -15), 12 or more (e.g., 12-15), 13 or more (e.g., 13-15), 14 or more (e.g., 14-15), or 15 of the features set forth in Table 5.

[0241] In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -69), 2 or more (e.g., 2-69), 3 or more (e.g., 3-69), 4 or more (e.g., 4-69), 5 or more (e.g., 5-69), 6 or more (e.g., 6-69), 7 or more (e.g., 7-69), 8 or more (e.g., 8- 69), 9 or more (e.g., 9-69), 10 or more (e.g., 10-69), 1 1 or more (e.g., 1 1 -69), 12 or more (e.g., 12-69), 13 or more (e.g., 13-69), 14 or more (e.g., 14-69), 15 or more (e.g., 15-69), 16 or more (e.g., 16-69), 17 or more (e.g., 17-69), 18 or more (e.g., 18-69), 19 or more (e.g., 19-69), 20 or more (e.g., 20-69),

[0242] 21 or more (e.g., 21 -69), 22 or more (e.g., 22-69), 23 or more (e.g., 23-69), 24 or more (e.g., 24-69),

[0243] 25 or more (e.g., 25-69), 26 or more (e.g., 26-69), 27 or more (e.g., 27-69), 28 or more (e.g., 28-69),

[0244] 29 or more (e.g., 29-69), 30 or more (e.g., 30-69), 31 or more (e.g., 31 -69), 32 or more (e.g., 32-69),

[0245] 33 or more (e.g., 33-69), 34 or more (e.g., 34-69), 35 or more (e.g., 35-69), 36 or more (e.g., 36-69),

[0246] 37 or more (e.g., 37-69), 38 or more (e.g., 38-69), 39 or more (e.g., 39-69), 40 or more (e.g., 40-69),

[0247] 41 or more (e.g., 41 -69), 42 or more (e.g., 42-69), 43 or more (e.g., 43-69), 44 or more (e.g., 44-69),

[0248] 45 or more (e.g., 45-69), 46 or more (e.g., 46-69), 47 or more (e.g., 47-69), 48 or more (e.g., 48-69),

[0249] 49 or more (e.g., 49-69), 50 or more (e.g., 50-69), 51 or more (e.g., 51 -69), 52 or more (e.g., 52-69),

[0250] 53 or more (e.g., 53-69), 54 or more (e.g., 54-69), 55 or more (e.g., 55-69), 56 or more (e.g., 56-69),

[0251] 57 or more (e.g., 57-69), 58 or more (e.g., 58-69), 59 or more (e.g., 59-69), 60 or more (e.g., 60-69),

[0252] 61 or more (e.g., 61 -69), 62 or more (e.g., 62-69), 63 or more (e.g., 63-69), 64 or more (e.g., 64-69),

[0253] 65 or more (e.g., 65-69), 66 or more (e.g., 66-69), 67 or more (e.g., 67-69), 68 or more (e.g., 68-69), or 69 of the cell types set forth in Table 6.

[0254] In some aspects of the invention, the method may include the step of measuring or determining a level of or 1 or more (e.g., 1 -8), 2 or more (e.g., 2-8), 3 or more (e.g., 3-8), 4 or more (e.g., 4-8), 5 or more (e.g., 5-8), 6 or more (e.g., 6-8), 7 or more (e.g., 7-8), or 8 of the cell types set forth in Table 7.

[0255] In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -80), 2 or more (e.g., 2-80), 3 or more (e.g., 3-80), 4 or more (e.g., 4-80), 5 or more (e.g., 5-80), 6 or more (e.g., 6-80), 7 or more (e.g., 7-80), 8 or more (e.g., 8- 80), 9 or more (e.g., 9-80), 10 or more (e.g., 10-80), 11 or more (e.g., 11 -80), 12 or more (e.g., 12-80), 13 or more (e.g., 13-80), 14 or more (e.g., 14-80), 15 or more (e.g., 15-80), 16 or more (e.g., 16-80),

[0256] 17 or more (e.g., 17-80), 18 or more (e.g., 18-80), 19 or more (e.g., 19-80), 20 or more (e.g., 20-80),

[0257] 21 or more (e.g., 21 -80), 22 or more (e.g., 22-80), 23 or more (e.g., 23-80), 24 or more (e.g., 24-80),

[0258] 25 or more (e.g., 25-80), 26 or more (e.g., 26-80), 27 or more (e.g., 27-80), 28 or more (e.g., 28-80),

[0259] 29 or more (e.g., 29-80), 30 or more (e.g., 30-80), 31 or more (e.g., 31 -80), 32 or more (e.g., 32-80),

[0260] 33 or more (e.g., 33-80), 34 or more (e.g., 34-80), 35 or more (e.g., 35-80), 36 or more (e.g., 36-80),

[0261] 37 or more (e.g., 37-80), 38 or more (e.g., 38-80), 39 or more (e.g., 39-80), 40 or more (e.g., 40-80),

[0262] 41 or more (e.g., 41 -80), 42 or more (e.g., 42-80), 43 or more (e.g., 43-80), 44 or more (e.g., 44-80),

[0263] 45 or more (e.g., 45-80), 46 or more (e.g., 46-80), 47 or more (e.g., 47-80), 48 or more (e.g., 48-80),

[0264] 49 or more (e.g., 49-80), 50 or more (e.g., 50-80), 51 or more (e.g., 51 -80), 52 or more (e.g., 52-80),

[0265] 53 or more (e.g., 53-80), 54 or more (e.g., 54-80), 55 or more (e.g., 55-80), 56 or more (e.g., 56-80),

[0266] 57 or more (e.g., 57-80), 58 or more (e.g., 58-80), 59 or more (e.g., 59-80), 60 or more (e.g., 60-80),

[0267] 61 or more (e.g., 61 -80), 62 or more (e.g., 62-80), 63 or more (e.g., 63-80), 64 or more (e.g., 64-80),

[0268] 65 or more (e.g., 65-80), 66 or more (e.g., 66-80), 67 or more (e.g., 67-80), 68 or more (e.g., 68-80),

[0269] 69 or more (e.g., 69-80), 70 or more (e.g., 70-80), 71 or more (e.g., 71 -80), 72 or more (e.g., 72-80),

[0270] 73 or more (e.g., 73-80), 74 or more (e.g., 74-80), 75 or more (e.g., 75-80), 76 or more (e.g., 76-80), 77 or more (e.g., 77-80), 78 or more (e.g., 78-80), 79 or more (e.g., 79-80), or 80 of the cell types set forth in Table 8.

[0271] In some aspects of the invention, the method may include the step of measuring or determining a level of 1 or more (e.g., 1 -8), 2 or more (e.g., 2-8), 3 or more (e.g., 3-8), 4 or more (e.g., 4-8), or 5 of the cell types set forth in Table 9.

[0272] In some aspects of the invention, the subject has previously been treated for the MM (e.g., an R / R MM). In some aspects, the subject has received at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment for the MM (e.g., an R / R MM) e.g., is 2L+, 3L+, 4L+, 5L+, 6L+, 7L+, 8L+, 9L+, 10L+, 11 L+, 12L+, 13L+, 14L+, or 15L+. In some aspects, the subject has received at least three prior lines of treatment for the MM (e.g., an R / R MM), e.g., is 4L+, e.g., has received three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more than fifteen lines of treatment.

[0273] In some aspects, the prior lines of treatment include one or more of a proteasome inhibitor (PI), e.g., bortezomib, carfilzomib, or ixazomib; an immunomodulatory drug (IMiD), e.g., thalidomide, lenalidomide, or pomalidomide; an autologous stem cell transplant (ASCT); an anti-CD38 agent, e.g., daratumumab (DARZALEX®) (U.S. Patent No: 7,829,673 and U.S. Pub. No: 20160067205 A1 ), “MOR202” (U.S. Patent No: 8,263,746), isatuximab (SAR-650984); a CAR-T therapy; a therapy comprising a bispecific antibody; an anti-SLAMF7 therapeutic agent (e.g., an anti-SLAMF7 antibody, e.g., elotuzumab); a nuclear export inhibitor (e.g., selinexor); and a histone deacetylase (HDAC) inhibitor (e.g., panobinostat). In some aspects, the prior lines of treatment include an antibody-drug conjugate (ADC). In some aspects, the prior lines of treatment include a B-cell maturation antigen (BCMA)-directed therapy, e.g., an antibody-drug conjugate targeting BCMA (BCMA-ADC).

[0274] In some aspects, the prior lines of treatment include all three of a proteasome inhibitor (PI), an IMiD, and an anti-CD38 agent (e.g., daratumumab).

[0275] In some aspects, the MM is refractory to the lines of treatment, e.g., is refractory to one or more of daratumumab, a PI, an IMiD, an ASCT, an anti-CD38 agent, a CAR-T therapy, a therapy comprising a bispecific antibody, an anti-SLAMF7 therapeutic agent, a nuclear export inhibitor, a HDAC inhibitor, an ADC, or a BCMA-directed therapy. In some aspects, the B cell proliferative disorder (e.g., MM) is refractory to daratumumab.

[0276] A step of administering a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab) may be performed using the dosing regimens described herein.

[0277] III. DIAGNOSTIC METHODS

[0278] The present invention provides methods useful for diagnosing (e.g., identifying or classifying) subjects having MM who would benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3. The invention is based, in part, on the discovery that (i) certain levels of one or more particular cell types present in a sample (e.g., bone marrow or blood) from a subject and / or (ii) the presence of certain clinical features (e.g., number of prior lines of therapy) about said subject can be used to (i) identify a subject as one who would benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 and / or (ii) classify a subject into one of three immune profiles: 1 ) an activated immune profile; 2) an inactivated immune profile; or 3) a suppressed immune profile, whereby subjects classified as having an activated immune profile or an inactivated immune profile have been found to benefit from treatment with the bispecific antibody compared to subjects classified as having a suppressed immune profile.

[0279] A. Methods of identifying

[0280] In some aspects, the invention provides a method of identifying a subject having an MM as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3. A subject may benefit from the treatment when the subject exhibits a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof. The method optionally includes a step of determining a level of one or more cell types set forth in Table 3, Table 4, Table 6, Table 7, Table 8, and / or Table 9 in a sample from the subject and / or determining one or more of the features set forth in Table 5. The sample from the subject may be from the subject’s bone marrow and / or blood.

[0281] Flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription- quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof, may be used to determine the level of one or more cell types in a sample (e.g., bone marrow or blood).

[0282] The method of identifying may include a step of identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3. If the subject has a decreased level of the one or more cell types set forth in Table 3, Table 6, and / or Table 8, as compared to a reference level; an increased level of the one or more cell types set forth in Table 4, Table 7 and / or Table 9, as compared to a reference level; and / or a lower number in one or more of the features set forth in Table 5, as compared to a reference number, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects, the reference level is a pre-assigned reference level set forth in Table 14. In some aspects, the reference number is a pre-assigned reference number set forth in Table 15.

[0283] In some aspects of the invention, if a sample from the subject’s bone marrow has a decreased level of one or more cell types set forth in Table 3 and / or Table 6, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects of the invention, if a sample from the subject’s bone marrow has an increased level of one or more cell types set forth in Table 4 and / or Table 7, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects of the invention, if a sample from the subject’s blood (e.g., whole blood, plasma, or serum) has a decreased level of one or more cell types set forth in Table 3 and / or Table 8, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3. In some aspects of the invention, if a sample from the subject’s blood (e.g., whole blood, plasma, or serum) has an increased level of one or more cell types set forth in Table 4 and / or Table 9, as compared to a reference level, then the subject can be identified as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

[0284] An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23,

[0285] 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50,

[0286] 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77,

[0287] 78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111 %, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about 170%, about 171%, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181%, about 182%, about 183%, about 184%, about 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191%, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about 200%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0288] An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23,

[0289] 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50,

[0290] 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77,

[0291] 78, 79, 80, 81 , 82, 83, 84, or all 85) cell types set forth in Table 3 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 3 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0292] An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be increased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101 %, about 102%, about 103%, about 104%, about 105%, about 106%, about 107%, about 108%, about 109%, about 110%, about 111 %, about 112%, about 113%, about 114%, about 115%, about 116%, about 117%, about 118%, about 119%, about 120%, about 121%, about 122%, about 123%, about 124%, about 125%, about 126%, about 127%, about 128%, about 129%, about 130%, about 131%, about 132%, about 133%, about 134%, about 135%, about 136%, about 137%, about 138%, about 139%, about 140%, about 141 %, about 142%, about 143%, about 144%, about 145%, about 146%, about 147%, about 148%, about 149%, about 150%, about 151%, about 152%, about 153%, about 154%, about 155%, about 156%, about 157%, about 158%, about 159%, about 160%, about 161%, about 162%, about 163%, about 164%, about 165%, about 166%, about 167%, about 168%, about 169%, about 170%, about 171%, about 172%, about 173%, about 174%, about 175%, about 176%, about 177%, about 178%, about 179%, about 180%, about 181%, about 182%, about 183%, about 184%, about 185%, about 186%, about 187%, about 188%, about 189%, about 190%, about 191%, about 192%, about 193%, about 194%, about 195%, about 196%, about 197%, about 198%, about 199%, or about 200%, as compared to a reference level, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0293] An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 4 in a sample (e.g., a baseline sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a level of a cell type in Table 4 may be decreased in a sample from the subject by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%, as compared to a reference level, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0294] An MM subject having a higher number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be higher by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0295] An MM subject having a lower number in one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, or all 14) features set forth in Table 5, as compared to a reference number, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, a number in one or more features in Table 5 may be lowered by one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, or 15, as compared to a reference number, thereby indicating that the subject would likely benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab).

[0296] An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 27% to about 80% (e.g., about 27% to about 54%, about 40% to about 60%, or about 54% to about 80%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+DR+Ki67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 83% (e.g., about 28% to about 55%, about 42% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 77% (e.g., about 26% to about 51%, about 38% to about 58%, or about 51% to about 77%), as compared to a reference level. In some embodiments, a level of CD4+Ki67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 46%, about 34% to about 51%, or about 46% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 40% (e.g., about 13% to about 27%, about 20% to about 30%, or about 27% to about 40%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 55% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 55%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +Ki67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 89% (e.g., about 30% to about 59%, about 45% to about 67%, or about 59% to about 89%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 26%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 70% (e.g., about 23% to about 47%, about 35% to about 53%, or about 47% to about 70%), as compared to a reference level. In some embodiments, a level of CD4+DR+Ki67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91 % (e.g., about 30% to about 61 %, about 46% to about 68%, or about 61 % to about 91 %), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 35% to about 104% (e.g., about 35% to about 70%, about 52% to about 78%, or about 70% to about 104%), as compared to a reference level. In some embodiments, a level of CD4+Ki67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 23% to about 68% (e.g., about 23% to about 45%, about 34% to about 51 %, or about 45% to about 68%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 51 % (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 51 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31% (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 35%, about 26% to about 39%, or about 35% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 21%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 32% (e.g., about 11% to about 21%, about 16% to about 24%, or about 21% to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 38%, about 28% to about 42%, or about 38% to about 56%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 17% to about 52% (e.g., about 17% to about 34%, about 26% to about 39%, or about 34% to about 52%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 41% to about 124% (e.g., about 41% to about 83%, about 62% to about 93%, or about 83% to about 124%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 38% to about 113% (e.g., about 38% to about 75%, about 56% to about 85%, or about 75% to about 113%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 37% to about 110% (e.g., about 37% to about 73%, about 55% to about 82%, or about 73% to about 110%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 67% (e.g., about 22% to about 45%, about 34% to about 50%, or about 45% to about 67%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 36% to about 107% (e.g., about 36% to about 71%, about 53% to about 80%, or about 71% to about 107%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 21 %, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 17% (e.g., about 6% to about 11%, about 9% to about 13%, or about 11 % to about 17%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 24% to about 72% (e.g., about 24% to about 48%, about 36% to about 54%, or about 48% to about 72%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 34% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21% to about 62% (e.g., about 21% to about 42%, about 31% to about 47%, or about 42% to about 62%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 26% to about 78% (e.g., about 26% to about 52%, about 39% to about 59%, or about 52% to about 78%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 18% to about 54% (e.g., about 18% to about 36%, about 27% to about 41 %, or about 36% to about 54%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 21 % to about 64% (e.g., about 21% to about 42%, about 32% to about 48%, or about 42% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 31% (e.g., about 10% to about 21 %, about 15% to about 23%, or about 21% to about 31%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 21% (e.g., about 7% to about 14%, about 11% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 19% to about 56% (e.g., about 19% to about 37%, about 28% to about 42%, or about 37% to about 56%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11% to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 20% (e.g., about 7% to about 13%, about 10% to about 15%, or about 13% to about 20%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 22% to about 65% (e.g., about 22% to about 43%, about 32% to about 49%, or about 43% to about 65%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 30% to about 91% (e.g., about 30% to about 61%, about 46% to about 69%, or about 61% to about 91%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 20% to about 59% (e.g., about 20% to about 39%, about 30% to about 44%, or about 39% to about 59%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 28% to about 85% (e.g., about 28% to about 57%, about 43% to about 64%, or about 57% to about 85%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 29% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 29%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is increased by about 10% to about 30% (e.g., about 10% to about 20%, about 15% to about 22%, or about 20% to about 30%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 13% to about 38% (e.g., about 13% to about 26%, about 19% to about 29%, or about 26% to about 38%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is increased by about 16% to about 48% (e.g., about 16% to about 32%, about 24% to about 36%, or about 32% to about 48%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is increased by about 7% to about 22% (e.g., about 7% to about 15%, about 11 % to about 17%, or about 15% to about 22%), as compared to a reference level.

[0297] An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, eight, nine, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, or all 69) cell types set forth in Table 6 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11 % to about 32% (e.g., about 11 % to about 21 %, about 16% to about 24%, or about 21 % to about 32%), as compared to a reference level. In some embodiments, a level of CD4+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 11 % to about 33% (e.g., about 11 % to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31% (e.g., about 10% to about 20%, about 15% to about 23%, or about 20% to about 31 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 16% (e.g., about 5% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 16%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 18% (e.g., about 6% to about 12%, about 9% to about 13%, or about 12% to about 18%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 16%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 10%, about 7% to about 1 1 %, or about 10% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 10%, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+PD1 -TIGIT+TIM3- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+TIGIT+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 28% (e.g., about 9% to about 19%, about 14% to about 21 %, or about 19% to about 28%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21 % to about 31 %, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 +OX40+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 17% (e.g., about 6% to about 1 1 %, about 8% to about 12%, or about 1 1 % to about 17%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 16%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD4+DR+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+GzB+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 6% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 11% to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21 % (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 21% (e.g., about 7% to about 14%, about 10% to about 15%, or about 14% to about 21 %), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 17% to about 50% (e.g., about 17% to about 33%, about 25% to about 37%, or about 33% to about 50%), as compared to a reference level. In some embodiments, a level of CD4+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 45% (e.g., about 15% to about 30%, about 22% to about 34%, or about 30% to about 45%), as compared to a reference level. In some embodiments, a level of CD4+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 15% to about 44% (e.g., about 15% to about 29%, about 22% to about 33%, or about 29% to about 44%), as compared to a reference level. In some embodiments, a level of CD4+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 13% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+PD1 +0X40+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 14% to about 42% (e.g., about 14% to about 28%, about 21% to about 32%, or about 28% to about 42%), as compared to a reference level. In some embodiments, a level of CD8+CD25-CD69+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+DR+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 3% to about 5%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 14% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +GzB+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 11% (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 11%), as compared to a reference level. In some embodiments, a level of CD8+PD1 +OX40- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 12% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31% (e.g., about 10% to about 21%, about 16% to about 23%, or about 21% to about 31%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 14%, about 1 1 % to about 16%, or about 14% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 17%, about 13% to about 19%, or about 17% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 6%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 8%, about 6% to about 8%, or about 8% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 7% to about 22% (e.g., about 7% to about 15%, about 1 1 % to about 17%, or about 15% to about 22%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 13% (e.g., about 4% to about 9%, about 7% to about 10%, or about 9% to about 13%), as compared to a reference level. In some embodiments, a level of CD8+GzB+ TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 8% (e.g., about 3% to about 5%, about 4% to about 6%, or about 5% to about 8%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TEM cells in a sample (e.g., bone marrow) from the subject is decreased by about 2% to about 7% (e.g., about 2% to about 5%, about 4% to about 6%, or about 5% to about 7%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TEMRA cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+DR+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+DR+GzB+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+DR+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD8+DR+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 24% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 24%), as compared to a reference level. In some embodiments, a level of CD8+KI67+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 1 1 % to about 34% (e.g., about 1 1 % to about 23%, about 17% to about 25%, or about 23% to about 34%), as compared to a reference level. In some embodiments, a level of CD8+PD1 + TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD3-DR+ cells in a sample (e.g., bone marrow) from the subject is decreased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of 0X40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 1 1 %, or about 10% to about 15%), as compared to a reference level. In some embodiments, a level of PD1 +OX40+ Treg cells in a sample (e.g., bone marrow) from the subject is decreased by about 6% to about 19% (e.g., about 6% to about 13%, about 9% to about 14%, or about 13% to about 19%), as compared to a reference level. In some embodiments, a level of true NK cells in a sample (e.g., bone marrow) from the subject is decreased by about 3% to about 9% (e.g., about 3% to about 6%, about 4% to about 7%, or about 6% to about 9%), as compared to a reference level.

[0298] An MM subject having an increased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is likely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 7%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 10% (e.g., about 3% to about 7%, about 5% to about 8%, or about 7% to about 10%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 14% (e.g., about 5% to about 9%, about 7% to about 1 1 %, or about 9% to about 14%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 12% (e.g., about 4% to about 8%, about 6% to about 9%, or about 8% to about 12%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 4% to about 1 1 % (e.g., about 4% to about 7%, about 5% to about 8%, or about 7% to about 1 1 %), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is increased by about 11% to about 33% (e.g., about 11 % to about 22%, about 17% to about 25%, or about 22% to about 33%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is increased by about 3% to about 9% (e.g., about 3% to about 6%, about 5% to about 7%, or about 6% to about 9%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is increased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 6% to about 19% (e.g., about 6% to about 12%, about 9% to about 14%, or about 12% to about 19%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is increased by about 8% to about 23% (e.g., about 8% to about 15%, about 11 % to about 17%, or about 15% to about 23%), as compared to a reference level. In some embodiments, a level of CD25+CD69- NK cells in a sample (e.g., bone marrow) from the subject is increased by about 5% to about 15% (e.g., about 5% to about 10%, about 8% to about 11 %, or about 10% to about 15%), as compared to a reference level.

[0299] An MM subject having a decreased level (e.g., presence or percentage) of one or more (e.g., one, two, three, four, five, six, seven, or all eight) cell types set forth in Table 7 in a bone marrow sample (e.g., a baseline bone marrow sample), as compared to a reference level, may be identified as one who is unlikely to benefit from treatment with a bispecific antibody that binds to FcRH5 and CD3 (e.g., cevostamab). For example, in some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 29% (e.g., about 10% to about 19%, about 15% to about 22%, or about 19% to about 29%), as compared to a reference level. In some embodiments, a level of CD4+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 25% (e.g., about 8% to about 16%, about 12% to about 18%, or about 16% to about 25%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 26% (e.g., about 9% to about 17%, about 13% to about 19%, or about 17% to about 26%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 12% to about 36% (e.g., about 12% to about 24%, about 18% to about 27%, or about 24% to about 36%), as compared to a reference level. In some embodiments, a level of CD4+ T cells in a sample (e.g., bone marrow) from the subject is decreased by about 10% to about 31 % (e.g., about 10% to about 21 %, about 16% to about 23%, or about 21 % to about 31%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD4+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 9% to about 27% (e.g., about 9% to about 18%, about 14% to about 20%, or about 18% to about 27%), as compared to a reference level. In some embodiments, a level of CD8+CD25+CD69- T cells in a sample (e.g., bone marrow) from the subject is decreased by about 28% to about 83% (e.g., about 28% to about 55%, about 41% to about 62%, or about 55% to about 83%), as compared to a reference level. In some embodiments, a level of CD8+NK T cells in a sample (e.g., bone marrow) from the subject is decreased by about 8% to about 23% (e.g., about 8% to about 16%, about 12% to about 17%, or about 16% to about 23%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 20% to about 61% (e.g., about 20% to about 41%, about 31 % to about 46%, or about 41% to about 61%), as compared to a reference level. In some embodiments, a level of CD8+ TCM cells in a sample (e.g., bone marrow) from the subject is decreased by about 21% to about 64% (e.g., about 21% to about 43%, about 32% to about 48%, or about 43% to about 64%), as compared to a reference level. In some embodiments, a level of CD8+ TN cells in a sample (e.g., bone marrow) from the subject is decreased by about 16% to about 47% (e.g., about 16% to about 31%, a...

Claims

WHAT IS CLAIMED IS:1 . A method of treating a subject having a multiple myeloma (MM), the method comprising administering to the subject a bispecific antibody that binds to Fc receptor-homolog 5 (FcRH5) and cluster of differentiation 3 (CD3), wherein, prior to the administering of the bispecific antibody:(a) a sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 3, as compared to a reference level;(b) a sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 4, as compared to a reference level; and / or(c) the subject has been determined to have a lower number in one or more of the features set forth in Table 5, as compared to a reference number.

2. The method of claim 1 , wherein:(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and / or(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 7, as compared to the reference level.

3. The method of claim 1 , wherein:(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 8, as compared to the reference level; and / or(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 9, as compared to the reference level.

4. A method of treating a subject having an MM, the method comprising:(I) determining:(a) a level of one or more cell types set forth in Table 3 and / or Table 4 in a sample from the subject; and / or(b) one or more of the features of the subject set forth in Table 5;(II) identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level;(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 4, as compared to a reference level; and / or(c) the subject has a lower number in one or more of the features set forth in Table 5, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3; and(III) administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

5. The method of claim 4, wherein the method comprises:(I) determining a level of one or more cell types set forth in Table 6 and / or Table 7 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

6. The method of claim 4, wherein the method comprises:(I) determining a level of one or more cell types set forth in Table 8 and / or Table 9 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 8, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 9, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

7. A method of identifying a subject having an MM as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3, the method comprising:(I) determining:(a) a level of one or more cell types set forth in Table 3 and / or Table 4 in a sample from the subject; and / or(b) one or more of the features set forth in Table 5 of the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 3, as compared to a reference level;(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 4, as compared to a reference level; and / or(c) the subject has a lower number in one or more of the features set forth in Table 5, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

8. The method of claim 7, wherein the method comprises:(I) determining a level of one or more cell types set forth in Table 6 and / or Table 7 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

9. The method of claim 7, wherein the method comprises:(I) determining a level of one or more cell types set forth in Table 8 and / or Table 9 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 8, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 9, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

10. The method of any one of claims 7-9, wherein the method further comprises administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.1 1 . The method of any one of claims 1 , 2, 4, 5, 7, 8, and 10, wherein the sample from the subject is a bone marrow sample.

12. The method of any one of claims 1 , 3, 4, 6, 7, 9, and 10, wherein the sample from the subject is a blood sample.

13. The method of any one of claims 4-12, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription- quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof.

14. The method of any one of claims 4-13, wherein determining the level of the one or more cell types comprises FC.

15. The method of any one of claims 1 -14, wherein the reference level is a mean Z-score of the one or more cell types in a population of subjects having the MM.

16. The method of any one of claims 1 -15, wherein the reference number is a mean of the one or more features set forth in Table 5 in a population of subjects of having the MM.

17. The method of any one of claims 4-16, wherein the benefit from the treatment comprises a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

18. The method of claim 17, wherein the benefit from the treatment comprises a relative increase in OS.

19. The method of any one of claims 1 -18, wherein the MM is a relapsed or refractory (R / R) MM.

20. The method of any one of claims 1 -19, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs):(a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 );(b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2);(c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3);(d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4);(e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and(f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).21 . The method of any one of claims 1 -20, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity tothe amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b).

22. The method of claim 21 , wherein the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

23. The method of any one of claims 1 -22, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs:(a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9);(b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10);(c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 );(d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12);(e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and(f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

24. The method of any one of claims 1 -23, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

25. The method of claim 24, wherein the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

26. The method of any one of claims 1 -25, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein:(a) H1 comprises the amino acid sequence of SEQ ID NO: 35;(b) L1 comprises the amino acid sequence of SEQ ID NO: 36;(c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and(d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

27. The method of any one of claims 1 -26, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an aglycosylation site mutation.

28. The method of claim 27, wherein the aglycosylation site mutation reduces effector function of the bispecific antibody.

29. The method of claim 27 or 28, wherein the aglycosylation site mutation is a substitution mutation.

30. The method of claim 29, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.31 . The method of any one of claims 1 -30, wherein the bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody.

32. The method of any one of claims 1 -31 , wherein the bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody.

33. The method of any one of claims 1 -32, wherein the bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody.

34. The method of any one of claims 1 -25 and 27-33, wherein the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment.

35. The method of claim 34, wherein the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

36. The method of any one of claims 1 -33, wherein the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody.

37. The method of any one of claims 1 -33 and 36, wherein the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody.

38. The method of claim 37, wherein the IgG antibody is an IgG 1 antibody.

39. The method of any one of claims 1 -33 and 36-38, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH2i)domain, a first CH3 (CH3i) domain, a second CH1 (CHI 2) domain, second CH2 (CH22) domain, and a second CH3 (CH32) domain.

40. The method of claim 39, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.41 . The method of claim 39 or 40, wherein the CH3i and CH32 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3i domain is positionable in the cavity or protuberance, respectively, in the CH32 domain.

42. The method of claim 41 , wherein the CH3i and CH32 domains meet at an interface between the protuberance and cavity.

43. The method of any one of claims 39-42, wherein the CH2i and CH22 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2i domain is positionable in the cavity or protuberance, respectively, in the CH22 domain.

44. The method of claim 43, wherein the CH2i and CH22 domains meet at an interface between said protuberance and cavity.

45. The method of claim 42, wherein the anti-FcRH5 arm comprises the protuberance and the anti- CD3 arm comprises the cavity.

46. The method of claim 45, wherein the anti-FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EU numbering) and the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

47. The method of any one of claims 1 -33 and 36-46, wherein the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

48. The method of any one of claims 1 -47, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a monotherapy.

49. The method of any one of claims 1 -47, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject as a combination therapy.

50. The method of claim 49, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject concurrently with one or more additional therapeutic agents.51 . The method of claim 49, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject prior to the administration of one or more additional therapeutic agents.

52. The method of claim 49, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject subsequent to the administration of one or more additional therapeutic agents.

53. The method of claim 52, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

54. The method of claim 53, wherein tocilizumab is administered to the subject by intravenous infusion.

55. The method of claim 53 or 54, wherein:(a) the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg;(b) the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg / kg; or(c) the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg / kg.

56. The method of any one of claims 53-55, wherein tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody.

57. The method of any one of claims 50-52, wherein the one or more additional therapeutic agents comprises an effective amount of a corticosteroid, an analgesic and antipyretic, an antihistamine, an anti-myeloma agent, a PD-1 axis binding antagonist, an anti-CD38 therapeutic agent, an immunomodulatory (IMiD) agent, a cereblon E3 ligase modulatory drug (CELMoD), a proteosome inhibitor (PI), a CAR-T therapy, an anti-neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

58. The method of any one of claims 1 -57, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject by intravenous infusion.

59. The method of any one of claims 1 -57, wherein the bispecific antibody that binds to FcRH5 and CD3 is administered to the subject subcutaneously.

60. The method of any one of claims 1 -59, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while suspending treatment with the bispecific antibody that binds to FcRH5 and CD3.61 . The method of claim 60, wherein the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

62. The method of claim 61 , wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg.

63. The method of claim 61 or 62, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

64. The method of claim 63, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.

65. A method of classifying an MM in a subject, the method comprising:(I) determining a level of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject, and(II) assigning the subject’s MM to one of the following immune profiles based on the level of the CD8+ T cells, Treg cells, and CD8+ TN cells:(a) an activated immune profile;(b) an inactivated immune profile; or(c) a suppressed immune profile, thereby classifying the MM in the subject.

66. The method of claim 65, wherein:(I) the activated immune profile comprises:(a) an increased level of CD8+ T cells;(b) a decreased level of Treg cells; and(c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level ;(ll) the inactivated immune profile comprises:(a) a decreased level of CD8+ T cells;(b) an increased level of Treg cells; and(c) an increased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level; or(III) the suppressed immune profile comprises:(a) an increased level of CD8+ T cells;(b) an increased level of Treg cells; and(c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level.

67. The method of claim 65 or 66, wherein the immune profile is assigned by a similarity network fusion (SNF) analysis.

68. A bispecific antibody that binds to FcRH5 and CD3 for use in a treatment of a subject having an MM, wherein prior to an administration of the bispecific antibody:(a) a sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 1 , as compared to a reference level;(b) a sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 2, as compared to a reference level; and / or(c) the subject has been determined to have a lower number in one or more of the features set forth in Table 3, as compared to a reference number.

69. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 68, wherein:(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 4, as compared to the reference level; and / or(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 5, as compared to the reference level.

70. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 68, wherein:(a) the sample from the subject has been determined to have a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and / or(b) the sample from the subject has been determined to have an increased level of one or more cell types set forth in Table 7, as compared to the reference level.71 . A bispecific antibody that binds to FcRH5 and CD3 for use in a treatment of a subject having an MM, the treatment comprising:(I) determining:(a) a level of one or more cell types set forth in Table 1 and / or Table 2 in a sample from the subject; and / or(b) one or more of the features of the subject set forth in Table 3;(II) identifying the subject as one who would benefit from a treatment comprising a bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 1 , as compared to a reference level;(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 2, as compared to a reference level; and / or(c) the subject has a lower number in one or more of the features set forth in Table 3, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3; and(III) administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

72. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 71 , wherein the treatment comprises:(I) determining a level of one or more cell types set forth in Table 4 and / or Table 5 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 4, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 5, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

73. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 71 , wherein the treatment comprises:(I) determining a level of one or more cell types set forth in Table 6 and / or Table 7 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

74. A bispecific antibody that binds to FcRH5 and CD3 for use in a method of identifying a subject having an MM as one who would benefit from a treatment comprising the bispecific antibody that binds to FcRH5 and CD3, the method comprising:(I) determining:(a) a level of one or more cell types set forth in Table 1 and / or Table 2 in a sample from the subject; and / or(b) one or more of the features set forth in Table 3 of the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of the one or more cell types set forth in Table 1 , as compared to a reference level;(b) the sample from the subject has an increased level of the one or more cell types set forth in Table 2, as compared to a reference level; and / or(c) the subject has a lower number in one or more of the features set forth in Table 3, as compared to a reference number, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

75. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 74, wherein the method comprises:(I) determining a level of one or more cell types set forth in Table 4 and / or Table 5 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 4, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 5, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

76. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 74, wherein the method comprises:(I) determining a level of one or more cell types set forth in Table 6 and / or Table 7 in a sample from the subject; and(II) identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3, wherein:(a) the sample from the subject has a decreased level of one or more cell types set forth in Table 6, as compared to the reference level; and / or(b) the sample from the subject has an increased level of one or more cell types set forth in Table 7, as compared to the reference level, thereby identifying the subject as one who would benefit from the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

77. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 74-76, wherein the method further comprises administering to the subject the treatment comprising the bispecific antibody that binds to FcRH5 and CD3.

78. A bispecific antibody that binds to FcRH5 and CD3 for use in treatment of a subject having an MM, the treatment comprising a step of classifying the subject, the step of classifying comprising:(I) determining a level of CD8+ T cells, Treg cells, and CD8+ TN cells in a sample from the subject, and(II) assigning the subject’s MM to one of the following immune profiles based on the level of the CD8+ T cells, Treg cells, and CD8+ TN cells:(a) an activated immune profile;(b) an inactivated immune profile; or(c) a suppressed immune profile, thereby classifying the MM in the subject.

79. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 78, wherein:(I) the activated immune profile comprises:(a) an increased level of CD8+ T cells;(b) a decreased level of Treg cells; and(c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level ;(ll) the inactivated immune profile comprises:(a) a decreased level of CD8+ T cells;(b) an increased level of Treg cells; and(c) an increased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level; or(III) the suppressed immune profile comprises:(a) an increased level of CD8+ T cells;(b) an increased level of Treg cells; and(c) a decreased level of CD8+ TN cells, in the sample from the subject, as compared to a reference level.

80. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 78 or 79, wherein the immune profile is assigned by SNF.81 . The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68, 69, 71 , 72, 74, 75, and 77-80, wherein the sample form the subject is a bone marrow sample.

82. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68, 69, 71 , 72, 74, 75, and 77-80, wherein the sample form the subject is a blood sample.

83. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 69-82, wherein determining the level of the one or more cell types comprises flow cytometry (FC), mass spectrometry (MS), immunohistochemistry (IHC), DNA sequencing (DNA-seq), RNA sequencing (RNA-seq), quantitative PCR (qPCR), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), multiplex qPCR or RT-qPCR, microarray analysis, serial analysis of gene expression (SAGE), MASSARRAY® technique, in situ hybridization (ISH), or a combination thereof.

84. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 71 -83, wherein determining the level of the one or more cell types comprises FC.

85. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-84, wherein the reference level is a mean Z-score of the one or more cell types in a population of subjects having the MM.

86. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-85, wherein the reference number is a mean of the one or more features set forth in Table 3 in a population of subjects of having the MM.

87. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 71 -86, wherein the benefit from the treatment comprises a relative increase in overall survival (OS), objective response rate (ORR), progression-free survival (PFS), complete response (CR), partial response (PR), or a combination thereof.

88. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 87, wherein the benefit from the treatment comprises a relative increase in OS.

89. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-88, wherein the MM is a relapsed or refractory (R / R) MM.

90. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-89, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising the following six hypervariable regions (HVRs):(a) an HVR-H1 comprising the amino acid sequence of RFGVH (SEQ ID NO: 1 );(b) an HVR-H2 comprising the amino acid sequence of VIWRGGSTDYNAAFVS (SEQ ID NO: 2);(c) an HVR-H3 comprising the amino acid sequence of HYYGSSDYALDN (SEQ ID NO:3);(d) an HVR-L1 comprising the amino acid sequence of KASQDVRNLVV (SEQ ID NO: 4);(e) an HVR-L2 comprising the amino acid sequence of SGSYRYS (SEQ ID NO: 5); and(f) an HVR-L3 comprising the amino acid sequence of QQHYSPPYT (SEQ ID NO: 6).91 . The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-90, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a first binding domain comprising (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 7; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 8; or (c) a VH domain as in (a) and a VL domain as in (b).

92. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 91 , wherein the first binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 7 and a VL domain comprising an amino acid sequence of SEQ ID NO: 8.

93. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-92, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising the following six HVRs:(a) an HVR-H1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 9);(b) an HVR-H2 comprising the amino acid sequence of WIYPENDNTKYNEKFKD (SEQ ID NO: 10);(c) an HVR-H3 comprising the amino acid sequence of DGYSRYYFDY (SEQ ID NO: 11 );(d) an HVR-L1 comprising the amino acid sequence of KSSQSLLNSRTRKNYLA (SEQ ID NO: 12);(e) an HVR-L2 comprising the amino acid sequence of WTSTRKS (SEQ ID NO: 13); and(f) an HVR-L3 comprising the amino acid sequence of KQSFILRT (SEQ ID NO: 14).

94. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-93, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-CD3 arm comprising a second binding domain comprising (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 15; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 16; or (c) a VH domain as in (a) and a VL domain as in (b).

95. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 94, wherein the second binding domain comprises a VH domain comprising an amino acid sequence of SEQ ID NO: 15 and a VL domain comprising an amino acid sequence of SEQ ID NO: 16.

96. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-95, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an anti-FcRH5 arm comprising a heavy chain polypeptide (H1 ) and a light chain polypeptide (L1 ) and an anti-CD3 arm comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein:(a) H1 comprises the amino acid sequence of SEQ ID NO: 35;(b) L1 comprises the amino acid sequence of SEQ ID NO: 36;(c) H2 comprises the amino acid sequence of SEQ ID NO: 37; and(d) L2 comprises the amino acid sequence of SEQ ID NO: 38.

97. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-96, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises an aglycosylation site mutation.

98. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 97, wherein the aglycosylation site mutation reduces effector function of the bispecific antibody.

99. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 97 or 98, wherein the aglycosylation site mutation is a substitution mutation.

100. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 99, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises a substitution mutation in the Fc region that reduces effector function.101 . The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-100, wherein the bispecific antibody that binds to FcRH5 and CD3 is a monoclonal antibody.

102. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-101 , wherein the bispecific antibody that binds to FcRH5 and CD3 is a chimeric antibody.

103. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-102, wherein the bispecific antibody that binds to FcRH5 and CD3 is a humanized antibody.

104. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-95 and 97- 103, wherein the bispecific antibody that binds to FcRH5 and CD3 is an antibody fragment.

105. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 104, wherein the antibody fragment is selected from the group consisting of Fab, Fab’-SH, Fv, scFv, and (Fab’)2 fragments.

106. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103, wherein the bispecific antibody that binds to FcRH5 and CD3 is a full-length antibody.

107. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103 and 106, wherein the bispecific antibody that binds to FcRH5 and CD3 is an IgG antibody.

108. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 107, wherein the IgG antibody is an IgG 1 antibody.

109. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103 and106-108, wherein the bispecific antibody that binds to FcRH5 and CD3 comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1 j) domain, a first CH2 (CH2j) domain, a first CH3 (CH3y) domain, a second CH1 (CH12) domain, second CH2 (CH22) domain, and a second CH3 (CH32) domain.

110. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 109, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

111. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 109 or 110, wherein the CH3y and CH32domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3y domain is positionable in the cavity or protuberance, respectively, in the CH32domain.

112. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 111 , wherein the CH3j and CH32domains meet at an interface between the protuberance and cavity.

113. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 109-112, wherein the CH2j and CH22domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2j domain is positionable in the cavity or protuberance, respectively, in the CH22domain.

114. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 113, wherein the CH2j and CH22domains meet at an interface between said protuberance and cavity.

115. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 112, wherein the anti- FcRH5 arm comprises the protuberance and the anti-CD3 arm comprises the cavity.

116. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 115, wherein the anti- FcRH5 arm comprises a protuberance comprising a T366W amino acid substitution mutation (EUnumbering) and the anti-CD3 arm comprises a cavity comprising T366S, L368A, and Y407V amino acid substitution mutations (EU numbering).

117. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-103 and 106-116, wherein the bispecific antibody that binds to FcRH5 and CD3 is cevostamab.

118. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-117, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for administration to the subject as a monotherapy.

119. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-117, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for administration to the subject as a combination therapy.

120. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 119, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated to be administered concurrently with one or more additional therapeutic agents to the subject.121 . The bispecific antibody that binds to FcRH5 and CD3 for use of claim 119, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated to be administered to the subject prior to the administration of one or more additional therapeutic agents.

122. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 119, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated to be administered to the subject subsequent to the administration of one or more additional therapeutic agents.

123. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 122, wherein the one or more additional therapeutic agents comprise an effective amount of tocilizumab.

124. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 123, wherein tocilizumab is administered to the subject by intravenous infusion.

125. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 123 or 124, wherein:(a) the subject weighs > 100 kg, and tocilizumab is administered to the subject at a dose of 800 mg;(b) the subject weighs > 30 kg and < 100 kg, and tocilizumab is administered to the subject at a dose of 8 mg / kg; or(c) the subject weighs < 30 kg, and tocilizumab is administered to the subject at a dose of 12 mg / kg.

126. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 123-125, wherein tocilizumab is administered to the subject 2 hours before administration of the bispecific antibody.

127. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 120-122, wherein the one or more additional therapeutic agents comprises an effective amount of a corticosteroid, an analgesic and antipyretic, an antihistamine, an anti-myeloma agent, a PD-1 axis binding antagonist, an anti-CD38 therapeutic agent, an immunomodulatory (IMiD) agent, a cereblon E3 ligase modulatory drug (CELMoD), a proteosome inhibitor (PI), a CAR-T therapy, an anti- neoplastic agent, a chemotherapeutic agent, a growth inhibitory agent, an anti-angiogenic agent, a radiation therapy, a cytotoxic agent, a cell-based therapy, or a combination thereof.

128. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-127, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for administration by intravenous infusion to the subject.

129. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-127, wherein the bispecific antibody that binds to FcRH5 and CD3 is formulated for subcutaneous administration to the subject.

130. The bispecific antibody that binds to FcRH5 and CD3 for use of any one of claims 68-129, wherein the subject has a cytokine release syndrome (CRS) event, and the method further comprises treating the symptoms of the CRS event while suspending treatment with the bispecific antibody that binds to FcRH5 and CD3.131 . The bispecific antibody that binds to FcRH5 and CD3 for use of claim 130, wherein the method further comprises administering to the subject an effective amount of tocilizumab to treat the CRS event.

132. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 131 , wherein tocilizumab is administered intravenously to the subject as a single dose of about 8 mg / kg.

133. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 131 or 132, wherein the CRS event does not resolve or worsens within 24 hours of treating the symptoms of the CRS event, the method further comprising administering to the subject one or more additional doses of tocilizumab to manage the CRS event.

134. The bispecific antibody that binds to FcRH5 and CD3 for use of claim 133, wherein the one or more additional doses of tocilizumab are administered intravenously to the subject at a dose of about 8 mg / kg.