Methods of Treating Cancer and Improving the Efficacy of BCMAxCD3 Bispecific Antibodies

Abstract

Methods of treating cancer, particularly relapsed or refractory multiple myeloma, and improving the efficacy of BCMAxCD3 bispecific antibodies are disclosed. In particular, methods of using BCMAxCD3 bispecific antibodies, CD38 antibodies, and / or pomalidomide to treat cancer are disclosed.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 275,368, filed November 03, 2021, U.S. Provisional Application No. 63 / 288,279, filed December 10, 2021, and U.S. Provisional Application No. 63 / 348,036, filed June 2, 2022, each of which is incorporated by reference in its entirety herein.

[0002] (Reference to electronically submitted sequence listing) This application contains a Sequence Listing that has been submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy, created on October 28, 2022, has the file name "258199.060902_PRD4190WOPCT1_SL.xml" and is 64.1 kilobytes in size.

[0003] FIELD OF THEINVENTION Methods of treating cancer and improving the efficacy of BCMAxCD3 bispecific antibodies are disclosed. [Background technology]

[0004] From 1990 to 2016, worldwide, multiple myeloma (MM) incident cases increased by 126% and deaths increased by 94%. In 2020, in the United States, an estimated 32,270 new cases of MM were diagnosed and 140,779 people are estimated to be living with the disease. In Europe, multiple myeloma is the second most common hematological malignancy, with an estimated 35,842 new cases in 27 European countries in 2020 (European Cancer Information System 2020). Despite multiple treatment options, the disease very frequently recurs and remains incurable. With each successive relapse, symptoms return, quality of life worsens, and the likelihood and duration of response typically decreases.

[0005] Relapsed and refractory multiple myeloma constitutes a special unmet medical need. Patients who progress after receiving standard therapy (such as proteasome inhibitors [PIs] or immunomodulatory drugs [IMiDs]) are difficult to treat because they have already been exposed to two major drug classes, and new effective and expedient treatment options are needed. Although myeloma remains an incurable disease, fewer than 40% of patients receive third-line therapy. Lenalidomide-containing regimens are increasingly becoming standard first-line therapy in both transplant-eligible and transplant-ineligible patients in the United States and most of Europe. As a result of these practice patterns, most patients with relapsed multiple myeloma are exposed to lenalidomide at the time of their first relapse.

[0006] T cell redirection killing is a desired mode of action in many therapeutic areas. Typically, T cell redirection molecules are engineered to have at least two antigen binding sites, one site that binds to a surface antigen on a target cell and the other site that binds to a T cell surface antigen. Among the T cell surface antigens, the human CD3 epsilon subunit of the TCR protein complex is the one that is most targeted to redirect T cell killing. Various bispecific antibody formats have been shown to mediate T cell redirection in both preclinical and clinical trials.

[0007] Tumors evade immune recognition by creating an immunosuppressive tumor microenvironment (TME). In the TME, under conditions of persistent antigen and inflammation, T cells become exhausted or dysfunctional, progressively losing their effector function and proliferation capacity. The impaired function and number of available T cells involved in therapeutic agent-mediated T cell redirected killing may impair the antitumor efficacy of the therapeutic agent. For optimal efficacy of therapeutic agents that mediate T cell redirected killing, there is a need to improve T cell functionality.

[0008] Teclistamab (Tec) is a bispecific antibody that binds to B-cell maturation antigen (BCMA) and CD3. Daratumumab (Dara) is a monoclonal antibody approved for the treatment of MM that targets CD38 on MM cells, resulting in direct cytotoxicity of MM cells. Novel agents are needed to treat cancer, particularly multiple myeloma (MM), which remains incurable and most patients (pts) relapse or become refractory to standard therapy. Summary of the Invention

[0009] Using the dosing regimens described in this application, it has been discovered that a combination of a BCMAxCD3 bispecific antibody and the anti-CD38 antibody DARZALEX® (daratumumab), each of which mediates killing of multiple myeloma cells upon target binding on the same cell, can be safely administered to a subject to treat cancer, particularly relapsed / refractory MM.

[0010] In one general aspect, the invention provides a method of treating cancer, such as multiple myeloma, in a subject in need of treatment, comprising: (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks.

[0011] In some embodiments, the BCMAxCD3 bispecific antibody is administered intravenously to a subject every 1-4 weeks at a dose of 200 μg / kg to 350 μg / kg, for example 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350 μg / kg, or any dose therebetween.

[0012] In some embodiments, the method comprises: (1) administering a BCMA x CD3 bispecific antibody subcutaneously to a subject at a dose of 1 mg / kg to 6 mg / kg or 200 mg to 400 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1600 mg to 2000 mg every 1 to 4 weeks.

[0013] In some embodiments, the method further comprises, prior to step (1), subcutaneously administering to the subject a BCMAxCD3 bispecific antibody at a dose of less than 0.5 mg / kg.

[0014] According to an embodiment of the present application, the BCMAxCD3 bispecific antibody is The BCMAxCD3 bispecific antibody may be administered subcutaneously to a subject once per week, once every two weeks, or once every four weeks at a dose of 1.5 mg / kg, 3.0 mg / kg, 5, 5.5, or 6 mg / kg, or at a fixed dose of 60, 100, 150, 200, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any dose in between. For example, a BCMAxCD3 bispecific antibody may be administered subcutaneously to a subject once per week, once every two weeks, or once every four weeks at a dose of 1.5 mg / kg, 3.0 mg / kg, or 300 mg every other week.

[0015] In one embodiment of the application, the BCMAxCD3 bispecific antibody is administered subcutaneously to a subject at a dose of 1.5 mg / kg weekly and the anti-CD38 antibody is administered subcutaneously to a subject at a dose of 1800 mg once per week during weeks 1-8 of treatment, once every two weeks during weeks 9-24 of treatment, and once every four weeks from week 24 onwards of treatment.

[0016] In another embodiment of the application, the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject once per week at a dose of 1.5 mg / kg during weeks 1-8 of treatment, and once every two weeks from week 8 of treatment onwards, e.g., between weeks 9-24 of treatment, at a dose of 3.0 mg / kg, and the anti-CD38 antibody is administered subcutaneously to the subject once per week at a dose of 1800 mg during weeks 1-8 of treatment, once every two weeks between weeks 9-24 of treatment, and once every four weeks after week 24 of treatment.

[0017] In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously once a month at 3.0 mg / kg after week 8 of treatment, e.g., 4-12 weeks after biweekly subcutaneous administration of 6.0 mg / kg.

[0018] In some embodiments, the anti-CD38 antibody is administered or provided for administration together with rHuPH20, for example, about 30,000 U of rHuPH20.

[0019] Any suitable BCMAxCD3 bispecific antibody may be used in the methods of the present application. In some embodiments, a BCMAxCD3 bispecific antibody useful in the present application is (i) a BCMA binding domain comprising a heavy chain variable region (VH) having heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, and a light chain variable region (VL) having light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, respectively; and (ii) a CD3 binding domain comprising a VH having HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively.

[0020] In some embodiments, the BCMA binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 24 and a VL having the amino acid sequence of SEQ ID NO: 25. The CD3 binding domain comprises a VH having the amino acid sequence of SEQ ID NO: 34 and a VL having the amino acid sequence of SEQ ID NO: 35. Preferably, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 26, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 27, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 36 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 37. More preferably, the BCMAxCD3 bispecific antibody is teclistamab.

[0021] In some embodiments, the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively, and a VL having LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively. Preferably, the anti-CD38 antibody comprises a VH having the amino acid sequence of SEQ ID NO:6 and a VL having the amino acid sequence of SEQ ID NO:7. More preferably, the anti-CD38 antibody is daratumumab.

[0022] In one embodiment, the present application provides a method of treating multiple myeloma in a subject in need thereof, comprising: (1) administering to the subject subcutaneously 1.5 mg / kg of the BCMA x CD3 bispecific antibody once per week during weeks 1 through 8 of treatment, and from week 8 of treatment onwards, administering 3.0 mg / kg of the BCMA x CD3 bispecific antibody once every two weeks and / or 6.0 mg / kg of the BCMA x CD3 bispecific antibody once per month; (2) administering 1,800 mg of an anti-CD38 antibody subcutaneously to the subject once per week during weeks 1 through 8 of treatment, once every two weeks during weeks 9 through 24 of treatment, and once every four weeks from week 24 of treatment onward; The present invention relates to a method, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) of SEQ ID NO: 26, a first light chain (LC1) of SEQ ID NO: 27, a second heavy chain (HC2) of SEQ ID NO: 36, and a second light chain (LC2) of SEQ ID NO: 37, and the anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13.

[0023] In some embodiments of the present application, the subject has undergone at least one prior treatment for multiple myeloma, preferably the subject is relapsed or refractory to at least one prior treatment, more preferably the prior treatment comprises at least one of a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). The subject may be refractory or relapsed to a treatment, such as a treatment selected from the group consisting of an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan and thalidomide, or any combination thereof. Preferably, if the subject has undergone only one prior treatment, the subject is lenalidomide refractory.

[0024] In some embodiments, the methods of the present application further include administering to the subject another treatment for cancer, including, but not limited to, pomalidomide, daratumumab, dexamethasone, bortezomib, and lenalidomide.

[0025] In some embodiments, methods according to embodiments of the present application result in T cell activation, such as an increase in at least one of CD25, PD-1, CD38 on CD4 and CD8 T cells. Methods according to embodiments of the present application may also result in an increase in the frequency of at least one of CD38+CD8+ T cells, CD38+CD4+ T cells, and Tregs T cells.

[0026] Another general aspect of the application relates to an anti-CD38 antibody as described herein for use in a method of treating cancer, such as MM, more specifically relapsed or refractory MM, the method comprising: (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks.

[0027] Another general aspect of the application relates to a BCMAxCD3 bispecific antibody as described herein for use in the treatment of cancer, such as MM, more specifically relapsed or refractory MM, the treatment comprising: (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks.

[0028] Yet another general aspect of the application is a combination or kit of an anti-CD38 antibody as described herein and a BCMAxCD3 bispecific antibody as described herein for use in the treatment of cancer, such as MM, more specifically relapsed or refractory MM, the treatment comprising: (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks.

[0029] The present application further relates to the use of a combination of an anti-CD38 antibody as described herein and a BCMAxCD3 bispecific antibody as described herein in the manufacture of a medicament for treating cancer, such as MM, more specifically relapsed or refractory MM, wherein the treatment comprises: (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks. [Brief description of the drawings]

[0030] The above Summary of the Invention and the following Detailed Description of the Invention will be better understood when read in conjunction with the appended drawings. It is to be understood that the invention is not limited to the precise embodiments shown in the drawings. [Figure 1] FIG. 1 is a schematic overview of Part 1 and Part 2 of a Phase 1 study of teclistamab administered in combination with subcutaneous daratumumab for relapsed or refractory multiple myeloma (RRMM). [Diagram 2] Response rates for patients treated with daratumumab and teclistamab in parts 1 and 2 of the study (cutoff date for analysis was April 6, 2022): Dara SC 1800mg + Tec SC (1.5mg / kg QW or 3mg / kg QW or 3mg / kg Q2W);CR, complete response;D / C=discontinued;dara, daratumumab;MR, minimal response;PD, progressive disease;PR, partial response;QW, weekly:Q2W, every other week;sCR, stringent complete response;SD, stable disease;tec, teclistamab;TR, 3-class refractory;VGPR, very good partial response. [Diagram 3] 1 shows CD8+ and CD4+ T cell counts in patients with RRMM treated with 1800 mg SC daratumumab and 1.5 mg / kg SC teclistamab weekly according to one embodiment of the application. [Figure 4] FIG. 1 shows T cell activation (CD25+) in patients with RRMM treated with 1800 mg SC daratumumab and SC teclistamab weekly, according to one embodiment of the application. [Diagram 5] FIG. 1 shows cytokine induction in RRMM patients treated with 1800 mg SC daratumumab and SC teclistamab weekly according to one embodiment of the application. TNF-α=tissue necrosis factor alpha; IL-8=interleukin 8; IFN-g=interferon gamma; IL-6=interleukin 6. [Figure 6]1 shows the increase in frequency of CD38+ T cells in four subjects with RRMM treated with 1800 mg SC daratumumab and SC teclistamab, according to one embodiment of the application. [Figure 7] 1 is a schematic diagram of the dosing schedule for Group A (Tec-Dara) of a clinical trial according to an embodiment of the present application, where the thick arrow indicates the SC dosing day of daratumumab and the thin arrow indicates the dosing day of teclistamab (the shorter one is the escalating dose). Dara, daratumumab; Tec, teclistamab. Detailed Description of the Invention

[0031] The method of the present disclosure can be more readily understood by reference to the following detailed description taken in conjunction with the accompanying drawings, which form a part of this disclosure. It is to be understood that the method of the present disclosure is not limited to the specific methods described and / or illustrated herein, and further, the terminology used herein is for the purpose of describing specific embodiments by way of example only, and is not intended to be limiting to the methods claimed. All patents, patent applications, and publications cited herein are incorporated by reference as if fully set forth herein.

[0032] Various terms relating to the embodiments of the present specification are used throughout the specification and claims. Unless otherwise indicated, such terms are to be given their ordinary meaning in the art. Other specifically defined terms are to be interpreted in a manner consistent with the definitions provided herein.

[0033] As used herein, the singular forms "a," "an," and "the" are intended to include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a cell" includes a combination of two or more cells, and the like.

[0034] Unless otherwise specified, any numerical values, such as concentrations or concentration ranges, described herein should be understood in all cases as being modified by the term "about". Thus, numerical values ​​typically include ±10% of the described value. For example, a dosage of 10 mg includes 9 mg to 11 mg. As used herein, the use of numerical ranges expressly includes all possible subranges, including integers and fractions of values ​​within the range, and all individual numerical values ​​within the range, unless the context clearly indicates otherwise.

[0035] "About," when used in reference to a numerical range, cutoff, or specific value, means within an acceptable range of error for the particular value as determined by one of ordinary skill in the art, which will depend in part on the limitations of the method, i.e., measurement system, by which the value is measured or determined. Unless expressly stated otherwise in the examples or elsewhere in the specification in the context of an assay, result, or embodiment, "about" means within one standard deviation or within 10%, whichever is greater, according to practice in the art.

[0036] "Antibody" has a broad meaning and includes monoclonal antibodies, including murine, human, humanized, and chimeric monoclonal antibodies, antigen-binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, dimeric, tetrameric, or multimeric antibodies, single-chain antibodies, domain antibodies, and immunoglobulin molecules, including any other modified form of an immunoglobulin molecule that contains an antigen-binding site of the required specificity. A "full-length antibody" is composed of two heavy chains (HC) and two light chains (LC), and multimers thereof (e.g., IgM), interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (consisting of domains CH1, hinge, CH2, and CH3). Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with framework regions (FRs). Each VH and VL is composed of three CDR and four FR segments arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Depending on the amino acid sequence of the heavy chain constant domain, immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. The antibody light chain of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain.

[0037] "Antigen-binding fragment" or "antigen-binding domain" refers to a portion of an immunoglobulin molecule that binds to an antigen. Antigen-binding fragments may be synthetic, enzymatically obtainable, or recombinant polypeptides, and include VH, VL, VH and VL, Fab, F(ab')2, Fd, and Fv fragments, domain antibodies (dAbs) consisting of one VH domain or one VL domain, shark variable IgNAR domain, camelized VH domain, and the minimum recognition unit consisting of amino acid residues reproducing the CDRs of an antibody, such as the FR3-CDR3-FR4 portion, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3. The VH and VL domains can be linked to each other via synthetic linkers to form various types of single chain antibody designs; when the VH and VL domains are expressed as separate single chain antibody constructs, the VH / VL domains can pair intramolecularly or intermolecularly to form monovalent antigen binding sites, such as single chain Fvs (scFvs) or diabodies, as described, for example, in WO 1998 / 44001, WO 1988 / 01649, WO 1994 / 13804, and WO 1992 / 01047.

[0038] "BCMA" refers to human B-cell maturation antigen, which is also known as CD269 or TNFRSF17. Human BCMA (UniProt Q02223) comprises the amino acid sequence of SEQ ID NO: 1. The extracellular domain of human BCMA spans residues 1-54 of SEQ ID NO: 1.

[0039] "Bispecific" refers to an antibody that specifically binds to two different antigens or two different epitopes on the same antigen. Bispecific antibodies may have cross-reactivity to other related antigens, e.g., the same antigen (homolog) from other species such as humans or monkeys, e.g., Macaca cynomolgus (cyno) or chimpanzees, or may bind to an epitope that is shared between two or more different antigens.

[0040] "Cancer" refers to a broad group of diverse diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth can lead to the formation of malignant tumors that invade adjacent tissues and may also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancerous tissue" can include tumors.

[0041] "CD3" refers to a human antigen expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and consisting of a homodimer or heterodimer formed from the association of two or four receptor chains: CD3 epsilon, CD3 delta, CD3 zeta, and CD3 gamma. Human CD3 epsilon comprises the amino acid sequence of SEQ ID NO: 2. SEQ ID NO: 3 shows the extracellular domain of CD3 epsilon.

[0042] "CD38" refers to the CD38 protein (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, cyclic ADP-ribose hydrolase 1). Human CD38 (UniProt Accession No. P28907) has the amino acid sequence shown in SEQ ID NO: 4. CD38 is a single-pass type II transmembrane protein, with amino acid residues 1-21 representing the cytoplasmic domain, amino acid residues 22-42 representing the transmembrane domain, and residues 43-300 representing the extracellular domain.

[0043] "CH3 region" or "CH3 domain" refers to a region of the CH3 of an immunoglobulin. The CH3 region of a human IgG1 antibody corresponds to amino acid residues 341 to 446. However, the CH3 region may also be of any of the other antibody isotypes described herein.

[0044] "Chimeric antigen receptor" or "CAR" refers to an engineered T cell receptor (e.g., naive T cells, central memory T cells, effector memory T cells, or a combination thereof) that transfers ligand or antigen specificity onto a T cell. CARs are also known as artificial T cell receptors, chimeric T cell receptors, or chimeric immune receptors. CARs include an extracellular domain that can bind to an antigen, a transmembrane domain, and at least one intracellular domain. The CAR intracellular domain includes a polypeptide that is known to function as a domain that transmits a signal that causes activation or inhibition of a biological process within the cell. The transmembrane domain includes any peptide or polypeptide that is known to span the cell membrane and can function to connect the extracellular domain and the signaling domain. The chimeric antigen receptor may optionally include a hinge domain that functions as a linker between the extracellular domain and the transmembrane domain.

[0045] By "combination" it is meant that two or more therapeutic agents are administered to a subject together in a mixture, simultaneously as single agents, or sequentially in any order as single agents.

[0046] "Complementarity determining region (CDR)" is the region of an antibody that binds to an antigen. CDRs can be defined using various descriptions, such as Kabat (Wu et al. J Exp Med 132:211-50, 1970) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al. J Mol Biol 196:901-17, 1987), IMGT (Lefranc et al. Dev Comp Immunol 27:55-77, 2003), and AbM (Martin and Thornton J Bmol Biol 263:800-15, 1996). Various descriptions and their correspondence with the numbering of variable regions have been described (see, for example, Lefranc et al. Dev Comp Immunol 27:55-77, 2003; Honegger and Pluckthun, J Mol Biol 309:657-70, 2001; International ImMunoGeneTics (IMGT) database; web resource, http: / / www_imgt_org). Available programs such as abYsis by UCL Business PLC can be used to describe CDRs. As used herein, the terms "CDR", "HCDR1", "HCDR2", "HCDR3", "LCDR1", "LCDR2" and "LCDR3" include CDRs defined by any of the methods of Kabat, Chothia, IMGT or AbM as described above, unless otherwise expressly stated in the specification. For example, the correspondence between numbering systems, including Kabat numbering and the IMGT specific numbering system, is well known to those of skill in the art (see, for example, Kabat; Chothia; Martin; Lefranc et al.).

[0047] [Table 1]

[0048] "Comprising" is intended to include examples encompassed by the terms "consisting essentially of" and "consisting of." Similarly, the term "consisting essentially of" is intended to include examples encompassed by the term "consisting of." Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprise," "comprising," and the like, are to be construed in an inclusive sense, i.e., "including, but not limited to," as opposed to an exclusive or exclusive sense.

[0049] "Improve" or "improved" refers to an improvement in one or more functions of a test molecule compared to a control molecule, or an improvement in one or more functions of a combination of test molecules compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effector functions (e.g., ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγR) or FcRn. "Improved" can be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more improvement, or a statistically significant improvement.

[0050] "Fc gamma receptor" (FcγR) refers to the well-known FcγRI, FcγRIIa, FcγRIIb, or FcγRIII. Activating FcγRs include FcγRI, FcγRIIa, and FcγRIII.

[0051] "Human antibody" refers to an antibody that is optimized to have a minimal immune response when administered to a human subject. The variable regions of a human antibody are derived from human immunoglobulin sequences. If the human antibody contains a constant region or a portion of a constant region, the constant region is also derived from a human immunoglobulin sequence. A human antibody contains heavy and light chain variable regions that are "derived" from sequences of human origin when the variable regions of the human antibody are derived from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Exemplary such systems are phage-displayed human immunoglobulin gene libraries and transgenic non-human animals, such as mice or rats, that carry human immunoglobulin loci. "Human antibodies" typically contain amino acid differences when compared to immunoglobulins expressed in humans, due to differences in the system used to obtain the human antibodies and human immunoglobulin loci, the intentional introduction of somatic mutations or substitutions into the framework or CDRs, or both. Typically, a "human antibody" is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin or rearranged immunoglobulin gene. In some cases, a "human antibody" may contain a consensus framework sequence obtained from human framework sequence analysis as described, for example, in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into a library of human immunoglobulin genes displayed on phage as described, for example, in Shi et al., (2010) J Mol Biol 397:385-96 and WO 2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of "human antibody."

[0052] "Humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one framework is derived from a human immunoglobulin sequence. Humanized antibodies can contain substitutions in the framework, such that the framework may not be an exact copy of an expressed human immunoglobulin or human immunoglobulin germline gene sequence.

[0053] "Isolated" refers to a protein that has been subjected to at least one purification or isolation step, as well as to a homogenous population of molecules (e.g., a protein such as a synthetic polynucleotide or an antibody) that have been substantially separated and / or purified from other components associated with the system in which the molecule is produced, such as a recombinant cell. An "isolated antibody" refers to an antibody that is substantially free of other cellular material and / or chemicals, and includes antibodies that have been isolated to greater degrees of purity, e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% purity.

[0054] By "monoclonal antibody" is meant an antibody obtained from a substantially homogeneous population of antibody molecules (i.e., the individual antibodies comprising the population are identical except for possible known alterations such as removal of the C-terminal lysine from the antibody heavy chain, or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation). A monoclonal antibody typically binds to one antigenic epitope. A bispecific monoclonal antibody binds to two different antigenic epitopes. A monoclonal antibody may have heterogeneous glycosylation within the antibody population. A monoclonal antibody may be monospecific or multispecific, such as bispecific, and may be monovalent, bivalent, or multivalent.

[0055] "Mutation" refers to an artificially engineered or naturally occurring change in a polypeptide or polynucleotide sequence compared to a reference sequence. The change may be a substitution, insertion, or deletion of one or more amino acids or polynucleotides.

[0056] "Non-fixed combination" refers to separate pharmaceutical compositions or unit dosage forms of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody that are administered as separate entities, either simultaneously, concurrently, or sequentially without any specific time of interruption, where such administration provides effective levels of the two compounds in the subject's body.

[0057] "Multispecific" refers to an antibody that specifically binds to at least two different antigens or to at least two different epitopes within the same antigen. A multispecific antibody may, for example, bind to two, three, four, or five different antigens, or to different epitopes within the same antigen.

[0058] A "pharmaceutical composition" refers to a composition comprising an active ingredient and a pharma- ceutically acceptable carrier.

[0059] A "pharmaceutically acceptable carrier" or "excipient" refers to an ingredient in a pharmaceutical composition, other than an active ingredient, that is not toxic to a subject.

[0060] "Philadelphia chromosome" or "Ph" refers to a well-known chromosomal translocation between chromosomes 9 and 22 that results in an oncogenic BCR-ABL gene fusion with constitutively active tyrosine kinase activity. This translocation fuses a portion of the BCR gene on chromosome 22q11 with a portion of the ABL gene on chromosome 9q34, which is designated t(9;22)(q34;q11) under the International System for Human Cytogenetic Nomenclature (ISCN). Depending on the exact location of the fusion, the molecular weight of the resulting fusion protein can range from 185 to 210 kDa. The "Philadelphia chromosome" refers to all BCR-ABL fusion proteins formed by the (9;22)(q34;q11) translocation.

[0061] "Recombinant" refers to DNA, antibodies, and other proteins that are prepared, expressed, produced, or isolated by recombinant means when segments from different sources are joined to produce the recombinant DNA, antibody, or protein.

[0062] "Reduce" or "reduced" refers to a reduction in one or more functions of a test molecule compared to a control molecule, or a reduction in one or more functions of a combination of test molecules compared to one or more control molecules. Exemplary functions that can be measured are tumor cell killing, T cell activation, relative or absolute T cell numbers, Fc-mediated effector functions (e.g., ADCC, CDC, and / or ADCP), or binding to Fcγ receptors (FcγR) or FcRn. "Reduced" can be about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or more reduction, or a statistically significant improvement.

[0063] "rHuPh20" refers to recombinant human hyaluronidase having the amino acid sequence of SEQ ID NO:5, which is a recombinant hyaluronidase (HYLENEX®) described in WO 2004 / 078140.

[0064] "Treated refractory" refers to cancer that is not repairable by surgical intervention and that initially does not respond to therapy.

[0065] "Recurrent" refers to cancer that responds to treatment but then recurs.

[0066] A "subject" includes any human or non-human animal. A "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Except where noted, the terms "patient" and "subject" are used interchangeably.

[0067] "BCMAxCD3 bispecific antibody" refers to a molecule that contains two or more binding regions, one of which specifically binds to the cell surface antigen B-cell maturation antigen (BCMA) on a target cell or tissue, and a second binding region of the molecule that specifically binds to the T-cell antigen CD3. This dual / multiple target binding ability recruits T cells to the target cell or tissue, resulting in eradication of the target cell or tissue.

[0068] "Therapeutically effective amount" refers to an amount effective to obtain the desired therapeutic result at the dosage and duration required. The therapeutically effective amount may vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic agent or combination of therapeutic agents include, for example, improved health of the patient.

[0069] "Treating" or "treatment" refers to both therapeutic treatment and prophylactic or preventative measures, in which the subject is to prevent or reduce (lessen) an undesirable physiological change or disease. Beneficial or desired clinical results include alleviation of symptoms, reduction in the extent of disease, a stable (i.e., not worsening) disease state, whether detectable or undetectable, a delay or slowing of disease progression, an improvement or palliation of a disease state, and remission (whether partial or total). "Treatment" can also mean prolonging the survival of a subject compared to expected survival if the subject were not receiving treatment. Those in need of treatment include those already with a condition or disease, as well as those prone to having a condition or disease, or those in whom the condition or disease is to be prevented.

[0070] "Tumor cells" or "cancer cells" refer to cancerous, precancerous, or transformed cells that have spontaneous or induced phenotypic changes, either in vivo, ex vivo, or in tissue culture. These changes do not necessarily involve the incorporation of new genetic material. Transformation can occur by infection with a transforming virus and incorporation of new genomic nucleic acid, incorporation of exogenous nucleic acid, or can occur spontaneously or after exposure to a carcinogen, which mutates endogenous genes. Transformation / cancer is exemplified by morphological changes, cellular immortalization, aberrant growth control, formation of lesions, proliferation, malignant lesions, modulation of tumor-specific marker levels, invasiveness, tumor growth in suitable animal hosts, such as nude mice, in vitro, in vivo, and ex vivo.

[0071] Throughout this specification, the numbering of amino acid residues in antibody constant regions is according to the EU index as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise expressly stated herein. The numbering of antibody constant chains can be found, for example, in the IMGT Web resource, IMGT Scientific charts, on the ImMunoGeneTics website.

[0072] Substitutions in the CH3 region are expressed as modified position(s) in the first CH3 domain of the first heavy chain / modified position(s) in the second CH3 domain of the second heavy chain. For example, F405L / K409R refers to an F405L mutation in the first CH3 region and a K09R mutation in the second CH3 region. L351Y_F405A_Y407V / T394W refers to an L351Y, F40FA, and Y407V mutation in the first CH3 region and a T394W mutation in the second CH3 region. D399FHKRQ / K409AGRH refers to a mutation in which D399 can be replaced by F, H, KR, or Q, and K409 can be replaced by A, G, R, or H.

[0073] The conventional two-letter and three-letter amino acid codes are used herein as shown in Table 1.

[0074] [Table 2]

[0075] "Pomalidomide", also known as "POMALYST®", refers to an analog of thalidomide, which is a third-generation IMiD (immunomodulatory drug) with antitumor activity. IMiDs such as lenalidomide and pomalidomide form the mainstay of several current multiple myeloma treatment regimens. Although their exact mechanism of action is not fully understood, IMiDs can have immunomodulatory effects on the multiple myeloma tumor microenvironment, affect the expression of tumor suppressor genes, promote apoptosis of myeloma cells, and enhance NK-mediated myeloma cell lysis. The combination of daratumumab with IMiDs has been evaluated in multiple trials and demonstrated significant improvements in efficacy.

[0076] The dosing frequency provided herein is understood to be synonymous with standard terms in the art. For example, "weekly" dosing is understood to be synonymous with "QW". For example, "biweekly" dosing is understood to be synonymous with "Q2W". For example, "once every 4 weeks" is understood to be synonymous with "Q4W". Unless expressly stated to the contrary, "once every 4 weeks" and "monthly" are used interchangeably in the context of dosing frequency. Thus, "monthly" or "once a month" is also understood to be synonymous with "Q4W" unless expressly stated otherwise.

[0077] In one general aspect, the application relates to a method of treating cancer, such as MM, preferably refractory or relapsed MM, comprising administering to a subject a BCMAxCD3 bispecific antibody at a dose of 100 μg / kg to 6 mg / kg or a fixed dose of 60 mg to 600 mg every 1 to 4 weeks, and administering to a subject an anti-CD38 antibody at a dose of 1200 mg to 2400 mg subcutaneously every 1 to 4 weeks.

[0078] The disclosure also provides a method of killing tumor cells in a subject in need thereof, comprising administering a BCMAxCD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or a fixed dose of 60 mg to 600 mg to the subject every 1 to 4 weeks and administering an anti-CD38 antibody at a dose of 1200 mg to 2400 mg subcutaneously to the subject every 1 to 4 weeks, thereby killing the tumor cells in the subject.

[0079] The disclosure further provides a method of enhancing the activity of at least one of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody in a subject in need thereof, comprising administering a BCMAxCD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or a fixed dose of 60 mg to 600 mg to the subject every 1 to 4 weeks, and administering an anti-CD38 antibody at a dose of 1200 mg to 2400 mg subcutaneously to the subject every 1 to 4 weeks, thereby killing the tumor in the subject.

[0080] In some embodiments, the anti-CD38 antibody is administered prior to administration of the BCMAxCD3 bispecific antibody. For example, the anti-CD38 antibody is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 hours prior to administration of the BCMAxCD3 bispecific antibody. In a specific embodiment, the anti-CD38 antibody and the BCMAxCD3 bispecific antibody are administered on the same day, and the anti-CD38 antibody is administered about 3 hours prior to subcutaneous administration of the BCMAxCD3 bispecific antibody.

[0081] In some embodiments, the BCMAxCD3 bispecific antibody is administered weekly, every other week, or every four weeks. In some embodiments, the BCMAxCD3 bispecific antibody is administered weekly. In some embodiments, the BCMAxCD3 bispecific antibody is administered every other week. In some embodiments, the BCMAxCD3 bispecific antibody is administered once every four weeks.

[0082] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are each administered to a subject with cancer, e.g., multiple myeloma, in an amount sufficient to alleviate or at least partially halt the disease being treated (a "therapeutically effective amount").

[0083] In some embodiments, the BCMAxCD3 bispecific antibody is administered at a dose of 100μg / kg to 6mg / kg, or a fixed dose of 60mg to 600mg, weekly, biweekly, monthly, or any frequency in between. For example, the BCMAxCD3 bispecific antibody may be administered intravenously at a dose of 100μg / kg, 150μg / kg, 200μg / kg, 250μg / kg, 300μg / kg, 350μg / kg, 400μg / kg, 500μg / kg, 550μg / kg, 600μg / kg, 650μg / kg, 700μg / kg, 750μg / kg, 800μg / kg, 850μg / kg, 900μg / kg, or 950μg / kg, or any value in between, and administration may be weekly, biweekly, or any frequency in between. BCMAxCD3 bispecific antibodies were administered at the following doses: 1000μg / kg, 1100μg / kg, 1200μg / kg, 1300μg / kg, 1400μg / kg, 1500μg / kg, 1600μg / kg, 1700μg / kg, 1800μg / kg, 1900μg / kg, 2000μg / kg, 2100μg / kg, 2200μg / kg kg, 2300μg / kg, 2400μg / kg, 2500μg / kg, 2600μg / kg, 2700μg / kg, 2800μg / kg, 2900μg / kg , 3000μg / kg, 3100μg / kg, 3200μg / kg, 3300μg / kg, 3400μg / kg, 3500μg / kg, 3600μg / kg, 3 The compound may be administered intravenously at a dose of 700 μg / kg, 3800 μg / kg, 3900 μg / kg, 4000 μg / kg, 4100 μg / kg, 4200 μg / kg, 4300 μg / kg, 4400 μg / kg, 4500 μg / kg, 4600 μg / kg, 4700 μg / kg, 4800 μg / kg, 4900 μg / kg, 5000 μg / kg, 5100 μg / kg, 5200 μg / kg, 5300 μg / kg, 5400 μg / kg, 5500 μg / kg, 5600 μg / kg, 5700 μg / kg, 5800 μg / kg, 5900 μg / kg, 6000 μg / kg, or any value in between, and administration may be weekly, biweekly, or any frequency in between.The BCMAxCD3 bispecific antibody may further be administered subcutaneously at a fixed dose of 60 mg, 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, 450 mg, 500 mg, 600 mg, or any value in between, and administration may be weekly, biweekly, monthly, or any frequency in between.

[0084] In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously weekly at a dose of 1500 μg / kg.

[0085] In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously every week or every other week at a dose of 3000 μg / kg.

[0086] In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of about 6 mg / kg, for example, once every four weeks.

[0087] In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 600 μg / kg, for example, once every four weeks.

[0088] In some embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously at a dose of 300 μg / kg every other week.

[0089] In some embodiments, the fixed dose of the BCMAxCD3 bispecific antibody is determined by the subject's weight, such that subjects below a certain weight threshold are administered a certain fixed dose of the BCMAxCD3 bispecific antibody and subjects above a certain weight threshold are administered another certain fixed dose of the BCMAxCD3 bispecific antibody, in some embodiments the weight threshold is 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, over 70 kg, or any value in between.

[0090] In some embodiments, the subject has a body weight below a body weight threshold selected from 50kg, 55kg, 60kg, 65kg, or 70kg and is administered a fixed dose of 60mg, 100mg, 150mg, 200mg, 300mg, 400mg, 450mg, 500mg, 600mg, or any value in between, subcutaneously, which may be weekly, biweekly, monthly, or any frequency in between. In some embodiments, the subject has a body weight above a body weight threshold selected from 50kg, 55kg, 60kg, 65kg, or 70kg and is administered a fixed dose of 60mg, 100mg, 150mg, 200mg, 300mg, 400mg, 450mg, 500mg, 600mg, or any value in between, subcutaneously, which may be weekly, biweekly, monthly, or any frequency in between. In some embodiments, subjects with a weight below the weight threshold and subjects with a weight above the weight threshold are administered the same fixed dose of a BCMAxCD3 bispecific antibody, in some embodiments subjects with a weight below the weight threshold and subjects with a weight above the weight threshold are administered different fixed doses of a BCMAxCD3 bispecific antibody.

[0091] In some embodiments, the anti-CD38 antibody is administered subcutaneously at a dose of about 8 mg / kg to about 16 mg / kg every 1 to 4 weeks. For example, the anti-CD38 antibody may be administered subcutaneously at a dose of 8 mg / kg, 8.5 mg / kg, 9 mg / kg, 9.5 mg / kg, 10 mg / kg, 10.5 mg / kg, 11 mg / kg, 11.5 mg / kg, 12 mg / kg, 12.5 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg, 16 mg / kg, or any value therebetween, and administration may be once a week, once every two weeks, once every three weeks, or once every four weeks, or any frequency therebetween.

[0092] In some embodiments, the anti-CD38 antibody is administered subcutaneously at a fixed dose of 1200-2400 mg every 1-4 weeks. For example, the anti-CD38 antibody may be administered subcutaneously at a dose of 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, or any value in between, and administration may be once a week, once every two weeks, once every three weeks, or once every four weeks, or any frequency in between. In some embodiments, the anti-CD38 antibody is administered subcutaneously at a dose range of 1600-2000 mg every 1-4 weeks. For example, the anti-CD38 antibody may be administered subcutaneously at a dose of 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, or any value in between, and administration may be once a week, once every two weeks, once every three weeks, or once every four weeks, or any frequency in between.

[0093] In some embodiments, the anti-CD38 antibody is administered subcutaneously at a dose of 1800 mg every week, every other week, every two weeks, or every four weeks.

[0094] Incremental doses of the BCMAxCD3 bispecific antibody may be administered in the first cycle. One or more incremental doses of the BCMAxCD3 bispecific antibody at lower dosages may be administered to the subject prior to the initial administration of the dosage levels for weekly or biweekly treatment according to embodiments of the present application. In certain embodiments, the methods according to the present application further comprise subcutaneously administering to the subject 0.01-0.10 mg / kg, for example 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, and 0.10 mg / kg of the BCMAxCD3 bispecific antibody on the first or second day of treatment, preferably on the second day of treatment after the first administration of the anti-CD38 antibody on day 1. In other embodiments, the methods according to the present application further comprise administering to the subject subcutaneously 0.10 to 0.50 mg / kg, such as 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45 or 0.50 mg / kg, or any value therebetween, of a BCMAxCD3 bispecific antibody on the 3rd, 4th or 5th day of treatment, preferably on day 4, prior to the first subcutaneous administration of the BCMAxCD3 bispecific antibody at a dose for weekly or biweekly administration.

[0095] In certain embodiments, the methods according to the present application further comprise administering subcutaneously to the subject a fixed dose of 1-10 mg, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg, of a BCMAxCD3 bispecific antibody on day 1 or day 2 of treatment, preferably on day 2 of treatment following an initial administration of an anti-CD38 antibody on day 1. In other embodiments, the methods according to the present application further comprise administering subcutaneously to the subject a fixed dose of 10-50 mg, such as 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg, or any value therebetween, of a BCMAxCD3 bispecific antibody on day 3, 4, or 5, preferably on day 4, of the BCMAxCD3 bispecific antibody, prior to the initial subcutaneous administration of a fixed dose for weekly or biweekly administration.

[0096] In some embodiments, the fixed dose of the BCMAxCD3 bispecific antibody is determined by the subject's weight, such that subjects below a certain weight threshold are administered a certain fixed dose of the BCMAxCD3 bispecific antibody and subjects above a certain weight threshold are administered another certain fixed dose of the BCMAxCD3 bispecific antibody, in some embodiments the weight threshold is 50 kg, 55 kg, 60 kg, 65 kg, 70 kg, over 70 kg, or any value in between.

[0097] In some embodiments, the subject has a body weight at or below a body weight threshold selected from 50 kg, 55 kg, 60 kg, 65 kg, or 70 kg, and is administered a fixed dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of BCMAxCD3 bispecific antibody subcutaneously on day 1 or day 2 of treatment, preferably on day 2 of treatment after the first administration of anti-CD38 antibody on day 1. In some embodiments, the subject has a body weight above a body weight threshold selected from 50 kg, 55 kg, 60 kg, 65 kg, or 70 kg, and is administered a fixed dose of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg of BCMAxCD3 bispecific antibody subcutaneously on day 1 or day 2 of treatment, preferably on day 2 of treatment after the first administration of anti-CD38 antibody on day 1. In some embodiments, subjects with a body weight at or below the body weight threshold and subjects with a body weight above the body weight threshold are administered the same fixed dose of BCMAxCD3 bispecific antibody. In some embodiments, subjects with a weight below the weight threshold and subjects with a weight above the weight threshold are administered different fixed doses of the BCMAxCD3 bispecific antibody.

[0098] In some embodiments, the subject has a body weight at or below a body weight threshold selected from 50 kg, 55 kg, 60 kg, 65 kg, or 70 kg, and is administered a fixed dose of 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg, or any value therebetween, of the BCMAxCD3 bispecific antibody subcutaneously on the 3rd, 4th, or 5th day of treatment, preferably on day 4, prior to the first subcutaneous administration of the BCMAxCD3 bispecific antibody at a dose for weekly or biweekly administration. In some embodiments, the subject has a body weight above a body weight threshold selected from 50 kg, 55 kg, 60 kg, 65 kg, or 70 kg, and is administered a fixed dose of 10, 15, 20, 25, 30, 35, 40, 45 or 50 mg, or any value therebetween, of BCMAxCD3 bispecific antibody subcutaneously on the 3rd, 4th, or 5th day of treatment, preferably on day 4, prior to the first subcutaneous administration of a dose of BCMAxCD3 bispecific antibody for weekly or biweekly administration. In some embodiments, subjects with a body weight below the body weight threshold and subjects with a body weight above the body weight threshold are administered the same fixed dose of BCMAxCD3 bispecific antibody. In some embodiments, subjects with a body weight below the body weight threshold and subjects with a body weight above the body weight threshold are administered different fixed doses of BCMAxCD3 bispecific antibody.

[0099] In certain embodiments, the methods of the present application further comprise administering to the subject subcutaneously 0.06 mg / kg of the BCMAxCD3 bispecific antibody on day 2 of treatment and 0.3 mg / kg of the BCMAxCD3 bispecific antibody on day 4 of treatment prior to the first weekly or biweekly subcutaneous administration of 1.5 mg / kg of the BCMAxCD3 bispecific antibody.

[0100] In certain embodiments, the method comprises administering 3 mg / kg of a BCMAxCD3 bispecific antibody subcutaneously to a subject every two weeks.

[0101] In certain embodiments, the methods of the present application comprise administering 1.5 mg / kg of BCMAxCD3 bispecific antibody subcutaneously to the subject once per week for 8 weeks (2 cycles), followed by 3.0 mg / kg of BCMAxCD3 bispecific antibody subcutaneously to the subject once every 2 weeks for 4 weeks (1 cycle), and 1800 mg of anti-CD38 antibody subcutaneously to the subject once per week during weeks 1-8 of treatment, once every 2 weeks during weeks 9-24 of treatment, and once every 4 weeks from week 24 of treatment onwards. In certain embodiments, the methods comprise administering 3 mg / kg of BCMAxCD3 bispecific antibody every other week on day 1 of the next scheduled 28 day cycle after completion of 3 cycles.

[0102] The BCMAxCD3 bispecific antibody and the anti-CD38 antibody may be administered in 28-day cycles, and the treatment may include multiple cycles, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles. In certain embodiments, the BCMAxCD3 bispecific antibody and / or the anti-CD38 antibody are administered continuously in cycles, unless the subject experiences progressive disease (PD). Repeated courses of treatment are also possible, as is administration over time. Repeated administration may be at the same dose or at different doses. For example, the BCMAxCD3 bispecific antibody may be administered subcutaneously at 1500 μg / kg or 3000 μg / kg every week for 8 weeks, followed by a further period of biweekly administration at 1500 μg / kg or 3000 μg / kg every other week for a further period. In another example, the BCMAxCD3 bispecific antibody may be administered subcutaneously at 3000 μg / kg or 300 μg / kg every other week for 8 weeks, followed by a further period of biweekly administration at the same dose or at a different dose. In another example, the BCMAxCD3 bispecific antibody may be administered subcutaneously at 3000 μg / kg or 6000 μg / kg every other week or every month for 8 weeks. In other embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously at 60 mg, 150 mg, or 200 mg, preferably 150 mg, every week for 8 weeks, followed by 300 mg of BCMAxCD3 bispecific antibody administered subcutaneously every other week. In other embodiments, the BCMAxCD3 bispecific antibody is administered subcutaneously at 1500 μg / kg every week for 8 weeks, followed by 3000 μg / kg of BCMAxCD3 bispecific antibody administered subcutaneously every other week.

[0103] According to embodiments of the present application, the frequency of administration of the anti-CD38 antibody may decrease over time of treatment. For example, the anti-CD38 antibody is administered subcutaneously to a subject at a dose of 1800 mg once per week during weeks 1-8 of treatment, once every two weeks during weeks 9-24 of treatment, and once every four weeks after week 24 of treatment.

[0104] The BCMAxCD3 bispecific antibody and anti-CD38 antibody may be administered by maintenance therapy, for example, once per week, once every two weeks, once every three weeks, or once every four weeks for a period of six months or more.

[0105] BCMAxCD3 bispecific antibodies and anti-CD38 antibodies may also be administered in pre-cancerous settings to reduce the risk of developing cancers such as multiple myeloma, delay the onset of events in the progression of cancer, and / or reduce the risk of recurrence when the cancer goes into remission.

[0106] In some embodiments, the BCMAxCD3 bispecific antibody is administered to the subject after administration of an anti-CD38 antibody to the subject. The BCMAxCD3 bispecific antibody and the anti-CD38 antibody may be administered on the same day. The BCMAxCD3 bispecific antibody may be administered 1 day, 1 week, 2 weeks, 3 weeks, 1 month, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months or more after administration of the anti-CD38 antibody.

[0107] In some embodiments, the method further comprises administering to the subject one or more anti-cancer therapies.

[0108] In some embodiments, the one or more anti-cancer therapies are selected from the group consisting of autologous stem cell transplant (ASCT), radiation, surgery, chemotherapeutic agents, immunomodulatory agents, and targeted cancer therapies.

[0109] In some embodiments, the one or more anti-cancer therapies are autologous stem cell transplant (ASCT). In some embodiments, the one or more anti-cancer therapies are radiation. In some embodiments, the one or more anti-cancer therapies are surgery. In some embodiments, the one or more anti-cancer therapies are chemotherapeutic agents. In some embodiments, the one or more anti-cancer therapies are immunomodulatory agents. In some embodiments, the one or more anti-cancer therapies are targeted cancer therapies. In some embodiments, the one or more anti-cancer therapies are lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, isatuximab, CELMoDs, dexamethasone, vincristine, cyclophosphamide, hydroxydaunorubicin, prednisone, rituximab, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib , saracatinib, tozasertib or danusertib, cytarabine, daunorubicin, idarubicin, mitoxantrone, hydroxyurea, decitabine, cladribine, fludarabine, topotecan, etoposide 6-thioguanine, corticosteroids, methotrexate, 6-mercaptopurine, azacitidine, arsenic trioxide and all-trans retinoic acid, or any combination thereof.

[0110] In some embodiments, the one or more anticancer therapies are selected from the group consisting of lenalidomide, thalidomide, pomalidomide, bortezomib, carfilzomib, elotozumab, ixazomib, melphalan, prednisone, or dexamethasone, or any combination thereof.

[0111] In some embodiments, the one or more anticancer therapies is pomalidomide.

[0112] In some embodiments, pomalidomide is administered orally at a dose of 2 mg or 4 mg.

[0113] In some embodiments, the one or more anticancer therapies is pomalidomide and dexamethasone.

[0114] In some embodiments, pomalidomide is administered on a delayed dosing schedule, which may occur on cycle 1, day 15 (C1D15) or cycle 2, day 1 (C2D1).

[0115] In some embodiments, pomalidomide is administered simultaneously with the BCMAxCD3 bispecific antibody and the anti-CD38 antibody.

[0116] In some embodiments, dexamethasone is administered during at least three complete initial IMiD-containing cycles.

[0117] CD38 is a multifunctional protein that has functions in receptor-mediated adhesion and signal transduction, as well as mediating calcium mobilization through its ectoenzymatic activity and catalyzing the formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates cytokine secretion and lymphocyte activation and proliferation (Funaro et al., J Immunol 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38 also regulates extracellular NAD+ levels through its NAD glycohydrolase activity, which has been implicated in regulating the regulatory T cell compartment (Adriouch et al., Microbes infect 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to signaling via Ca2+, CD38 signaling occurs via crosstalk with antigen receptor complexes or other types of receptor complexes, such as major histocompatibility complex (MHC) molecules, on T and B cells, and thus CD38 is also involved in several cellular responses as well as IgG1 switching and secretion.

[0118] Any suitable anti-CD38 antibody may be used in the methods of the present invention.

[0119] In some embodiments, the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO:8, an HCDR2 of SEQ ID NO:9, an HCDR3 of SEQ ID NO:10, an LCDR1 of SEQ ID NO:11, an LCDR2 of SEQ ID NO:12, and an LCDR3 of SEQ ID NO:13.

[0120] The above CDRs are of the Kabat numbering system. However, as provided herein, the CDRs of the present disclosure may be provided by any suitable numbering system, such as the Kabat, Chothia, IMGT, or AbM numbering systems. Table 3 provides exemplary CDRs utilizing the Kabat, Chothia, IMGT, and AbM numbering systems.

[0121] [Table 3]

[0122] In some embodiments, the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO:8, an HCDR2 of SEQ ID NO:9, an HCDR3 of SEQ ID NO:10, an LCDR1 of SEQ ID NO:11, an LCDR2 of SEQ ID NO:12, and an LCDR3 of SEQ ID NO:13.

[0123] In some embodiments, the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO:46, an HCDR2 of SEQ ID NO:47, an HCDR3 of SEQ ID NO:10, an LCDR1 of SEQ ID NO:11, an LCDR2 of SEQ ID NO:12, and an LCDR3 of SEQ ID NO:13.

[0124] In some embodiments, the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO:48, an HCDR2 of SEQ ID NO:49, an HCDR3 of SEQ ID NO:10, an LCDR1 of SEQ ID NO:11, an LCDR2 of SEQ ID NO:12, and an LCDR3 of SEQ ID NO:13.

[0125] In some embodiments, the anti-CD38 antibody comprises an HCDR1 of SEQ ID NO:50, an HCDR2 of SEQ ID NO:51, an HCDR3 of SEQ ID NO:52, an LCDR1 of SEQ ID NO:53, an LCDR2 having the amino acid sequence DAS, and an LCDR3 of SEQ ID NO:13.

[0126] In some embodiments, the anti-CD38 antibody comprises a VH of SEQ ID NO:6 and a VL of SEQ ID NO:7.

[0127] In some embodiments, the anti-CD38 antibody comprises a HC of SEQ ID NO:12 and a LC of SEQ ID NO:13.

[0128] Other anti-CD38 antibodies used in the methods of the invention may be known antibodies, such as mAb003 described in US Patent No. 7,829,673. The VH and VL of mAb003 may be expressed as IgG1 / Kappa; mAb024 described in US Patent No. 7,829,673. The VH and VL of mAb024 may be expressed as IgG1 / Kappa; MOR-202 (MOR-03087) described in US Patent No. 8,088,896. The VH and VL of MOR-202 may be expressed as IgG1 / Kappa; or Isatuximab; described in US Patent No. 8,153,765. The VH and VL of Isatuximab may be expressed as IgG1 / Kappa. In some embodiments, the anti-CD38 antibody comprises a) a VH of SEQ ID NO: 38 and a VL of SEQ ID NO: 39, b) a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 41, c) a VH of SEQ ID NO: 42 and a VL of SEQ ID NO: 43, or d) a VH of SEQ ID NO: 44 and a VL of SEQ ID NO: 45.

[0129] In some embodiments, the anti-CD38 antibody is DARZALEX® (daratumumab).

[0130] In some embodiments, daratumumab comprises a VH of SEQ ID NO:6 and a VL of SEQ ID NO:7.

[0131] In some embodiments, daratumumab comprises a HC of SEQ ID NO:12 and a LC of SEQ ID NO:13.

[0132] In some embodiments, the anti-CD38 antibody is chimeric, humanized, or human.

[0133] In some embodiments, the anti-CD38 antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0134] In some embodiments, the anti-CD38 antibody is of the IgG1 isotype.

[0135] B-cell maturation antigen (BCMA) is a cell membrane-bound tumor necrosis factor receptor family member involved in the differentiation of B cells into plasma cells. BCMA expression is restricted to the B-cell lineage, where it is expressed primarily within the intrafollicular regions of germinal centers and on differentiated plasma cells and plasmablasts. BCMA is virtually absent on naive and memory B cells (Tai and Anderson, Immunotherapy 7:1187-99, 2015). BCMAxCD3 bispecific antibodies target the CD3 receptor complex on T cells and BCMA on plasma cells. The dual binding site allows BCMAxCD3 bispecific antibodies to attract CD3+ T cells into close proximity to myeloma cells, regardless of T receptor specificity or dependence on MHC class 1 molecules on the surface of antigen-presenting cells for activation, resulting in cell death of BCMA-positive cells.

[0136] Any suitable BCMAxCD3 bispecific antibody may be used in the methods of the present application. Exemplary multispecific and / or bispecific formats include dual targeting molecules, Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one antibodies (Genentech), and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), Ts2Ab (MedImmune / AZ), and BsAb (Zymogenetics), HERCULES (Biogen Idec), and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS), and Dual Affinity Retargeting Technology (DAT). Technology, Fc-DART (MacroGenics), F(ab)2 (Medarex / AMGEN), dual activity or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), bivalent bispecific (Biotecnol), and Fab-Fv (UCB-Celltech), bispecific T Cell Engager (BITE) (Micromet), Tandem Diabody (Tandab) (Affimed), dual affinity retargeting technology (DART) (MacroGenics), single chain diabodies (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusions (Merrimack), and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies. Various formats of bispecific antibodies are described, for example, in Chames and Baty (2009) Curr Opin Drug Disc Dev 12:276 and Nunez-Prado et al., (2015) Drug Discovery Today 20(5):588-594.

[0137] In some embodiments, the BCMAxCD3 bispecific antibody and the anti-CD38 antibody are antigen-binding fragments. Exemplary antigen-binding fragments are Fab, F(ab')2, Fd, and Fv fragments.

[0138] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized, or human.

[0139] In some embodiments the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH with HCDR1 of SEQ ID NO: 18, HCDR2 of SEQ ID NO: 19, HCDR3 of SEQ ID NO: 20 and a VL with LCDR1 of SEQ ID NO: 21, LCDR2 of SEQ ID NO: 22 and LCDR3 of SEQ ID NO: 23, and a CD3 binding domain comprising a VH with HCDR1 of SEQ ID NO: 28, HCDR2 of SEQ ID NO: 29, HCDR3 of SEQ ID NO: 30 and a VL with LCDR1 of SEQ ID NO: 31, LCDR2 of SEQ ID NO: 32 and LCDR3 of SEQ ID NO: 33. The HCDRs and LCDRs of the BCMAxCD3 bispecific antibodies are listed in Table 4 below.

[0140] [Table 4]

[0141] The CDRs listed in the above table are of the Kabat numbering system. However, as provided herein, the CDRs of the present disclosure may be provided by any suitable numbering system, such as the Kabat, Chothia, IMGT, or AbM numbering systems. Tables 5-7 below provide exemplary CDRs utilizing the Chothia, AbM, and IMGT numbering systems.

[0142] [Table 5]

[0143] [Table 6]

[0144] [Table 7]

[0145] In some embodiments the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH with an HCDR1 of SEQ ID NO: 18, an HCDR2 of SEQ ID NO: 19, an HCDR3 of SEQ ID NO: 20 and a VL with an LCDR1 of SEQ ID NO: 21, an LCDR2 of SEQ ID NO: 22, and an LCDR3 of SEQ ID NO: 23, and a CD3 binding domain comprising a VH with an HCDR1 of SEQ ID NO: 28, an HCDR2 of SEQ ID NO: 29, an HCDR3 of SEQ ID NO: 30 and a VL with an LCDR1 of SEQ ID NO: 31, an LCDR2 of SEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 33.

[0146] In some embodiments the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH with an HCDR1 of SEQ ID NO: 54, an HCDR2 of SEQ ID NO: 55, an HCDR3 of SEQ ID NO: 20 and a VL with an LCDR1 of SEQ ID NO: 21, an LCDR2 of SEQ ID NO: 22, and an LCDR3 of SEQ ID NO: 23, and a CD3 binding domain comprising a VH with an HCDR1 of SEQ ID NO: 56, an HCDR2 of SEQ ID NO: 57, an HCDR3 of SEQ ID NO: 30 and a VL with an LCDR1 of SEQ ID NO: 31, an LCDR2 of SEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 33.

[0147] In some embodiments the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH with an HCDR1 of SEQ ID NO: 58, an HCDR2 of SEQ ID NO: 59, an HCDR3 of SEQ ID NO: 20 and a VL with an LCDR1 of SEQ ID NO: 21, an LCDR2 of SEQ ID NO: 22, and an LCDR3 of SEQ ID NO: 23, and a CD3 binding domain comprising a VH with an HCDR1 of SEQ ID NO: 60, an HCDR2 of SEQ ID NO: 61, an HCDR3 of SEQ ID NO: 30 and a VL with an LCDR1 of SEQ ID NO: 31, an LCDR2 of SEQ ID NO: 32, and an LCDR3 of SEQ ID NO: 33.

[0148] In some embodiments the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH with an HCDR1 of SEQ ID NO: 62, an HCDR2 of SEQ ID NO: 63, an HCDR3 of SEQ ID NO: 64, a VL with an LCDR1 of SEQ ID NO: 65, an LCDR2 with the amino acid sequence DDS, and an LCDR3 of SEQ ID NO: 23, and a CD3 binding domain comprising a VH with an HCDR1 of SEQ ID NO: 66, an HCDR2 of SEQ ID NO: 67, an HCDR3 of SEQ ID NO: 68, an LCDR1 of SEQ ID NO: 69, an LCDR2 with the amino acid sequence GTN, and a LCDR3 of SEQ ID NO: 33.

[0149] In some embodiments the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH of SEQ ID NO:24 and a VL of SEQ ID NO:25, and a CD3 binding domain comprising a VH of SEQ ID NO:34 and a VL of SEQ ID NO:35.

[0150] In some embodiments, a BCMAxCD3 bispecific antibody that binds BCMA comprises a first heavy chain (HC1) of SEQ ID NO: 26, a first light chain (LC1) of SEQ ID NO: 27, a second heavy chain (HC2) of SEQ ID NO: 36, and a second light chain (LC2) of SEQ ID NO: 37.

[0151] In some embodiments, the BCMA binding arm of the BCMAxCD3 bispecific antibody and the CD3 binding arm of the BCMAxCD3 bispecific antibody comprise the amino acid sequences provided in Tables 8a and 8b.

[0152] [Table 8]

[0153] [Table 9]

[0154] In some embodiments, the BCMAxCD3 bispecific antibody is selected from the group consisting of the BCMA binding domain of ACTR cancer therapy by Seattle Genetics, AFM-26, ALLO-715, anti-BCMA allogeneic CAR-T cancer therapy by CRISPR Therapeutics, anti-BCMA CAR-T by Sorrento Therapeutics, anti-CD19 / BCMA CAR-T cancer therapy by Hrain Biotechnology, BCMA CAR-T therapy by Chineo Med (Beijing), BCMA TAC-T cancer therapy by Triumvira Immunologics, BCMA-CAR by Shanghai Universitas Therapeutics, T cancer therapy, BCMA / CD3 antibody by Regeneron, CAR-NK cancer therapy by NantKwest, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb-2121, AUTO-2, BCMA chimeric antigen receptor therapy by Pregene, BCMA-CAR T cells by Shanghai Bioray Laboratory, BCMA-CAR-T cells by CARsgen Therapeutics, CAR-T / TCR-T cell immunotherapy by Shenzhen BinDeBio, ET-140, P-BCMA-101, REGN-5458, AMG-701, anti-BCMA by Cellular Biomedicine Group The CAR-T cancer therapy comprises a BCMA binding domain that binds to BCMA selected from the group consisting of bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228, or PF-06863135.

[0155] In some embodiments, the BCMAxCD3 bispecific antibody may be, but is not limited to, erlanatamab (aka PF-06863135), teneobio (aka TNB-383B), REGN5458, REGN5459, pavlutamab (aka AMG-701), BI 836909, CC-93269, WVT078, or teclistamab (aka JNJ-957 or JNJ-64007957).

[0156] In some embodiments, teclistamab comprises a first heavy chain (HC1), a first light chain (LC1), a second heavy chain (HC2), and a second light chain (LC2), where HC1 associates with LC1, HC2 associates with LC2, and HC1 and LC1 form a first antigen-binding site that immunospecifically binds to BCMA, and HC2 and LC2 form a second antigen-binding site that immunospecifically binds to CD3. In some embodiments, teclistamab comprises an HC1 of SEQ ID NO:26, an LC1 of SEQ ID NO:27, an HC2 of SEQ ID NO:36, and an LC2 of SEQ ID NO:37. In some embodiments, the BCMA arm and the CD3 arm of teclistamab form a functional bispecific antibody through interactions between their respective Fc domains.

[0157] In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the CD3 binding domains described in WO2017 / 031104.

[0158] In some embodiments, the BCMAxCD3 bispecific antibody is of the IgG1, IgG2, IgG3, or IgG4 isotype.

[0159] In some embodiments, the BCMAxCD3 bispecific antibody is of the IgG1 isotype.

[0160] In some embodiments, the BCMAxCD3 bispecific antibody is of the IgG2 isotype.

[0161] In some embodiments, the BCMAxCD3 bispecific antibody is of the IgG3 isotype.

[0162] In some embodiments, the BCMAxCD3 bispecific antibody is of the IgG4 isotype.

[0163] The BCMAxCD3 bispecific antibody can be of any allotype. The allotype is not expected to affect the properties of the BCMAxCD3 bispecific antibody, such as binding or Fc-mediated effector functions. The immunogenicity of therapeutic antibodies is associated with a high risk of infusion reactions and a shorter duration of therapeutic response (Baert et al., (2003) N Engl J Med 348:602-08). The extent to which a therapeutic antibody induces an immune response in the host may be determined in part by the antibody allotype (Stickler et al., (2011) Genes and Immunity 12:213-21). The antibody allotype is related to the amino acid sequence variation at a specific position in the antibody constant region sequence. Table 9 shows selected IgG1, IgG2, and IgG4 allotypes.

[0164] [Table 10]

[0165] In some embodiments, the multispecific antibody comprises one or more Fc substitutions that reduce binding of the multispecific antibody to Fcγ receptors (FcγR). Substitutions that reduce binding of the multispecific antibody to FcγR reduce Fc effector functions such as ADCC, ADCP, and / or CDC of the multispecific antibody. Particular substitutions can be made relative to the wild type IgG1 of SEQ ID NO: 16 or the wild type IgG4 of SEQ ID NO: 17.

[0166] In some embodiments, the one or more Fc substitutions are F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E on IgG1. / L358M, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236deletion / G237A / P238S on IgG4, where the numbering of residues is according to the EU index.

[0167] In some embodiments, the one or more Fc substitutions is F234A / L235A on IgG4.

[0168] In some embodiments, the one or more Fc substitutions is L234A / L235A on IgG1.

[0169] In some embodiments, the one or more Fc substitutions are V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2.

[0170] In some embodiments, the one or more Fc substitutions is F234A / L235A on IgG4.

[0171] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A on IgG4.

[0172] In some embodiments, the one or more Fc substitutions is N297A on all Ig isotypes.

[0173] In some embodiments, the one or more Fc substitutions is V234A / G237A on IgG2.

[0174] In some embodiments, the one or more Fc substitutions are K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M on IgG1.

[0175] In some embodiments, the one or more Fc substitutions are H268Q / V309L / A330S / P331S on IgG2.

[0176] In some embodiments, the one or more Fc substitutions are S267E / L328F on IgG1. In some embodiments, the one or more Fc substitutions are L234F / L235E / D265A on IgG1.

[0177] In some embodiments, the one or more Fc substitutions are L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1.

[0178] In some embodiments, the one or more Fc substitutions are S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4.

[0179] In some embodiments, the multispecific antibody further comprises a S228P substitution.

[0180] In some embodiments, the multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0181] In some embodiments, the one or more asymmetric substitutions are F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T3 66I_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0182] In some embodiments, the one or more asymmetric substitutions are F450L / K409R. In some embodiments, the one or more asymmetric substitutions are wild type / F409L_R409K. In some embodiments, the one or more asymmetric substitutions are T366Y / F405A. In some embodiments, the one or more asymmetric substitutions are T366W / F405W. In some embodiments, the one or more asymmetric substitutions are F405W / Y407A. In some embodiments, the one or more asymmetric substitutions are T394W / Y407T. In some embodiments, the one or more asymmetric substitutions are T394S / Y407A. In some embodiments, the one or more asymmetric substitutions are T366W / T394S. In some embodiments, the one or more asymmetric substitutions are F405W / T394S. In some embodiments, the one or more asymmetric substitutions are T366W / T366S_L368A_Y407V. In some embodiments, the one or more asymmetric substitutions are L351Y_F405A_Y407V / T394W. In some embodiments, the one or more asymmetric substitutions are T366I_K392M_T394W / F405A_Y407V. In some embodiments, the one or more asymmetric substitutions are T366L_K392M_T394W / F405A_Y407V. In some embodiments, the one or more asymmetric substitutions are L351Y_Y407A / T366A_K409F. In some embodiments, the one or more asymmetric substitutions are L351Y_Y407A / T366V_K409F. In some embodiments, the one or more asymmetric substitutions are Y407A / T366A_K409F. In some embodiments, the one or more asymmetric substitutions are T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0183] In some embodiments the BCMAxCD3 bispecific antibody is of IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 of the first heavy chain (HC1), and a leucine at position 405 and a lysine at position 409 of the second heavy chain (HC2), where the numbering of the residues is according to the EU index.

[0184] In some embodiments, the BCMAxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0185] In some embodiments, the cancer is a hematological malignancy or a solid tumor.

[0186] In some embodiments, the hematological malignancy is selected from the group consisting of multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), Waldenstrom's hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic leukemia, myelodysplastic syndrome (MS ... and malignant lymphomas such as myeloid leukemia (CML), erythroblastic lymphoid tumors (ALT), leukemia, myelogenous leukemia (MDS), chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasms, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphatic tissue (MALT), plasma cell leukemia, anaplastic large-cell lymphoma (ALCL), leukemia, or lymphoma.

[0187] In some embodiments, the hematological malignancy is multiple myeloma. In some embodiments, the multiple myeloma is newly diagnosed multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM).

[0188] In some embodiments, the multiple myeloma is high-risk multiple myeloma. Subjects with high-risk multiple myeloma are known to relapse early and have poor prognosis and outcome. Subjects can be classified as having high-risk multiple myeloma if they have one or more of the following cytogenetic abnormalities: t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p, or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p.

[0189] In some embodiments, subjects with high-risk multiple myeloma may have one or more chromosomal abnormalities including t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof.

[0190] A variety of qualitative and / or quantitative methods can be used to determine recurrence or refractory nature of the disease. Possible associated symptoms are, for example, a decline or plateau in the patient's health, recurrence or worsening of various symptoms associated with solid tumors, and / or metastasis of cancerous cells from one location to other organs, tissues, or cells within the body.

[0191] Cytogenetic abnormalities can be detected, for example, by fluorescent in situ hybridization (FISH). In chromosomal translocations, oncogenes are translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. t(4;14)(p16;q32) involves translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain-containing protein (MMSET) (also known as WHSC1 / NSD2), and t(14;16)(q32;q23) involves translocation of MAF transcription factor C-MAF. 17p deletion (del17p) involves loss of the p53 locus.

[0192] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof.

[0193] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with lenalidomide. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with bortezomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with pomalidomide. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with carfilzomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with elotuzumab. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with ixazomib. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with melphalan. In some embodiments, the multiple myeloma is relapsed or refractory to treatment with thalidomide.

[0194] In some embodiments, the hematological malignancy is AML.

[0195] In some embodiments, the AML is an AML with at least one genetic abnormality. In some embodiments, the AML is an AML with multilineage dysplasia. In some embodiments, the AML is therapy-related AML. In some embodiments, the AML is an undifferentiated AML. In some embodiments, the AML is an AML with minimal maturation. In some embodiments, the AML is a mature AML. In some embodiments, the AML is an acute myelomonocytic leukemia. In some embodiments, the AML is an acute monocytic leukemia. In some embodiments, the AML is an acute erythroleukemia. In some embodiments, the AML is an acute megakaryoblastic leukemia. In some embodiments, the AML is an acute basophilic leukemia. In some embodiments, the AML is an acute panmyelosis with fibrosis. In some embodiments, the AML is a myeloid sarcoma.

[0196] In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 8 and 21, a translocation or inversion of chromosome 16, a translocation between chromosomes 15 and 17, an alteration of chromosome 11, or an alteration of any of the following: fms-related tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), DNA (cytosine-5)-methyltransferase 3 (DNMT3A), CCAAT / enhancer binding protein alpha (CEBPA), U2 small nuclear RNA auxiliary factor 1 (U2 small nuclear RNA auxiliary factor 2 ... These include mutations in enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), structural maintenance of chromosomes 1A (SMC1A), or structural maintenance of chromosomes 3 (SMC3).

[0197] In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 8 and 21. In some embodiments, the at least one genetic abnormality is a translocation or inversion of chromosome 16. In some embodiments, the at least one genetic abnormality is a translocation between chromosomes 15 and 17. In some embodiments, the at least one genetic abnormality is an alteration in chromosome 11. In some embodiments, the at least one genetic abnormality is a mutation in fms-related tyrosine kinase 3 (FLT3). In some embodiments, the at least one genetic abnormality is a mutation in nucleophosmin (NPM1). In some embodiments, the at least one genetic abnormality is a mutation in isocitrate dehydrogenase 1 (IDH1). In some embodiments, the at least one genetic abnormality is a mutation in isocitrate dehydrogenase 2 (IDH2). In some embodiments, the at least one genetic abnormality is a mutation in DNA (cytosine-5)-methyltransferase 3 (DNMT3A). In some embodiments, the at least one genetic abnormality is a mutation in CCAAT / enhancer binding protein alpha (CEBPA). In some embodiments, the at least one genetic abnormality is a mutation in U2 small nuclear RNA auxiliary factor 1 (U2AF1). In some embodiments, the at least one genetic abnormality is a mutation in enhancer of polycomb repressive complex 2 subunit zeste2 (EZH2). In some embodiments, the at least one genetic abnormality is a mutation in structural maintenance of chromosome 1A (SMC1A). In some embodiments, the at least one genetic abnormality is a mutation in structural maintenance of chromosome 3 (SMC3).

[0198] 14. The method of claim 13, wherein in some embodiments, the at least one genetic abnormality is a translocation t(8;21)(q22;q22), an inversion inv(16)(p13;q22), a translocation t(16;16)(p13;q22), a translocation t(15;17)(q22;q12), a mutation in FLT3-ITD, a R132H or R100Q / R104V / F108L / R119Q / I130V mutation in IDH1, or a R140Q or R172 mutation in IDH2.

[0199] In some embodiments, the at least one genetic abnormality is a translocation t(8;21)(q22;q22). In some embodiments, the at least one genetic abnormality is an inversion inv(16)(p13;q22). In some embodiments, the at least one genetic abnormality is a translocation t(16;16)(p13;q22). In some embodiments, the at least one genetic abnormality is a translocation t(15;17)(q22;q12). In some embodiments, the at least one genetic abnormality is a mutation FLT3-ITD. In some embodiments, the at least one genetic abnormality is a mutation R132H in IDH1. In some embodiments, the at least one genetic abnormality is R100Q / R104V / F108L / R119Q / I130V in IDH1. In some embodiments, the at least one genetic abnormality is a mutation R140Q in IDH2. In some embodiments, the at least one genetic abnormality is a mutation R172 in IDH2.

[0200] In some embodiments, the hematological malignancy is ALL.

[0201] In some embodiments, the ALL is B-lineage ALL, T-lineage ALL, adult ALL, or childhood ALL.

[0202] In some embodiments, the ALL is B-lineage ALL. In some embodiments, the ALL is T-lineage ALL. In some embodiments, the ALL is adult ALL. In some embodiments, the ALL is childhood ALL.

[0203] In some embodiments, the subject with ALL has the Philadelphia chromosome or is resistant to or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0204] In some embodiments, the subject with ALL has the Philadelphia chromosome, hi some embodiments, the subject with ALL is resistant to or has acquired resistance to treatment with a BCR-ABL kinase inhibitor.

[0205] Ph chromosome is present in about 20% of adults with ALL and a small percentage of children with ALL, and is associated with poor prognosis. At relapse, patients with Ph+ positive ALL may be on a tyrosine kinase inhibitor (TKI) regimen and may therefore become resistant to TKI. Thus, anti-CD38 antibodies may be administered to subjects who have become resistant to selective or partially selective BCR-ABL inhibitors. Exemplary BCR-ABL inhibitors are, for example, imatinib, dasatinib, nilotinib, bosutinib, ponatinib, bafetinib, saracatinib, tozasertib, or danusertib.

[0206] Other chromosomal rearrangements identified in B-lineage ALL patients are t(v;11q23) (MLL rearrangement), t(1;19)(q23;p13.3);TCF3-PBX1 (E2A-PBX1), t(12;21)(p13;q22);ETV6-RUNX1 (TEL-AML1) and t(5;14)(q31;q32);IL3-IGH).

[0207] In some embodiments, the subject has ALL with t(v;11q23) (MLL rearrangement), t(1;19)(q23;p13.3);TCF3-PBX1 (E2A-PBX1), t(12;21)(p13;q22);ETV6-RUNX1 (TEL-AML1), or t(5;14)(q31;q32);IL3-IGH chromosomal rearrangement.

[0208] Chromosomal rearrangements can be identified using well-known methods, such as fluorescent in situ hybridization, karyotyping, pulsed-field gel electrophoresis, or sequencing.

[0209] In some embodiments, the hematological malignancy is smoldering multiple myeloma. In some embodiments, the hematological malignancy is MGUS. In some embodiments, the hematological malignancy is ALL. In some embodiments, the hematological malignancy is DLBLC. In some embodiments, the hematological malignancy is BL. In some embodiments, the hematological malignancy is FL. In some embodiments, the hematological malignancy is MCL. In some embodiments, the hematological malignancy is Waldenstrom's hypergammaglobulinemia. In some embodiments, the hematological malignancy is plasma cell leukemia. In some embodiments, the hematological malignancy is AL. In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia. In some embodiments, the hematological malignancy is precursor B-cell lymphoblastic leukemia. In some embodiments, the hematological malignancy is myelodysplastic syndrome (MDS). In some embodiments, the hematological malignancy is CLL. In some embodiments, the hematological malignancy is a B-cell malignancy. In some embodiments, the hematological malignancy is CML. In some embodiments, the hematological malignancy is HCL. In some embodiments, the hematological malignancy is blastic plasmacytoid dendritic cell neoplasm. In some embodiments, the hematological malignancy is Hodgkin's lymphoma. In some embodiments, the hematological malignancy is non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is MZL. In some embodiments, the hematological malignancy is MALT. In some embodiments, the hematological malignancy is plasma cell leukemia. In some embodiments, the hematological malignancy is ALCL. In some embodiments, the hematological malignancy is leukemia. In some embodiments, the hematological malignancy is lymphoma.

[0210] In one embodiment, the disclosure also provides a method of treating cancer in a subject, comprising administering a therapeutically effective amount of a BCMAxCD3 bispecific antibody to the subject to treat the cancer, wherein the subject has been treated with an anti-CD38 antibody prior to administration of the BCMAxCD3 bispecific antibody.

[0211] The disclosure also provides a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a BCMAxCD3 bispecific antibody to treat the cancer, wherein the subject is relapsed or refractory to treatment with a previous anti-cancer therapeutic agent.

[0212] In some embodiments, the subject administered a BCMAxCD3 antibody is resistant and / or refractory to treatment with an anti-CD38 antibody.

[0213] In some embodiments, the cancer is a BCMA-expressing cancer.

[0214] In some embodiments, the cancer is a hematological malignancy.

[0215] In some embodiments, the cancer is multiple myeloma, smoldering multiple myeloma, benign monoclonal gammopathy (MGUS), B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, Waldenstrom's hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis, or non-Hodgkin's lymphoma. An experienced physician will perform the cancer diagnosis.

[0216] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody or lenalidomide, or a combination thereof.

[0217] In some embodiments, the subject is relapsed or refractory to treatment with an anti-CD38 antibody, hi some embodiments, the subject is relapsed or refractory to treatment with lenalidomide.

[0218] In some embodiments, the subject is relapsed or refractory to treatment with a previous anti-cancer therapy, such as a therapeutic agent used to treat multiple myeloma or other hematological malignancies.

[0219] In some embodiments, the subject is refractory or relapsed to treatment with THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), elotuzumab (Empliciti®), SARCLISA® (isatuximab), or melphalan (Alkeran®).

[0220] In some embodiments, the subject is relapsed to treatment with DARZALEX® (daratumumab).

[0221] In some embodiments, the anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 20 mg / mL to about 120 mg / mL of anti-CD38 antibody in about 25 mM acetic acid, about 60 mM sodium chloride, about 140 mM mannitol, and about 0.04% w / v polysorbate-20 (PS-20) at a pH of about 5.5.

[0222] In some embodiments, the anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 1,800 mg of anti-CD38 antibody and about 30,000 U of rHuPH20.

[0223] In some embodiments, the anti-CD38 antibody is administered or provided for administration in a pharmaceutical composition comprising about 120 mg / mL of anti-CD38 antibody and about 2,000 U / mL of rHuPH20.

[0224] In some embodiments, the anti-CD38 antibody about 5 mM to about 15 mM histidine; About 100 mM to about 300 mM sorbitol; About 0.01% w / v to about 0.04% w / v of PS-20; It is administered or provided for administration in a pharmaceutical composition comprising about 1 mg / mL to about 2 mg / mL methionine and a pH of about 5.5 to 5.6.

[0225] In some embodiments, the anti-CD38 antibody Approximately 1,800 mg of anti-CD38 antibody, Approximately 30,000 U of rHuPH20, Approximately 10 mM histidine, About 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, and about 1 mg / mL methionine and a pH of about 5.6.

[0226] In some embodiments, the anti-CD38 antibody Approximately 120 mg / mL of anti-CD38 antibody; Approximately 2,000 U / mL of rHuPH20, Approximately 10 mM histidine, About 300 mM sorbitol; Approximately 0.04% (w / v) PS-20, The pharmaceutical composition comprises about 1 mg / mL methionine and has a pH of about 5.6.

[0227] The invention also provides a pharmaceutical composition comprising a BCMAxCD3 bispecific antibody as described herein and an anti-CD38 antibody. For example, the composition may comprise a BCMA binding domain comprising a VH of SEQ ID NO:24 and a VL of SEQ ID NO:25, a CD3 binding domain comprising a VH of SEQ ID NO:34 and a VL of SEQ ID NO:35, an anti-CD38 antibody comprising a VH of SEQ ID NO:6 and a VL of SEQ ID NO:7.

[0228] In some embodiments the pharmaceutical composition comprises a BCMAxCD3 bispecific antibody comprising an HC1 of SEQ ID NO: 26, an LC1 of SEQ ID NO: 27, an HC2 of SEQ ID NO: 36, an LC2 of SEQ ID NO: 37, and an anti-CD38 antibody comprising an HC of SEQ ID NO: 14 and an LC of SEQ ID NO: 15. In some embodiments the BCMAxCD3 bispecific antibody is of IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 in the first heavy chain (HC1) and a leucine at position 405 and a lysine at position 409 in the second heavy chain (HC2), the numbering of the residues being according to the EU index. In some embodiments the BCMAxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2.

[0229] The present disclosure also provides a kit or combination comprising a BCMAxCD3 bispecific antibody and an anti-CD38 antibody for use in the methods of the application.

[0230] Methods for generating antibodies for use in the methods of the invention Antibodies used in the methods of the invention that bind to a particular antigen may be selected de novo from, for example, a phage display library, where phage are engineered to express human immunoglobulins or portions thereof, such as Fabs, single chain antibodies (scFvs), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol 296:57-86, 2000; Krebs et al., J Immunol Meth 254:67-84, 2001; Vaughan et al., Nature Biotechnology 14:309-14, 1996; Sheets et al., PITAS(USA) 95:6157-62(1998); Hoogenboom and Winter, J Mol Biol 227:381, 1991; Marks et al., J Mol Biol 222:581, 1991). A phage display library expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein as described in Shi et al (2010) J. Mol. Biol. 397:385-96 and WO 2009 / 085462. The antibody library is screened for binding to a desired antigen such as BCMA, and the resulting positive clones may be further characterized and Fabs isolated from clonal lysates prior to cloning as full-length antibodies. Such phage display methods for isolating human antibodies are well established in the art. See, for example, U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, 5,427,908, 5,580,717, 5,969,108, 6,172,197, 5,885,793, 6,521,404, 6,544,731, 6,555,313, 6,582,915, and 6,593,081.

[0231] T cell redirecting bispecific antibodies may be generated by introducing asymmetric mutations in the CH3 regions of two monospecific homodimeric antibodies in a cell-free environment and forming a bispecific heterodimeric antibody from two parent monospecific homodimeric antibodies under reducing conditions that cause disulfide bonds to isomerize, according to the method described in WO 2011 / 131746. In this method, two monospecific bivalent antibodies are engineered to have specific substitutions in the CH3 domain that promote the stability of the heterodimer. These antibodies are incubated together under reducing conditions sufficient to cause the cysteines in the hinge region to isomerize the disulfide bonds, thereby generating the bispecific antibody by Fab arm exchange. The incubation conditions can be optimally returned to non-reducing conditions. Representative reducing agents that can be used are 2-mercaptoethylamine (2-MEA), dithiothreitol (DTT), dithioerythritol (DTE), glutathione, tris(2-carboxyethyl)phosphine (TCEP), L-cysteine, and β-mercaptoethanol, preferably a reducing agent selected from the group consisting of 2-mercaptoethylamine, dithiothreitol, and tris(2-carboxyethyl)phosphine. For example, a temperature of at least 20° C., in the presence of at least 25 mM 2-MEA or in the presence of at least 0.5 mM dithiothreitol, at a pH of 5 to 8, for example pH 7.0 or pH 7.4, and incubation for at least 90 minutes can be used.

[0232] Exemplary CH3 mutations that can be used in the first and second heavy chains of a bispecific antibody are K409R and / or F405L.

[0233] Additional CH3 mutations that may be used include techniques such as Duobody® mutations (Genmab), knob-in-hole mutations (Genentech), electrostatic match mutations (Chugai, Amgen, NovoNordisk, Oncomed), strand-exchange engineered domain bodies (SEED bodies) (EMD Serono), and other asymmetric mutations (e.g., Zymeworks).

[0234] Duobody® mutations (Genmab) are disclosed, for example, in U.S. Pat. No. 9,150,663 and U.S. Patent Application Publication No. 2014 / 0303356, and include the following mutations: F405L / K409R, wild type / F405L_R409K, T350I_K370T_F405L / K409R, K370W / K409R, D399AFGHILMNRSTVWY / K409R, T366ADEFGHILMQVY / K409R, L368ADEGHNRSTVQ / K409AGRH, D399FHKRQ / K409AGRH, F405IKLSTVW / K409AGRH, and Y407LWQ / K409AGRH.

[0235] Knob-in-hole mutations are disclosed, for example, in WO 1996 / 027011 and include mutations on the interface of the CH3 domains in which an amino acid with a small side chain (hole) is introduced into the first CH3 domain and an amino acid with a large side chain (knob) is introduced into the second CH3 domain, resulting in preferential interactions between the first and second CH3 domains. Exemplary CH3 domain mutations that form knobs and holes are T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V.

[0236] Heavy chain heterodimer formation can be promoted by using electrostatic interactions by substituting a positively charged residue on the first CH3 region with a negatively charged residue on the second CH3 region as described in U.S. Patent Application Publication No. 2010 / 0015133, U.S. Patent Application Publication No. 2009 / 0182127, U.S. Patent Application Publication No. 2010 / 028637, or U.S. Patent Application Publication No. 2011 / 0123532.

[0237] Other asymmetric mutations that can be used to promote heavy chain heterodimerization include L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V, T366L ... M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, or T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W.

[0238] SEED body mutations involve replacing selected IgG residues with IgA residues to promote heavy chain heterodimerization, as described in US Patent Application Publication No. 20070287170.

[0239] Other exemplary mutations that may be used include R409D_K370E / D399K_E357K, S354C_T366W / Y349C_T366S_L368A_Y407V, Y349C_T366W / S354C_T366S_L368A_Y407V, and Y349C_T366W / S354C_T366S_L368A_Y407V, as described in WO 2007 / 147901, WO 2011 / 143545, WO 2013157954, WO 2013096291, and U.S. Patent Application Publication No. 2018 / 0118849. S_L368A_Y407V, T366K / L351D, L351K / Y349E, L351K / Y349D, L351K / L368E, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, K392D / D399K, K392D / E356K, K253E_D282K_K322D / D239K_E240K_K292D, K392D_K409D / D356K_D399K.

[0240] Additional bispecific or multispecific structures that may be used as BCMAxCD3 bispecific antibodies include dual variable domain immunoglobulins (DVDs) (WO 2009 / 134776, a DVD is a full-length antibody comprising a heavy chain with the structure VH1-linker-VH2-CH and a light chain with the structure VL1-linker-VL2-CL, the linker being optional), structures comprising various dimerization domains to link two antibody arms with different specificities, e.g. leucine zippers or collagen dimerization domains (WO 2012 / 022811, US Pat. Nos. 5,932,448, 6,833,441), two or more domain antibodies (dAbs) conjugated together, heavy chain only antibodies such as diabodies, camelid antibodies and genetically engineered camelid antibodies, dual targeting (DT)-Ig (GSK / Domantis), two-in-one antibodies (Genentech), cross-linked Mabs (Karmanos Cancer Center), mAb2 (F-Star) and CovX-body (CovX / Pfizer), IgG-like bispecific (InnClone / Eli Lilly), Ts2Ab (MedImmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idec) and TvAb (Roche), ScFv / Fc fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion,Zymogenetics / BMS)), Dual Affinity Retargeting Technology (Fc-DART) (MacroGenics) and Dual(ScFv)2-Fab (National Research Center for Antibody Medicine--China), Dual-Action or Bis-Fab (Genentech), Dock-and-Lock (DNL) (ImmunoMedics), Bivalent Bispecific (Biotecnol) and Fab-Fv (UCB-Celltech).ScFv antibodies, diabody-based antibodies, and domain antibodies include, but are not limited to, Bispecific T Cell Engager (BiTE) (Micromet), Tandem Diabody (Tandab) (Affimed), Dual Affinity Retargeting Technology (DART) (MacroGenics), single chain diabodies (Academic), TCR-like antibodies (AIT, ReceptorLogics), human serum albumin ScFv fusions (Merrimack), and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies.

[0241] Fc Engineering of Antibodies The Fc region of a bispecific or multispecific antibody or a BCMAxCD3 bispecific antibody, such as an anti-CD38 antibody, may comprise at least one substitution in the Fc region that reduces binding of the BCMAxCD3 bispecific antibody to activating Fcγ receptors (FcγR) and / or reduces an Fc effector function, such as C1q binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), or antibody-dependent cell-mediated phagocytosis (ADCP).

[0242] Fc positions that may be substituted to reduce binding of the Fc to activating FcγRs and in turn reduce effector function are L234A / L235A in IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S in IgG2, F234A / L235A in IgG4, S228P / F234A / L235A in IgG4, N297A in all Ig isotypes, V234A / G237A in IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331S in IgG1, and K214T / E233P / L234V / L235A / G236 deletion / A327G / P331S in IgG2. 31A / D365E / L358M, H268Q / V309L / A330S / P331S in IgG2, S267E / L328F in IgG1, L234F / L235E / D265A in IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S in IgG1, S228P / F234A / L235A / G237A / P238S in IgG4, and S228P / F234A / L235A / G236 deletion / G237A / P238S substitutions in IgG4, where residue numbering is according to the EU index.

[0243] An Fc substitution that can be used to reduce CDC is the K322A substitution.

[0244] To improve the stability of IgG4, the well-known S228P substitution can further be made in the IgG4 antibody.

[0245] An exemplary wild-type IgG1 comprises the amino acid sequence of SEQ ID NO: 16. An exemplary wild-type IgG4 comprises the amino acid sequence of SEQ ID NO: 17.

[0246] "Antibody-dependent cellular cytotoxicity", "antibody-dependent cell-mediated cytotoxicity", or (ADCC) is a mechanism for inducing cell death that depends on the interaction of antibody-coated target cells with lytic activity, such as natural killer cells (NK), monocytes, macrophages, and neutrophils, via Fcγ receptors (FcγR) expressed on the effector cells. For example, NK cells express FcγRIIIa, while monocytes express FcγRI, FcγRII, and FcγRIIIa. ADCC activity of an antibody may be assessed using an in vitro assay using cells expressing the protein to which the antibody binds as target cells and NK cells as effector cells. Cytolysis can be detected by the release of label (e.g., radioactive substrates, fluorescent dyes, or natural intracellular proteins) from lysed cells. In an exemplary assay, target cells are used in a ratio of one target cell to four effector cells. Target cells are pre-labeled with BATDA and combined with effector cells and test antibodies. Samples are incubated for 2 hours and cytolysis is measured by measuring BATDA released into the supernatant. Data are normalized to maximal cytotoxicity with 0.67% Triton X-100 (Sigma Aldrich) and a minimum control determined by spontaneous release of BATDA from target cells in the absence of any antibody.

[0247] "Antibody-dependent cellular phagocytosis" ("ADCP") refers to a mechanism for the elimination of antibody-coated target cells by uptake by phagocytic cells, such as macrophages or dendritic cells. ADCP can be assessed by using monocyte-derived macrophages as effector cells and cells expressing a protein to which the antibody binds as target cells that are also engineered to express GFP or another marker molecule. In an exemplary assay, the effector:target cell ratio can be, for example, 4:1. Effector cells can be incubated with target cells for 4 hours, with or without the addition of an antibody of the invention. After incubation, cells can be detached using activase. Macrophages can be identified using anti-CD11b and anti-CD14 antibodies conjugated to a fluorescent label, and the rate of phagocytosis can be measured using standard methods to measure the CD11 + CD14 + It can be calculated based on the % GFP fluorescence in macrophages.

[0248] "Complement-dependent cytotoxicity" or "CDC" refers to a mechanism for inducing cell death in which the Fc effector domain of a target-binding antibody binds and activates complement component C1q, which in turn activates the complement cascade, resulting in cell death of the target cell. Complement activation can also result in the deposition of complement components on the target cell surface, facilitating CDC through the binding of complement receptors (e.g., CR3) to leukocytes. CDC of cells, for example, can be performed by incubating Daudi cells at 1×10 5 Lysing can be measured by plating 100 cells / well (50 μL / well), adding 50 μL of test protein to the well at a final concentration of 0-100 μg / mL, incubating the reaction at room temperature for 15 minutes, adding 11 μL of pooled human serum to the well, and incubating the reaction at 37° C. for 45 minutes. The percentage of lysed cells can be detected as the % of propidium iodide stained cells in a FACS assay using standard methods.

[0249] Binding of antibodies to FcγR or FcRn can be assessed using flow cytometry in cells engineered to express the respective receptor. In an exemplary binding assay, 2×10 5 Cells are seeded at 1 / well and blocked in BSA staining buffer (BD Biosciences, San Jose, USA) for 30 min at 4°C. Cells are incubated with test antibodies on ice for 1.5 h at 4°C. After washing twice with BSA staining buffer, cells are incubated with R-PE-labeled anti-human IgG secondary antibody (Jackson Immunoresearch Laboratories) for 45 min at 4°C. Cells are washed twice with staining buffer and then resuspended in 150 μL of staining buffer containing 1:200 diluted DRAQ7 live / dead cell staining reagent (Cell Signaling Technology, Danvers, USA). PE and DRAQ7 signals of stained cells were detected using B2 and B4 channels, respectively, by a Miltenyi MACSQuant flow cytometer (Miltenyi Biotec, Auburn, USA). Live cells are gated by DRAQ7 exclusion, and the geometric mean fluorescent signal is determined for at least 10,000 live cell events collected. Analysis is performed using FlowJo software (Tree Star). Data is plotted as the logarithm of the mean fluorescence signal versus the antibody concentration. Non-linear regression analysis is performed.

[0250] Chimeric antigen receptors (CARs) Chimeric antigen receptors (CARs) are genetically engineered receptors. These engineered receptors can be easily inserted into and expressed by immune cells, including T cells, according to techniques known in the art. With CARs, a single receptor can be programmed to recognize a specific antigen and, upon binding to that antigen, activate immune cells to attack and destroy cells carrying that antigen. If these antigens are present on tumor cells, immune cells expressing CARs can target tumor cells and kill them.

[0251] CARs typically comprise an extracellular domain that binds to an antigen (e.g., prostate neoantigen or B-cell maturation antigen (BCMA)), an optional linker, a transmembrane domain, and a cytoplasmic domain that comprises a costimulatory domain and / or a signaling domain.

[0252] The extracellular domain of the CAR may contain any polypeptide that binds to a desired antigen (e.g., prostate neoantigen). The extracellular domain may comprise a portion of an antibody or an optional scaffold, scFv. CARs may also be engineered to bind two or more desired antigens, which may be arranged in tandem and separated by a linker sequence. For example, one or more domain antibodies, scFvs, llama VHH antibodies, or other VH-only antibody fragments may be configured in tandem via linkers to provide bispecificity or multispecificity to the CAR.

[0253] The transmembrane domain of the CAR may be the transmembrane domain of CD8, the alpha, beta, or zeta chain of the T cell receptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CDI la, CD18), ICOS (CD278), 4-1BB (CD137), 4-1BBL, GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD19, IL2R beta, IL2R gamma, IL7R a, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDI Id, ITGAE, CD103, ITGAL, CDI la, LFA-1, ITGAM, CDI lb, ITGAX, CDI lc, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (tactile), CEACAM1, CRT The IL-16 / IL-16 T cells may be derived from AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D, and / or NKG2C.

[0254] The intracellular costimulatory domain of the CAR can be derived from the intracellular domain of one or more costimulatory molecules. Costimulatory molecules are well-known cell surface molecules other than antigen receptors or Fc receptors that provide a second signal necessary for efficient activation and function of T lymphocytes upon binding to antigen. Exemplary costimulatory domains that can be used in the CAR are the intracellular domains of 4-1BB, CD2, CD7, CD27, CD28, CD30, CD40, CD54 (ICAM), CD83, CD134 (OX40), CD150 (SLAMF1), CD152 (CTLA4), CD223 (LAG3), CD270 (HVEM), CD278 (ICOS), DAP10, LAT, NKD2C SLP76, TRIM, and ZAP70.

[0255] The intracellular signaling domain of a CAR can be derived, for example, from the signaling domains of O'O3zeta, CD3epsilon, CD22, CD79a, CD66d, or CD39. "Intracellular signaling domain" refers to the portion of a CAR polypeptide that is involved in transducing the message of effective CAR binding to a target antigen inside an immune effector cell to elicit effector cell function, such as activation, cytokine production, proliferation, and cytotoxic activity (including release of cytotoxic factors into a CAR-bound target cell, or other cellular response elicited following antigen binding to the extracellular CAR domain).

[0256] The linker of any CAR, located between the extracellular and transmembrane domains, can be a polypeptide of about 2 to 100 amino acids in length. The linker can include or consist of flexible residues such as glycine and serine so that adjacent protein domains can move freely relative to one another. Longer linkers can be used if it is desirable to ensure that two adjacent domains do not sterically interfere with one another. The linker can be cleavable or non-cleavable. Examples of cleavable linkers include 2A linkers (e.g., T2A), 2A-like linkers, or functional equivalents and combinations thereof. The linker can also be derived from the hinge region or a portion of the hinge region of any immunoglobulin.

[0257] An exemplary CAR that can be used is, for example, a CAR that contains an extracellular domain that binds to a multiple myeloma neo-antigen of the present disclosure, a CD8 transmembrane domain, and a CD3 zeta signaling domain. Other exemplary CARs contain an extracellular domain that binds to an ovarian neo-antigen of the present disclosure, a CD8 or CD28 transmembrane domain, a CD28, 41BB, or OX40 costimulatory domain, and a CD3 zeta signaling domain.

[0258] CARs are generated by standard molecular biology techniques. The extracellular domain that binds to the desired antigen can be derived from an antibody or antigen-binding fragment thereof generated using the techniques described herein.

[0259] Outcome In some embodiments, a subject treated by the methods provided herein has a partial response (PR) or better. In some embodiments, a subject treated by the methods provided herein has a very good partial response (VGPR) or better. In some embodiments, a subject treated by the methods provided herein has a complete response (CR) or better. In some embodiments, a subject treated by the methods provided herein has a stringent complete response (sCR) or better. In some embodiments, PR, VGPR, CR, and sCR are as defined by the IMWG 2016 criteria. In some embodiments, PR is defined as a >50% reduction in serum M protein and a >90% or to <200 mg / 24 hr reduction in 24 hr urinary M protein. In some embodiments, VGPR is defined as having serum and urinary M protein levels detectable by immunofixation but not by electrophoresis, or a >90% reduction in serum M protein + urinary M protein levels <100 mg / 24 hr. In some embodiments, CR is defined as having negative immunofixation for serum and urine, and disappearance of any soft tissue plasmacytoma and <5% plasma cells in bone marrow. In some embodiments, sCR is defined as CR definition as above plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence.

[0260] In some embodiments, treatment with the methods provided herein results in T cell activation. In some embodiments, T cell activation results in an increase in at least one of CD25, PD-1, CD38 on CD4+ T cells, CD38 on CD8+ T cells, or any combination thereof. In some embodiments, T cell activation results in an increase in CD25. In some embodiments, T cell activation results in an increase in PD-1. In some embodiments, T cell activation results in an increase in CD38 on CD4+ T cells. In some embodiments, T cell activation results in an increase in CD38 on CD8+ T cells. In some embodiments, treatment with the methods provided herein results in an increase in the frequency of at least one of CD38+CD8+ T cells, CD38+CD4+ T cells, Tregs T cells, or any combination thereof. In some embodiments, treatment with the methods provided herein results in an increase in the frequency of CD38+CD8+ T cells. In some embodiments, treatment with the methods provided herein results in an increase in the frequency of CD38+CD4+ T cells. In some embodiments, treatment with the methods provided herein results in an increase in the frequency of Treg T cells.

[0261] In some embodiments, the methods provided herein result in enhanced activity or improved efficacy of the components of the methods when administered as monotherapy. In some embodiments, treatment with the methods provided herein results in enhanced activity of the BCMAxCD3 bispecific antibody compared to treatment without the anti-CD38 antibody. In some embodiments, treatment with the methods provided herein results in enhanced activity of the anti-CD38 antibody compared to treatment without the BCMAxCD3 bispecific antibody.

[0262] Numbered embodiments The present disclosure also provides the following numbered embodiments: 1. A method of treating a subject in need of treatment, comprising: (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 200 μg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks. 1a. A method of treating a subject in need of treatment, comprising: (1) administering a BCMA x CD3 bispecific antibody intravenously to a subject at a dose of 200 μg / kg to 1 mg / kg every 1 to 2 weeks; and (2) subcutaneously administering an anti-CD38 antibody to a subject at a dose of 1200 mg to 2400 mg every 1 to 4 weeks. The method of embodiment 1a, wherein the BCMAxCD3 bispecific antibody is administered intravenously to the subject weekly at a dose of 270 μg / kg. 1a2. The method of embodiment 1a or 1a1, wherein the anti-CD38 antibody is administered subcutaneously every week, every other week, every three weeks, or every four weeks at a dose of 1800 mg. 1a3. The method of embodiment 1a1, wherein the anti-CD38 antibody is administered subcutaneously at a dose of 1800 mg once per week during weeks 1-8 of treatment, once every two weeks during weeks 9-24 of treatment, and once every four weeks after week 24 of treatment. 2. (1) administering to a subject a BCMA x CD3 bispecific antibody at a dose of 1 mg / kg to 6 mg / kg or 60 mg to 600 mg every 1 to 4 weeks; and (2) subcutaneously administering to the subject an anti-CD38 antibody at a dose of 1600 mg to 2000 mg every 1 to 4 weeks. 3. The method of embodiment 2, further comprising, prior to step (1), subcutaneously administering to the subject a BCMAxCD3 bispecific antibody at a dose of less than 0.5 mg / kg. 3a. The method of embodiment 3, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose lower than 0.5 mg / kg after the first administration of the anti-CD38 antibody, preferably the BCMAxCD3 bispecific antibody is initially administered to the subject at least 20 hours after the first administration of the anti-CD38 antibody at a dose lower than 0.5 mg / kg. 3b. The method of embodiment 3 or 3a, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 0.01-0.10 mg / kg, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, and 0.10 mg / kg, on day 1 of treatment. 3c. The method of embodiment 3 or 3a, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject on the second day of treatment at a dose of 0.01-0.10 mg / kg, for example, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, and 0.10 mg / kg. 3d. The method of any one of embodiments 3-3c, wherein 0.10-0.50 mg / kg, e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mg / kg, or any value therebetween, of the BCMAxCD3 bispecific antibody is administered on day 3 of treatment. 3e. The method of any one of embodiments 3-3c, wherein 0.10-0.50 mg / kg, for example 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mg / kg, or any value therebetween, of the BCMAxCD3 bispecific antibody is administered on day 4 of treatment. 3f. The method of any one of embodiments 3-3c, wherein 0.10-0.50 mg / kg, e.g., 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 mg / kg, or any value therebetween, of the BCMAxCD3 bispecific antibody is administered on day 5 of treatment. 3g. The method of any one of embodiments 3-3f, wherein an initial dose of 1 mg / kg to 6 mg / kg or 200 mg to 600 mg of the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject on day 6, 7, or 8 of treatment. 4. The method of any one of embodiments 2-3g, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject once per week or once every two weeks at a dose of 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0 mg / kg, or 100, 150, 200, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, or any dose in between. 4a. BCMA × CD3 bispecific antibody was administered at the following doses: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg 5. The method of embodiment 4, wherein the compound is administered subcutaneously to the subject weekly at a dose of 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, or 6.0 mg / kg. 4b. BCMA × CD3 bispecific antibody was administered at the following doses: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg 5. The method of embodiment 4, wherein the compound is administered subcutaneously to the subject every other week at a dose of 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, or 6.0 mg / kg. 4c. BCMA×CD3 bispecific antibody was administered at the following doses: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, or 6.0 mg / kg is administered subcutaneously to the subject every three weeks. 4d. BCMA×CD3 bispecific antibody was administered at the following doses: 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4.0mg / kg, 4.1mg / kg 5. The method of embodiment 4, wherein the compound is administered subcutaneously to the subject monthly at a dose of 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, or 6.0 mg / kg. 4e. The method of embodiment 4, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject once a week at a dose of 100, 150, 200, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, or 350 mg, or any dose in between. 4f. The method of any one of embodiments 4-4c, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject once every two weeks at a dose of 100, 150, 200, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 mg, or any dose in between. 5. The method of embodiment 4, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 1.5 mg / kg weekly, 150 mg weekly, 3.0 mg / kg weekly or every other week, 6.0 mg / kg biweekly or monthly, 300 mg biweekly, or 600 mg biweekly or monthly. 6. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 1.5 mg / kg weekly. 6a. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 60-150 mg weekly. 6b. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 3 mg / kg weekly. 6c. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 3.0 mg / kg every two weeks or every three weeks. 6d. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 150-300 mg weekly. 6e. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 150-300 mg every two weeks or every three weeks. 6f. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 6.0 mg / kg every other week. 6g. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 6.0 mg / kg every 3 weeks or every month. 6h. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 300-600 mg every other week. 6i. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 300-600 mg every three weeks or every month. 6j. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 60-150 mg weekly for the first 8 weeks, after which the BCMAxCD3 bispecific antibody is administered at a dose of 150-300 mg every other week. 6. The method of embodiment 5, wherein the 6k.BCMAxCD3 bispecific antibody is administered subcutaneously to the subject weekly for 8 weeks (2 cycles) at a dose of 1.5 mg / kg, followed by administration of the BCMAxCD3 bispecific antibody subcutaneously every other week for, e.g., 4-12 weeks (1-3 cycles) at a dose of 3.0 mg / kg. 61. The method of embodiment 6k, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject weekly at a dose of 1.5 mg / kg for 8 weeks (2 cycles), followed by biweekly administration of the BCMAxCD3 bispecific antibody at a dose of 3.0 mg / kg, for example, for 4 to 12 weeks, followed by monthly administration of the BCMAxCD3 bispecific antibody at a dose of 6.0 mg / kg. 6. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject weekly for 8 weeks (2 cycles) at a dose of 60-150 mg, followed by administration of the BCMAxCD3 bispecific antibody subcutaneously every other week for, e.g., 4-12 weeks (1-3 cycles) at a dose of 150-300 mg. 6n. The method of embodiment 5, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject weekly at a dose of 60-150 mg for 8 weeks (2 cycles), followed by, for example, biweekly subcutaneous administration of the BCMAxCD3 bispecific antibody at a dose of 150-300 mg for 4-12 weeks (1-3 cycles), followed by monthly subcutaneous administration of the BCMAxCD3 bispecific antibody at a dose of 300-600 mg. 7. The method of any one of embodiments 1-6n, wherein the anti-CD38 antibody is administered subcutaneously to the subject at a dose of 1800 mg once per week during weeks 1-8 of treatment, once every two weeks during weeks 9-24 of treatment, and once every four weeks after week 24 of treatment. 7a. The method of any one of embodiments 1-6n, wherein the anti-CD38 antibody is administered subcutaneously to the subject at a dose of 1800 mg once a week. 7b. The method of any one of embodiments 1-6n, wherein the anti-CD38 antibody is administered subcutaneously to the subject at a dose of 1800 mg once every two weeks. 7c. The method of any one of embodiments 1-6n, wherein the anti-CD38 antibody is administered subcutaneously to the subject at a dose of 1800 mg once every three weeks. 7d. The method of any one of embodiments 1-6n, wherein the anti-CD38 antibody is administered subcutaneously to the subject at a dose of 1800 mg once every four weeks. 8. The method of any one of embodiments 1-7d, wherein the anti-CD38 antibody is administered or provided for administration together with rHuPH20, e.g., about 30,000 U of rHuPH20. 8a. The method of any one of embodiments 1-7d, further comprising administering rHuPH20 to the subject to reduce the required injection volume and facilitate subcutaneous administration of the anti-CD38 antibody. 8b. The method of embodiment 8a, wherein rHuPH20 is administered subcutaneously together with an anti-CD38 antibody. 8c. The method of embodiment 8a, wherein rHuPH20 is administered subcutaneously separately from the anti-CD38 antibody. 8d. The method of any one of embodiments 8a-8d, wherein rHuPH20 is administered subcutaneously at a dose of 10,000-50000 U, for example, 10,000, 20,000, 30,000, 40,000, or 50,000 U, or any value therebetween. 8e. The method of any one of embodiments 8a-8d, wherein rHuPH20 is administered subcutaneously at a dose of 30,000 U. 8d. The method of any one of embodiments 8-8e, wherein rHuPH20 and an anti-CD38 antibody are administered together in the same pharmaceutical composition. 9. BCMA x CD3 bispecific antibodies (i) a BCMA binding domain comprising a heavy chain variable region (VH) having heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, and a light chain variable region (VL) having light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23, respectively; and (ii) A method according to any one of embodiments 1 to 8d, comprising a CD3 binding domain comprising a VH having HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, and a VL having LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively. 9a.BCMA×CD3 bispecific antibodies are used in the BCMA binding domain of ACTR cancer therapy by Seattle Genetics, AFM-26, ALLO-715, anti-BCMA allogeneic CAR-T cancer therapy by CRISPR Therapeutics, anti-BCMA CAR-T by Sorrento Therapeutics, anti-CD19 / BCMA CAR-T cancer therapy by Hrain Biotechnology, BCMA CAR-T by Chineo Med (Beijing), BCMA TAC-T cancer therapy by Triumvira Immunologics, and BCMA-CAR by Shanghai Universitas Therapeutics. T cancer therapy, BCMA / CD3 antibody by Regeneron, CAR-NK cancer therapy by NantKwest, CC-93629, CMD-505, CTX-4419, CYAD-211, HDP-101, HPN-217, P-BCMA-ALLO1, TNB-383B, bb-2121, AUTO-2, BCMA chimeric antigen receptor therapy by Pregene, BCMA-CAR T cells by Shanghai Bioray Laboratory, BCMA-CAR-T cells by CARsgen Therapeutics, CAR-T / TCR-T cell immunotherapy by Shenzhen BinDeBio, ET-140, P-BCMA-101, REGN-5458, AMG-701, anti-BCMA by Cellular Biomedicine Group The method of any one of embodiments 1-8d, comprising a BCMA binding domain that binds to BCMA selected from the group consisting of CAR-T cancer therapy, bb-21217, BI-836909, CC-93269, Descartes-08, IM-21, JNJ-64007957, MEDI-2228, or PF-06863135. 9b. The method according to any one of embodiments 1 to 8d, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain as described in WO2017 / 031104. 10. The method of embodiment 9, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a VH having the amino acid sequence of SEQ ID NO: 24 and a VL having the amino acid sequence of SEQ ID NO: 25, and a CD3 binding domain comprising a VH having the amino acid sequence of SEQ ID NO: 34 and a VL having the amino acid sequence of SEQ ID NO: 35. 11. The method of embodiment 10, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 26 and a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 27, and a CD3 binding domain comprising a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 36 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 37. 11a. The method of any one of embodiments 1-8d, wherein the BCMAxCD3 bispecific antibody comprises erlanatamab (also known as PF-06863135), teneobio (also known as TNB-383B), REGN5458, REGN5459, pavlutamab (also known as AMG-701), BI 836909, CC-93269, WVT078, or teclistamab (also known as JNJ-957 or JNJ-64007957). 11b. The method of any one of embodiments 1 to 8d, wherein the BCMAxCD3 bispecific antibody comprises an antigen-binding fragment, such as a Fab, F(ab')2, Fd, or Fv fragment. 11c. The method of any one of embodiments 1 to 8d, wherein the BCMAxCD3 bispecific antibody is chimeric, humanized, or human. 11d. The method of any one of embodiments 1 to 8d, wherein the BCMAxCD3 bispecific antibody is of the IgG1, IgG2, and IgG3, or IgG4 isotype. 11e. The method of any one of embodiments 1 to 8d, wherein the BCMAxCD3 bispecific antibody is of the IgG4 isotype. 12. The method of any one of embodiments 1 to 11e, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively, and a VL having LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively. 12a. The method of any one of embodiments 1-11a, wherein the anti-CD38 antibody comprises a) a VH of SEQ ID NO: 38 and a VL of SEQ ID NO: 39, b) a VH of SEQ ID NO: 40 and a VL of SEQ ID NO: 41, c) a VH of SEQ ID NO: 42 and a VL of SEQ ID NO: 43, or d) a VH of SEQ ID NO: 44 and a VL of SEQ ID NO: 45. 13. The method of embodiment 12, wherein the CD38 antibody comprises a VH having the amino acid sequence of SEQ ID NO:6 and a VL having the amino acid sequence of SEQ ID NO:7. 13a. The method of any one of embodiments 1-11a, wherein the anti-CD38 antibody is selected from the group consisting of mAb003 described in U.S. Pat. No. 7,829,673, mAb024 described in U.S. Pat. No. 7,829,673, MOR-202 (MOR-03087) described in U.S. Pat. No. 8,088,896, or isatuximab described in U.S. Pat. No. 8,153,765, and daratumumab. 13b. The method of any one of embodiments 1 to 11a, wherein the anti-CD38 antibody comprises a HC of SEQ ID NO:12 and a LC of SEQ ID NO:13. 13c. The method of any one of embodiments 1-11a, wherein the anti-CD38 antibody is chimeric, humanized, or human. 13d. The method of any one of embodiments 1-11a, wherein the anti-CD38 antibody is of the IgG1, IgG2, and IgG3, or IgG4 isotype. 13e. The method of any one of embodiments 1-11a, wherein the anti-CD38 antibody is of the IgG1 isotype. 13f. The method of any one of embodiments 1 to 13e, wherein the BCMAxCD3 bispecific antibody and / or the anti-CD38 antibody comprises one or more Fc substitutions as described herein. 13g.Fc substitutions: F234A / L235A on IgG4, L234A / L235A on IgG1, V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2, F234A / L235A on IgG4, S228P / F234A / L235A on IgG4, N297A on all Ig isotypes, V234A / G237A on IgG2, K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M on IgG1, and V234A / G237A on IgG2. 13a. The method of embodiment 13f, wherein the amino acid sequence of the IgG1 polypeptide is selected from the group consisting of H268Q / V309L / A330S / P331S, S267E / L328F on IgG1, L234F / L235E / D265A on IgG1, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236deletion / G237A / P238S on IgG4, wherein the numbering of the residues is according to the EU index. 13h.Fc substitutions, (1) F234A / L235A on IgG4; (2) L234A / L235A on IgG1; (3) V234A / G237A / P238S / H268A / V309L / A330S / P331S on IgG2; (4) F234A / L235A on IgG4; (5) S228P / F234A / L235A on IgG4; (6) N297A on all Ig isotypes; (7) V234A / G237A on IgG2; (8) K214T / E233P / L234V / L235A / G236 deletion / A327G / P331A / D365E / L358M on IgG1; (9) H268Q / V309L / A330S / P331S on IgG2; (10) S267E / L328F on IgG1; (11) L234F / L235E / D265A on IgG1; (12) L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgG1; (13) S228P / F234A / L235A / G237A / P238S on IgG4 and S228P / F234A / L235A / G236 deletion / G237A / P238S on IgG4; and / or (14) The method of embodiment 13f, wherein the amino acid sequence is selected from the group consisting of S228P substitution. 13i. The method of any one of embodiments 1 to 13e, wherein the BCMAxCD3 multispecific antibody comprises one or more asymmetric substitutions in the first CH3 domain or the second CH3 domain, or in both the first CH3 domain and the second CH3 domain. 13j. One or more asymmetric substitutions are F450L / K409R, wild type / F409L_R409K, T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V, L351Y_F405A_Y407V / T394W, T366I_K392M_T 394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, and T350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W. The method according to any one of embodiments 1 to 13e, wherein the 13k.BCMAxCD3 bispecific antibody is of IgG4 isotype and comprises a phenylalanine at position 405 and an arginine at position 409 of the first heavy chain (HC1), and a leucine at position 405 and a lysine at position 409 of the second heavy chain (HC2), wherein the numbering of the residues is according to the EU index. The method of embodiment 13k, wherein the BCMAxCD3 bispecific antibody further comprises a proline at position 228, an alanine at position 234, and an alanine at position 235 in both HC1 and HC2. 14. The method of any one of embodiments 1-13l, wherein the cancer is a hematological malignancy or a solid tumor. 14a. Hematological malignancies include multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL), mantle-cell lymphoma (MCL), Waldenstrom's hypergammaglobulinemia, plasma cell leukemia, light-chain amyloidosis (AL), precursor B-cell lymphoblastic leukemia, precursor B-cell lymphoblastic leukemia, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myelodysplastic syndrome (MS). 15. The method of embodiment 14, wherein the malignant tumor is selected from the group consisting of chronic lymphocytic leukemia (CLL), B-cell malignancies, chronic myeloid leukemia (CML), hairy cell leukemia (HCL), blastic plasmacytoid dendritic cell neoplasm, Hodgkin's lymphoma, non-Hodgkin's lymphoma, marginal zone B-cell lymphoma (MZL), mucosa-associated lymphatic tissue (MALT), plasma cell leukemia, anaplastic large-cell lymphoma (ALCL), leukemia, or lymphoma. 14b. The method of embodiment 14a, wherein the hematological malignancy comprises multiple myeloma. 14c. The method of embodiment 14b, wherein the multiple myeloma is newly diagnosed multiple myeloma. 14d. The method of embodiment 14b, wherein the multiple myeloma is relapsed or refractory multiple myeloma (RRMM). 14e. The method of embodiment 14b, wherein the multiple myeloma is high-risk multiple myeloma. 14f. The method of embodiment 14b, wherein the subject with high-risk multiple myeloma has one or more chromosomal abnormalities including t(4;14)(p16;q32), t(14;16)(q32;q23), del17p, 1qAmp, t(4;14)(p16;q32) and t(14;16)(q32;q23), t(4;14)(p16;q32) and del17p, t(14;16)(q32;q23) and del17p; or t(4;14)(p16;q32), t(14;16)(q32;q23) and del17p, or any combination thereof. 14g. The method of any one of embodiments 1-14f, wherein the cancer comprises multiple myeloma that is relapsed or refractory to treatment. 14h. The method of embodiment 14g, wherein the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, melphalan, or thalidomide, or any combination thereof. 14i. The method of any one of embodiments 1-14, wherein the cancer comprises AML. 14j. The method of embodiment 14i, wherein the AML is AML with at least one genetic abnormality, AML with multilineage dysplasia, therapy-related AML, anaplastic AML, minimally differentiated AML, differentiated AML, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythrocytic leukemia, acute megakaryoblastic leukemia, acute basophilic leukemia, acute panmyelosis with fibrosis, or myeloid sarcoma. 14k. The method of any one of embodiments 1-14, wherein the cancer comprises any BCMA-expressing cancer, such as multiple myeloma, smoldering multiple myeloma, benign monoclonal gammopathy (MGUS), B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, Waldenstrom's hypergammaglobulinemia, plasma cell leukemia, light chain amyloidosis, or non-Hodgkin's lymphoma. 14l. The method of any one of embodiments 1-14, wherein the subject is relapsed or refractory to treatment with an anti-CD38 antibody or lenalidomide, or a combination thereof. 14m. The method of any one of embodiments 1-14, wherein the subject is refractory or relapsed to treatment with THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARADYK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), elotuzumab (Empliciti®), SARCLISA® (isatuximab), or melphalan (Alkeran®). 14n. The method of any one of embodiments 1-14, wherein the subject is relapsed to treatment with DARZALEX® (daratumumab). 15. A method of treating multiple myeloma in a subject in need thereof, comprising: (1) administering to the subject subcutaneously 1.5 mg / kg of the BCMA x CD3 bispecific antibody once per week during weeks 1 through 8 of treatment, and from week 8 of treatment onwards, administering 3.0 mg / kg of the BCMA x CD3 bispecific antibody once every two weeks and / or 6.0 mg / kg of the BCMA x CD3 bispecific antibody once per month; (2) administering 1,800 mg of an anti-CD38 antibody subcutaneously to the subject once per week during weeks 1 through 8 of treatment, once every two weeks during weeks 9 through 24 of treatment, and once every four weeks after week 24 of treatment; The present invention relates to a method, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) of SEQ ID NO: 26, a first light chain (LC1) of SEQ ID NO: 27, a second heavy chain (HC2) of SEQ ID NO: 36, and a second light chain (LC2) of SEQ ID NO: 37, and the anti-CD38 antibody comprises a HC of SEQ ID NO: 12 and a LC of SEQ ID NO: 13. 15a. The method of claim 15, wherein the BCMAxCD3 bispecific antibody is administered subcutaneously to the subject at a dose of 1.5 mg / kg once per week during weeks 1-8 of treatment, at a dose of 3.0 mg / kg once every two weeks during weeks 9-20 of treatment, and 6.0 mg / kg thereafter. 16. The method of embodiment 15 or 15a, further comprising administering to the subject subcutaneously 0.06 mg / kg of BCMAxCD3 bispecific antibody on day 2 of treatment and 0.3 mg / kg of BCMAxCD3 bispecific antibody on day 4 of treatment prior to the first weekly or biweekly subcutaneous administration of 1.5 mg / kg of BCMAxCD3 bispecific antibody. 17. The method of embodiment 15 or 15a, further comprising administering 3 mg / kg of the bispecific antibody every other week on day 1 of the next scheduled 28 day cycle. 18. The method of any one of embodiments 1-17, wherein the subject has undergone at least one prior treatment for multiple myeloma, preferably, the subject is relapsed or refractory to at least one prior treatment, more preferably, the prior treatment comprises at least one of a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD). 19. The method of embodiment 18, wherein the subject is refractory or relapsed to a treatment selected from the group consisting of an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, isatuximab, melphalan, and thalidomide, or any combination thereof, preferably, the subject is lenalidomide refractory. 20. The method of any one of embodiments 1-19, further comprising administering to the subject another treatment, such as pomalidomide and / or dexamethasone. 21. The method of any one of embodiments 1 to 20, wherein the treatment results in T cell activation, such as an increase in at least one of CD25, PD-1, CD38 on CD4+ and CD8+ T cells. 22. The method of any one of embodiments 1-21, wherein the treatment results in an increase in the frequency of at least one of CD38+CD8+ T cells, CD38+CD4+ T cells, and Tregs T cells. 23. The method according to any one of embodiments 1 to 20, wherein the treatment results in enhanced activity of the BCMAxCD3 bispecific antibody compared to treatment without an anti-CD38 antibody. 24. The method of any one of embodiments 1 to 20, wherein the treatment results in enhanced activity of an anti-CD38 antibody compared to treatment without a BCMAxCD3 bispecific antibody. 25. A BCMAxCD3 bispecific antibody for use in treating cancer in a subject in need thereof, using a method according to any one of embodiments 1 to 24. 26. An anti-CD38 antibody for use in treating cancer in a subject in need thereof, using the method according to any one of embodiments 1-24. 27. A combination of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody for use in treating cancer in a subject in need thereof, using the method according to any one of embodiments 1-24. 28. Use of a BCMAxCD3 bispecific antibody in the manufacture of a medicament for treating cancer in a subject in need thereof, using a method according to any one of embodiments 1 to 24. 29. Use of an anti-CD38 antibody in the manufacture of a medicament for treating cancer in a subject in need thereof, using a method according to any one of embodiments 1 to 24. 30. Use of a combination of a BCMAxCD3 bispecific antibody and an anti-CD38 antibody in the manufacture of a medicament for treating cancer in a subject in need thereof, using a method according to any one of embodiments 1 to 243. 31. A kit comprising a BCMAxCD3 bispecific antibody, an anti-CD38 antibody, and instructions for using the antibodies in treating cancer in a subject in need thereof using the method of any one of embodiments 1-24.

[0263] Having described the invention in general terms, embodiments of the invention are further disclosed in the following examples, which should not be construed as limiting the scope of the claims. EXAMPLES

[0264] The following examples are provided to further illustrate some of the embodiments disclosed herein and are intended to be illustrative and not limiting of the embodiments of the present disclosure.

[0265] General Materials and Methods Antibodies and Reagents Anti-BCMA / anti-CD3 antibody JNJ-64007957 (referred to as JNJ-957) (described in WO2017031104(A1)) and daratumumab were manufactured by Janssen Pharmaceuticals. CNTO7008 (CD3xnull), BC3B4 (BCMAxnull), and 3930 (IgG isotype control), all from Janssen Pharmaceuticals, were used as control antibodies.

[0266] JNJ-957 (BCMA) contains the BCMA-binding arm BCMB69 and the CD3-binding arm CD3B219, the amino acid sequences of which are shown in Tables 8a and 8b, respectively.

[0267] Bone marrow and peripheral blood mononuclear cells Peripheral blood mononuclear cells (PBMCs) from healthy donors and MM patients, as well as bone marrow mononuclear cells (BM-MNCs) from MM patient BM aspirates, were isolated by Ficoll-Hypaque density gradient centrifugation.

[0268] Flow cytometric analysis of bone marrow and blood samples from MM patients Identify BM-localized MM cells and measure 1.0 x 10 6 Cells / mL were analyzed for cell surface marker expression levels by staining with HuMax-003 (CD38) FITC (this antibody binds to an epitope distinct from that bound by daratumumab, Janssen Pharmaceuticals), CD138 PE, CD56 PC7, CD45 Krome Orange (all Beckman Coulter), CD269 (BCMA) APC (Biolegend), CD274 (PD-L1) BV421, and CD19 APC-H7 (both Becton Dickinson). BM or PB immune cell subsets were identified and analyzed at 1.0 × 10 6Cells / mL were measured using CD45 Chrome Orange, CD56 PC7 (both Beckman Coulter), CD14 APC-H7, CD19 APC-H7, CD3 V450, CD4 APC-H7 or PE, CD8 FITC, CD45-RA APC, CD127 PE.Cy7, CD62L PE, CD274 (PD-1) BV421, CD16 APC, HLA-DR APC-H7 (all Becton Dickinson), and CD25 PE (Dako), or CD4 BUV395 (BD Biosciences), CD8 BUV737 (BD Biosciences), PD-1 BV421 (BD Biosciences), TIM-3 BV650 (BD Biosciences), CD3 BV711 (BD Biosciences), CD45RO BV786 (BD Biosciences), CD38 Cell surface marker expression levels were analyzed by staining with Humab-003-FITC (Janssen), CD45RA PerCP-Cy5.5 (BD Biosciences), HLA-DR PE (BD Biosciences), LAG-3 PE-eF610 (ThermoFisher), CD25 PE-Cy7 (BD Biosciences), CCR7 AF647 (BD Biosciences), and CD127 APC-eF780 (ThermoFisher). All BM samples were analyzed within 24 hours of sample collection.

[0269] Flow cytometry was performed using a 7-laser LSRFORTESSA (Becton Dickinson). Fluorescently labeled beads (CS&T beads, Becton Dickinson) were used daily to monitor the performance of the flow cytometer and to verify the light path and flow rates. This procedure allows for controlled and standardized results, allowing the determination of long-term drift and accidental changes in the flow cytometer. No changes were observed that could affect the results. Compensation beads were used to determine the spectral overlap, and compensation was calculated automatically using Diva software. Flow cytometry data was analyzed using FACS Diva software.

[0270] Bioluminescence imaging (BLI)-based lysis assay using LUC-transduced MM cell lines LUC-transduced MM cell lines were cultured for 16 h in the presence or absence of pooled BM stromal cells (BMSCs) from newly diagnosed MM patients (n=12) and then incubated with effector cells (freshly isolated PBMCs from healthy donors) at an effector-to-target ratio of 9:1 and serially diluted JNJ-957 (0.00256–4.0 μg / mL) or control antibody in 96-well flat-bottom plates (Greiner-Bio-One) for 48 h. + -MM cell viability was determined 10 min after addition of the substrate luciferin (150 μg / mL; Promega). MM cell lysis was determined using the following formula: % lysis = 1 - (mean BLI signal in the presence of effector cells and JNJ-957 / mean BLI signal in the presence of effector cells and untreated antibody) x 100%.

[0271] To evaluate the effect of in vivo pretreatment of PB MNCs with daratumumab monotherapy on the efficacy of JNJ-957, LUC-transduced MM cell line 4 was also cocultured (effector-to-target ratio of 9:1) with PB MNCs obtained from MM patients before the initiation of daratumumab monotherapy and at the time of best response to daratumumab monotherapy. BLI assays were performed as previously described.

[0272] Cytogenetic analysis Cytogenetic abnormalities were assessed in purified MM cells by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism (SNP) arrays. High-risk disease was defined by the presence of del(17p), del(1p), ampl(1q), t(4;14), or t(14;16-2.

[0273] Soluble BCMA assay Soluble BCMA (sBCMA) was measured in cell culture supernatants using MSD GOLD™ 96-well Small Spot Streptavidin SECTOR plates (Meso Scale Diagnostics) according to the manufacturer's recommended protocol.

[0274] Multiplex cytokine assay Cytokines [interferon-gamma (IFN-γ), interleukin (IL)-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α)] in cell culture supernatants were analyzed using the V-Plex Proinflammatory Panel 1 Human Kit (Meso Scale Diagnostics) according to the manufacturer's protocol.

[0275] Statistics When data did not follow a normal distribution, comparisons between variables were performed using two-tailed (paired) Student's t-test, or Mann-Whitney U test, or Wilcoxon matched-pairs signed-rank test. Correlation between variables was performed using Spearman's rank correlation coefficient. A p-value of less than 0.05 was considered significant. In the case of combinatorial treatment of JNJ-957 and daratumumab, expected lysis values ​​were calculated to test the null hypothesis that there is only an additive effect between JNJ-957 and daratumumab using the following formula: expected lysis % = (% lysis by JNJ-957 + % lysis by daratumumab) - (% lysis by JNJ-957 × % lysis by daratumumab). The null hypothesis of an "additive effect" was rejected if the observed value was significantly higher (P < 0.05) than the expected value.

[0276] Example 1. Phase 1 Study of Teclistamab (JNJ-957) Administered in Combination with Subcutaneous Daratumumab for Relapsed or Refractory Multiple Myeloma (RRMM) A phase 1b open-label, multicenter, multicohort study of teclistamab in combination with a subcutaneous (SC) dosing regimen of daratumumab administered to adult subjects with multiple myeloma was conducted. The two treatment combinations also included pomalidomide (and concomitant dexamethasone for at least the first cycle). In the pomalidomide-containing treatment combination, dexamethasone administration was required throughout the first three full immunomodulator (IMiD)-containing cycles to enhance the IMiD-driven antimyeloma effect and serve as a pretreatment agent for daratumumab and teclistamab. The overall objective of the study was to evaluate the safety of daratumumab in combination with teclistamab (and concomitant dexamethasone for at least the first cycle) with or without pomalidomide, and to evaluate preliminary anticancer activity. Safety was monitored by the Study Evaluation Team (SET).

[0277] Objectives and Endpoints

[0278] [Table 11] Abbreviations: MR = minimal response; MRD = minimal residual disease; ORR = overall response rate; PFS = progression-free survival; RP2D = recommended phase 2 dose.

[0279] Study design The test was conducted in two parts. Part 1: Dose escalation to establish the RP2D(s) for each treatment combination Part 2: Dose expansion at RP2D(s) for selected treatment combination(s)

[0280] A schematic diagram of parts 1 and 2 is shown in Figure 1. The following treatment combinations were tested: SC daratumumab and IV teclistamab SC daratumumab and SC teclistamab ·SC daratumumab, SC teclistamab, and pomalidomide.

[0281] Part 1 (dose escalation) In Part 1 (dose escalation), all subjects will receive daratumumab at the dose approved in multiple myeloma. Subjects receiving pomalidomide will receive it at its approved dose or a lower modified dose, if applicable. For the first cohort of subjects treated in the study (where a therapeutic dose of 270 μg / mg IV teclistamab was evaluated), escalating dosing of the bispecific antibody followed dosing schedule A, with escalating dosing beginning on day 9 of cycle 1. This cohort utilized a therapeutic dose (e.g., a therapeutic dose of 270 μg / kg IV teclistamab) associated with the escalating dosing regimen (i.e., dose, number of escalating dose(s), and number of days between escalating dose(s)) and a therapeutic dose level below the last cleared dose level for the appropriate route of administration in the ongoing monotherapy study. Based on new data, SET has approved implementation of dosing schedule B, with escalating dosing beginning on day 2 of cycle 1. For subsequent cohorts, the escalating dosing regimen and treatment dose will be determined based on a statistical model that uses all available safety, pharmacokinetic, and pharmacodynamic data to identify safe and tolerable RP2D(s). The escalating and treatment doses tested in this study will not exceed doses previously cleared by SET in monotherapy studies of teclistamab. The relevant treatment doses were planned to be administered on a weekly basis in 28-day cycles following the escalating dose(s). However, other schedules, including biweekly dosing, were also tested in the cohorts. At least 30 subjects will be evaluated in Part 1. The total number of subjects treated will depend on the number of dose levels explored to identify RP2D(s) and the number of subjects enrolled at each dose level.

[0282] Part 2 (dose expansion) The RP2D(s) for each treatment combination selected for further testing in Part 2 (NCT04108195CTX) will be based on the doses recommended by BLRM (Bayesian logistic regression model) based on findings from Part 1. In addition, SET will consider all available safety, pharmacokinetic, pharmacodynamic, and efficacy data for each treatment combination in Part 1, if applicable, before determining the RP2D(s) for that treatment combination in Part 2. SET may select one or more RP2D(s) for each treatment combination. Up to approximately 40 subjects will be evaluated at each of the RP2Ds for each treatment combination selected for testing in Part 2.

[0283] Target population The study was conducted in subjects aged 18 years or older with multiple myeloma who had received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an IMiD, or had disease that was dual refractory to a PI and an IMiD. Subjects who had received anti-CD38 therapy for 90 days or less were excluded. For subjects enrolled in treatment combinations containing pomalidomide, prior IMiD therapy should have included lenalidomide.

[0284] The inclusion and exclusion criteria for enrolling subjects in this study are described below. All study inclusion / exclusion criteria were confirmed to be met at screening and prior to the first dose of study medication.

[0285] Inclusion criteria Each subject was required to meet all of the following criteria to be enrolled in the study: 1. 18 years of age or older. 2. Documented initial diagnosis of multiple myeloma according to IMWG diagnostic criteria. 3. Must have one of the following: ● Received at least 3 prior lines of therapy (see definition below) including a PI (2 cycles or more than 2 months of treatment) and an IMiD (2 cycles or more than 2 months of treatment) in any sequence during treatment (excluding subjects who discontinued any of these treatments due to severe allergic reactions within the first 2 cycles / months). Received at least one complete cycle of treatment per treatment unless progressive disease was the best response to treatment. For prior therapy without a PI and / or IMiD, to meet the criteria for at least prior therapy, the subject must have received at least one complete cycle or one month of therapy, unless the progressive disease responded best to treatment or the subject discontinued due to an adverse reaction; or Disease doubly refractory to a PI and an IMiD: For subjects who have received more than one type of PI, the disease must be refractory to the most recent type. Similarly, for patients who have received more than one type of IMiD, the disease must be refractory to the most recent type. NOTE: Subjects must have documented evidence of progressive disease within 12 months of their last treatment based on investigator response assessment by IMWG 2016 criteria as described by Kumar et al. 2016 (Lancet Oncol. 2016;17(8):e328-346.). Confirmation may be from either central or local testing. Also eligible are subjects with proven evidence of progressive disease within the past 6 months (as above) who are subsequently refractory or non-responsive to their most recent treatment. NOTE: For subjects enrolled in a treatment combination containing pomalidomide, prior IMiD therapy should have included lenalidomide. 4. Measurable disease at screening defined as any of the following: Serum monoclonal protein (M protein) level ≥ 1.0 g / dL (in non-IgG myeloma, M protein level ≥ 0.5 g / dL); or Urinary M-protein level ≥ 200 mg / 24 hours; or ●Light chain multiple myeloma: serum Ig free light chain (FLC) ≥ 10 mg / dL and abnormal serum Ig kappa lambda FLC ratio. 5. Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1 at screening and on Day 1 of pretreatment cycle 1 6. Laboratory values ​​meeting the following criteria prior to administration of daratumumab on Day 1 of Cycle 1:

[0286] [Table 12] Abbreviations: G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; ULN = upper limit of normal; RBC = red blood cells. 7. Females of childbearing potential must have a negative high-sensitivity serum beta-human chorionic gonadotropin (β-hCG) pregnancy test (<5 IU / mL) at screening, a negative urine or serum pregnancy test within 24 hours prior to the first dose of study drug, and consent to further serum or urine pregnancy tests during the study. 8. Women must be either: A. There is no possibility of pregnancy b. Have childbearing capacity, and -Practice true asceticism, - or have only one partner who has had a vasectomy -or practice at least one highly effective user-independent method of contraception (e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation / occlusion, or an implantable progestogen-only hormonal method associated with the inhibition of ovulation). If hormonal contraception is used (e.g., oral estrogen / progestin), male or female condoms with or without spermicide (e.g., spermicidal foam / gel / film / cream / suppository) must also be used. - For subjects receiving pomalidomide, females of childbearing potential must be receiving two methods of reliable contraception simultaneously while receiving study treatment and until 100 days after the last dose of study treatment: one method of contraception that is significantly more effective (tubal ligation, intrauterine device, hormonal [oral, injection, transdermal patch, vaginal ring, or implant], or partner's vasectomy) and one additional method of effective contraception (male latex or synthetic condom, diaphragm, or cervical cap). -For subjects not receiving pomalidomide, females of childbearing potential using oral contraceptives must use an additional method of contraception. Subjects must agree to continue the above while receiving study drug and for 100 days after the last dose. Females of childbearing potential must agree to a pregnancy test (serum or urine) within 100 days after the last dose of study drug. Note: If a woman is of childbearing potential after the start of the study, she must comply with item (b) above. Women who use oral contraceptives must use an additional method of contraception in addition to the requirements listed above. 9. Men must wear condoms (with or without spermicidal foam / gel / film / cream / suppository) during the study and for 100 days after the last dose of study drug when engaging in activities that allow the passage of ejaculated semen to another person. Female partners must also be using highly effective contraception (e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), combined (estrogen- and progestogen-containing) hormonal contraception associated with the inhibition of ovulation) if pregnancy is possible. If a man has had a vasectomy, he must continue to use condoms (with or without spermicidal foam / gel / film / cream / suppository), but his female partner does not need to use contraception. 10. Women must not donate or freeze eggs (eggs, oocytes) for assisted reproduction during the study or for future use for at least 100 months after receiving their last dose of the study drug. 11. Male participants must agree not to donate semen for reproductive purposes during the study and for at least 100 days after receiving the last dose of study drug. 12. The subject signs an informed consent form (ICF) indicating that they understand the purpose of the study and the procedures it will entail, and are willing and able to participate in the study. Consent must be obtained prior to the start of any study-related tests or procedures that are not part of the standard of care for the subject's disease. 13. Must be willing and able to abide by the prohibitions and restrictions specified in this Protocol. NOTE: A single treatment may consist of one or more agents and may include induction, hematopoietic stem cell transplant, and maintenance therapy. Radiation therapy, bisphosphonates, or a single short course of steroids (i.e., the equivalent of dexamethasone 40 mg / day or less for 4 days) are not considered prior lines of treatment.

[0287] Exclusion criteria Potential subjects meeting any of the following criteria will be excluded from participating in the study: 1. Treatment with anti-CD38 therapy (e.g., daratumumab) within the past 90 days, or discontinuation of prior anti-CD38 therapy at any time due to adverse events related to anti-CD38 therapy. 2. Antitumor therapy prior to the first dose of study drug, including: ·Targeted, epigenetic, or investigational therapy, or treatment with an investigational drug for 21 days or less or at least 5 half-lives or less, or an invasive medical device. Monoclonal antibody therapy within 21 days (anti-CD38 therapy cannot be used within the past 90 days). Cytotoxic therapy within 21 days. -PI therapy within 14 days. IMiD therapy within 7 days. Radiation therapy within 21 days. However, if the radiation portal was 5% or less of bone marrow reserve, subjects were eligible regardless of the end date of radiation therapy. · Genetically modified adoptive cell therapy (e.g., chimeric antigen receptor modified T cells, NK cells) within 90 months. 3. Cumulative administration of corticosteroids equivalent to ≥ 140 mg prednisone within a 14-day period prior to the first dose of study drug. 4. Live attenuated vaccines within 4 weeks prior to the first dose of study drug, unless approved by the sponsor. 5. Toxicity from prior anticancer therapy that has not resolved to baseline levels or Grade 1 or less (excluding alopecia [any grade] or peripheral neuropathy Grade 3 or less). 6. Stem cell transplant: · Subjects receiving allogeneic transplants must be off all immunosuppressive medications for at least 42 days without signs of graft-versus-host disease. Autologous stem cell transplant within 12 weeks of the first dose of study drug. 7. Clinical signs of central nervous system or meningeal involvement of multiple myeloma. If either is suspected, brain magnetic resonance imaging (MRI) and lumbar cytology are indicated. 8. Active plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathies, M protein, and skin changes), or primary amyloid light chain amyloidosis. 9. Known to be seropositive for human immunodeficiency virus. 10. Seropositive for Hepatitis B (defined by a positive test for Hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative with antibodies to total Hepatitis B core antigen [anti-HBc] with or without the presence of Hepatitis B surface antibodies [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of HBV DNA levels. Those who are PCR positive are excluded. Exception: Subjects with serological findings suggestive of HBV vaccination (anti-HBs positivity as the only serological marker) and a known history of prior HBV vaccination do not need to be tested for HBV DNA by PCR. 11. Active hepatitis C infection was measured by a positive hepatitis C virus (HCV)-RNA test. Subjects with a history of positive hepatitis C virus antibodies must undergo HCV-RNA testing. 12. Any of the following: Known chronic obstructive pulmonary disease (COPD) with forced vital capacity in 1 second (FEV1) less than 50% of predicted normal. Note: Please note that FEV1 testing is required for subjects suspected of having COPD and subjects must be excluded if FEV1 is less than 50% of predicted normal. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note: Please note that subjects with currently controlled intermittent asthma or controlled mild persistent asthma are allowed in the study. 13. Known allergy, hypersensitivity, or intolerance to the study intervention or its excipients (see Investigator's Brochure and Package Insert). 14. Any serious underlying medical condition, including: Evidence of severe active viral, bacterial, or uncontrolled systemic fungal infection; Active autoimmune disease requiring systemic immunosuppressive therapy within 6 months prior to the start of study treatment. Exceptions: Participants with vitiligo, type I diabetes, and previous autoimmune thyroiditis who are now euthyroid based on clinical symptoms and laboratory tests are eligible regardless of when these conditions were diagnosed. Mental health disorders (e.g., alcohol or drug abuse), dementia, or abnormal mental states Any other issue that may impair the subject's ability to receive, undertake, or tolerate the planned treatment at the treatment facility, or that may impair the subject's ability to provide informed consent or any conditions under which, in the investigator's judgment, participation would not be in the subject's best interest (e.g., impairing quality of life), or that may interfere with, limit, or confuse the evaluations specified in the protocol. 15. The following cardiac conditions: New York Heart Association stage III or IV heart failure - Myocardial infarction or unstable angina within 6 months prior to enrollment History of clinically significant ventricular arrhythmias or unexplained asphyxia not thought to be due to vasovagal natural causes or dehydration History of severe non-ischemic cardiomyopathy A screening 12-lead electrocardiogram (ECG) showing a mean baseline QT interval >470 ms corrected by the Fridericia formula (QTc) 16. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 100 days after the last dose of study drug. 17. Planning to father a child while enrolled in this study or within 100 days after the last dose of study drug. 18.Has undergone major surgery within 2 weeks of the first dose or is not expected to fully recover from surgery, or is scheduled for surgery at the time the subject is expected to be treated on the study. NOTE: Subjects who are scheduled for a surgical procedure performed under local anesthesia are eligible to participate. Subjects who may meet any of the following criteria will be excluded from participating in this study. 19. Subject has previously experienced a pomalidomide-related adverse event requiring discontinuation of treatment. NOTE: Investigators should ensure that all study entry criteria are met at screening and before the first dose of study medication. If after screening, but before the first dose of study medication is administered, the subject's clinical condition changes (including receipt of any available laboratory results or additional medical records) and the subject no longer meets all eligibility criteria, supportive care may be administered according to local standard of care, if necessary, so that the eligibility criteria are met and laboratory tests are repeated once to determine if the subject is eligible for the study. If the inclusion / exclusion criteria are not met after further evaluation, the subject should be excluded from participation in the study.

[0288] Study intervention Treatment was administered in 28-day cycles. Daratumumab was administered to all subjects by SC injection at a dose of 1800 mg as follows: weekly for cycles 1-2, every 2 weeks (Q2W) for cycles 3-6, and every 4 weeks thereafter. Note that recombinant human hyaluronidase PH20 (rHuPH20) was used to reduce the required injection volume and facilitate SC administration of daratumumab.

[0289] Daratumumab SC (Dara) was administered with teclistamab (Tec) at different dose levels: weekly Dara 1800mg + Tec 270μg / kg IV; weekly Dara 1800mg + Tec 1500μg / kg SC; weekly Dara 1800mg + Tec 3000μg / kg SC; every other week Dara 1800mg + Tec 300mg SC starting on day 1 of cycle 3 (in cycles 1-2, weekly Tec 150mg SC); every other week Dara 1800mg + Tec 3000μg / kg SC; Dara 1800mg + Tec 6000μg / kg (weekly in cycles 1 and 2, biweekly in cycles 3-6, once every 4 weeks in cycles 7 and subsequent cycles); Dara 1800mg + Tec 100mg weekly in cycles 1-2, Tec 200mg biweekly in cycles 3-7, Tec 200mg once every 4 weeks in cycles 7 and subsequent cycles (subjects must be ≦60kg); Dara 1800mg + Tec 150mg weekly in cycles 1-2, Tec 300mg biweekly in cycles 3-7, Tec 300mg once every 4 weeks in cycles 7 and subsequent cycles (subjects must be >60kg). Some subjects in the weekly Dara 1800mg + Tal 1500μg / kg SC cohort switched to Tal 3000μg / kg biweekly SC dosing after day 1 of cycle 3. Teclistamab titration began on day 2 of cycle 1, except for the 270 μg / kg teclistamab IV weekly cohort, which began titration dosing on day 9 of cycle 1. When daratumumab and teclistamab were administered on the same day, daratumumab was administered first. Titration dose 1 of teclistamab was administered at least 20 hours after SC daratumumab. If applicable, subsequent titration dose(s) and the first treatment dose of teclistamab were administered approximately 3 hours after SC daratumumab. Subsequent treatment doses of teclistamab were administered approximately 1 hour after SC daratumumab (when both study drugs were administered on the same day).

[0290] For treatments involving a combination of daratumumab SC, teclistamab SC, and pomalidomide, 4 mg of pomalidomide was administered orally once daily. Pomalidomide may be taken before or after the study drug in the combination treatment. To minimize the potential for increased risk of cytokine release syndrome (CRS) due to coadministration of bispecific antibodies and pomalidomide, the first cohort of subjects will receive a delayed dosing schedule of pomalidomide. If deemed appropriate by SET, a reduced starting dose or a later start date (e.g., starting on day 1 of cycle 2) may be implemented for pomalidomide for future cohorts based on review of safety data for the regimen. Dexamethasone will be given concurrently with the first three complete IMiD-containing cycles. During week 1 of cycle 1, dexamethasone 20 mg will be given on day 1 of cycle 1 prior to daratumumab SC, and two additional doses of dexamethasone 16 mg will be given, one each prior to titration dose 1 and titration dose 2 of the bispecific antibody. For the remainder of cycle 1 and any required cycles thereafter, dexamethasone will be given at 40 mg (oral or IV) weekly (except for subjects over 75 years of age or with a body mass index [BMI] < 18.5 who should receive 20 mg dexamethasone prior to SC administration of daratumumab only). Dexamethasone will be given approximately 1-3 hours prior to daratumumab SC (or bispecific antibody on days when daratumumab SC is not administered). After the required dexamethasone cycles above, the continuation and dosing schedule of dexamethasone to enhance the IMiD-driven antimyeloma effect will be based on the investigator's clinical judgment. If pomalidomide is permanently discontinued due to toxicity or intolerance, high-dose dexamethasone may also be discontinued based on the investigator's clinical judgment.

[0291] To minimize the potential for increased risk of cytokine release syndrome (CRS) with coadministration of the bispecific antibody and pomalidomide, the first cohort of subjects received a delayed dosing schedule of pomalidomide (C2D1 (Cycle 2, Day 1) or C1D15 (Cycle 1, Day 15)). The first subject in each cohort in Part 1 was observed for at least 36 hours after the first dose of teclistamab or before treating any subsequent subjects with a therapeutic dose.

[0292] Treatment also includes required and optional pre- and post-treatment medications associated with SC daratumumab and pomalidomide. Required and optional pre- and post-treatment medications for daratumumab can be a 2-week glucocorticoid taper, which can include, for example, IV or oral glucocorticoids (e.g., methylprednisolone 20-100 mg, dexamethasone 4-12 mg) before and after daratumumab administration for subjects not receiving pomalidomide; IV or oral antihistamines (e.g., diphenhydramine 25-50 mg or equivalent) or antipyretics (acetaminophen 650-1000 mg) as required prior to daratumumab administration for all subjects; and optional IV or oral glucocorticoids (methylprednisolone 60 mg (or dexamethasone 4-12 mg) prior to daratumumab administration for all subjects. Treatment with IV or oral glucocorticoids (e.g., dexamethasone, 8-16 mg), antihistamines (e.g., diphenhydramine 25-50 mg or equivalent), or antipyretics (acetaminophen 650-1000 mg) may also be required for subjects who experience Grade 2 or higher CRS / IRR, e.g., prior to all escalation doses and the first treatment dose, as pretreatment for teclistamab, or for the next two subsequent doses of teclistamab.

[0293] For subjects of any treatment combination at higher risk of respiratory complications (e.g., subjects with mild asthma or subjects with COPD who have an FEV1 <80% at screening or who will have an FEV1 <80% during the study and no history of the disease), the following post-injection medications should be considered: antihistamines, short-acting β2 adrenergic receptor agonists such as salbutamol, comparator medications for pulmonary disease (e.g., inhaled corticosteroids ± long-acting β2 adrenergic receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or salmeterol ± inhaled corticosteroids for subjects with COPD).

[0294] Research evaluation Safety, pharmacokinetic, immunogenicity, biomarker, efficacy, and other measures will be taken.

[0295] Safety will be assessed, for example, by physical examination (including neurological evaluation), Eastern Cooperative Oncology Group (ECOG) performance status, laboratory tests, vital signs, adverse event monitoring, and concomitant medication use. All adverse events, whether serious or non-serious, and special reporting circumstances will be reported from the time a signed and dated ICF is obtained until 100 days after the last dose of study drug, or if earlier, until the start of subsequent systemic anticancer therapy, and may include contact for safety follow-up. Adverse events (AEs) will be assessed by NCI-CTCAE v5.0, with the exception of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines. CRS (any grade) events will be followed until resolution or no further improvement.

[0296] Blood and serum or plasma samples were collected for assessment of pharmacokinetics and immunogenicity (e.g., antibodies to daratumumab, rHuPH20, or teclistamab). Selection of dose regimen (dose level and frequency) for dose expansion was determined based on pharmacokinetic and pharmacodynamic information obtained during dose escalation. Samples for pharmacokinetic and immunogenicity analysis were collected at scheduled times and any time a suspected IRR or CRS event was observed during the study (in case of CRS events, samples were collected at onset, 24 hours, and 72 hours).

[0297] Each serum sample was split evenly into three aliquots (one for daratumumab pharmacokinetics and immunogenicity, one for teclistamab pharmacokinetics and immunogenicity, and one backup). Each plasma sample for anti-rHuPH20 antibodies was split into five aliquots (three for anti-rHuPH20 antibodies and two for neutralizing antibodies for rHuPH20). Samples collected for pharmacokinetic and immunogenicity analysis may be used to evaluate safety or efficacy aspects to address concerns that arise during or after the study period, to evaluate sBCMA, or for further characterization of immunogenicity. For pharmacokinetic analysis, serum samples were analyzed to determine daratumumab and teclistamab concentrations using validated, specific, and sensitive assays. Pharmacokinetic parameters included area under the curve (AUC) (0-t) , AUC tau , C max , and T max These include, but are not limited to, and are calculated when sufficient data are available for the estimate. For immunogenicity analysis, detection and characterization of antibodies to daratumumab, rHuPH20, and teclistamab were performed using validated assay methods. Samples positive for binding antibodies were tested for neutralizing antibodies to daratumumab or teclistamab. For rHuPH20 immunogenicity assessment, plasma samples were screened for antibodies binding to rHuPH20 and evaluated in confirmatory and potency assays as appropriate.

[0298] Biomarker evaluation was performed in both parts 1 and 2. Biomarker evaluation focused on several main objectives: (1) immune responses indicative of T cell redirection for their potential contribution to response to the test agents; (2) the ability of each treatment combination to induce MRD negativity in subjects with multiple myeloma who achieved a CR; (3) serum proteomic profiling of cytokines (such as IL-6, IL-2, and IL-10) or other serum proteins indicative of an immune response; (4) biomarkers of response / resistance to myeloma cells (e.g., BCMA, CD38, and PD-L1); (5) determine the clinical benefit (ORR, duration of response [DOR], and time to response) of each treatment combination in subjects with cytogenetic alterations (del17p, t4;14;16) or other high-risk molecular subtypes); (6) immunophenotype of immune cell subsets such as CD4+ and CD8+ T cells, as well as regulatory T cells that may directly impact the mechanism of action. Additional biomarker samples can be collected to aid in understanding unexplained adverse events. Further sample(s) for cytokines could also be collected at any time points where a suspected IRR or CRS event was observed or reported during the study.

[0299] Disease assessment will be performed by a central laboratory until disease progression (additional samples may be collected for analysis by local laboratories). The study will use the IMWG-based response criteria described by Kumar et al. (2016) (Lancet Oncol. 2016;17(8):e328-346). For subjects with suspected daratumumab interference in serum immunofixation electrophoresis (IFE), a second reflex assay using an anti-idiotypic monoclonal antibody will be used to confirm daratumumab migration in IFE. Subjects who meet all other IMWG criteria for CR and whose positive IFE is confirmed to be daratumumab interference will be considered complete responders. For subjects with light chain multiple myeloma, both serum and urine IFE and serum FLC assays will be performed every 4 weeks. Additional serum samples may be utilized to monitor potential daratumumab interference with IFE and response as determined according to the IMWG-based response criteria. Quantitative immunoglobulins (QIg, e.g., IgG, IgA, IgM, IgE, and IgD), FLC and IFE measurements in serum and urine as well as serum β-microglobulin measured by electrophoresis (SPEP) are analyzed by a central laboratory. Disease progression based on only one of the laboratory tests was confirmed by at least one repeat study performed 1-3 weeks later. Disease evaluation continues beyond relapse from CR until disease progression is confirmed. Serum and urine IFE and serum FLC assays are performed at screening and thereafter if CR or sCR is suspected (if serum or 24-hour urine M-protein electrophoresis [by SPEP or UPEP] is 0 or not quantifiable). The development of hypercalcemia (corrected serum calcium >11 mg / dL) may indicate disease progression or recurrence if it is not attributable to any other cause. Therefore, corrected serum calcium or free ionized calcium was also analyzed in blood samples until the occurrence of confirmed disease progression.

[0300] Bone marrow aspirates or biopsies are performed for clinical and biomarker evaluation. Clinical staging (morphology, cytogenetics, and immunohistochemistry or immunofluorescence or flow cytometry) may be performed by a local laboratory. A portion of the bone marrow aspirate was used for immunophenotyping to monitor BCMA, CD38, and checkpoint ligand expression on CD138-positive multiple myeloma cells, as well as checkpoint expression on T cells. Bone marrow aspirate samples were required to confirm CR and sCR prior to the next scheduled dose of study drug. MRD negativity has been evaluated in the art as a potential surrogate for progression-free survival (PFS). Baseline bone marrow aspirates were used to define myeloma clones, and post-treatment samples were used to assess MRD negativity in subjects experiencing CR / sCR. Bone marrow aspirate DNA may be used to monitor MRD using next-generation sequencing, while serum MRD negativity is assessed via mass spectrometry.

[0301] A complete skeletal survey (including skull, entire spine, pelvis, thorax, humerus, femur, and any other bones suspected by the investigator to be involved by disease) was performed during the screening phase and assessed by either radiography or low-dose computed tomography (CT) scan (or positron emission tomography [PET] / CT) without the use of IV contrast. When assessing progression during treatment, the same methodology used at baseline should be used. MRI may also be included to assess bone disease.

[0302] statistical analysis No formal statistical hypothesis testing will be performed in this study. Part 1 (dose escalation) will be supported by a statistical model, a modified Continual Reassessment Method (mCRM) based on the Bayesian Logistic Regression Model (BLRM), using the Escalation with Overdosage Control (EWOC) principle. One or more RP2D(s) may be identified for each treatment combination. In Part 2 (dose expansion), subjects will be treated with each RP2D(s) to further evaluate the safety and antitumor activity of the selected treatment combination(s).

[0303] Endpoint definition ORR is defined as the proportion of subjects with PR or better according to IMWG criteria. Response to treatment will be assessed by the investigator. Clinical benefit rate (ORR+MR) is defined as the proportion of subjects with ≥ MR according to IMWG criteria, as assessed by the investigator. MRD negativity is defined as the proportion of subjects achieving MRD-negativity. DOR is defined as the time from the first documentation of response (PR or better) as defined by IMWG criteria to the first documentation of evidence of progressive disease or death from progressive disease, whichever occurs first. Relapse from CR is not considered disease progression. For subjects who have not progressed, data are censored at the time of the last disease assessment before the initiation of any subsequent anti-myeloma therapy. Time to response is defined as the time between the date of first administration of study drug and the first efficacy assessment at which the subject met all criteria for PR or better. PFS is defined as the time from the date of first dose of study drug to the date of first documented disease progression as defined by IMWG criteria or death from any cause, whichever occurs first. For subjects who are alive and have not progressed, data are censored at the time of the last disease assessment before the initiation of any subsequent anti-myeloma therapy.

[0304] Preliminary results for weight-based cohort (analysis cut-off April 6, 2022).

[0305] The study is ongoing and, as of the analysis cutoff date, had evaluated 65 patients treated with teclistamab and daratumumab.

[0306] Teclistamab SC (1.5 mg / kg QW and 3.0 mg / kg Q2W) + daratumumab SC cohort SC treatment with daratumumab and teclistamab was administered in 28-day cycles (with escalating dosing for teclistamab). Preliminary data as of April 6, 2022 included results for 65 subjects treated with 1800 mg of SC daratumumab and teclistamab (1.5 mg / kg weekly (1500 μg / kg) + 3 mg / kg weekly or every other week (3000 μg / kg)). An overview of the teclistamab and daratumumab dosing cohorts is shown in Table 12.

[0307] [Table 13] a. Used for teclistamab (including PIs and IMiDs), 1-3 escalating doses were given within 1 week prior to the full dose. Note: 9 patients were switched from 1.5 mg / kg SC Q1W to 3 mg / kg SC Q2W in cycles 4-9. Premedication (glucocorticoids, antihistamines, and antipyretics) was limited to the escalating doses of teclistamab and the first full dose. There was no steroid requirement for teclistamab after the first full dose. IMiD, immunomodulator; PI, proteasome inhibitor; qw, weekly; Q2W, once every 2 weeks

[0308] The median age range of the 65 subjects evaluated was 67 years (range 40-81 years), and 30 subjects were female (46.2%). The median number of prior therapies was 5 (range 1-15), and 80% of subjects were refractory to last treatment, 58.5% were 3-class refractory, 55.4% were 5-class exposed, and 30.8% were 5-class refractory. A summary of subject demographics and baseline characteristics is shown in Table 13.

[0309] [Table 14] a. Daratumumab SC 1800mg + teclistamab SC (1.5mg / kg QW or 3mg / kg QW or 3mg / kg Q2W) b. Includes one patient reported as Asian and one patient whose race was not reported. c included soft tissue plasmacytomas not involving bone; d. Percentages calculated from del(17p), t(4:14), and / or t(14;16); n = 48; Percentage calculated from en=54; f.BCMA CAR-T therapy or BCMA non-CAR-T therapy; g. Daratumumab or Isatuximab; h. thalidomide, lenalidomide, and / or pomalidomide; i. ≧1 PI, ≧1 IMiD, and ≧1 anti-CD38 mAb; j. ≥2 PI, ≥2 IMiD, and ≥1 anti-CD38 mAb; BCMA, B-cell maturation antigen; CAR-T, chimeric antigen T cell; IMiD, immunomodulatory agent; ISS, international staging system; PI, proteasome inhibitor; QW, weekly; Q2W, biweekly; SC, subcutaneous; mAb, monoclonal antibody.

[0310] The combination of teclistamab and daratumumab showed a well-tolerated, manageable safety profile with no new safety signals observed compared to the single agents and no overlapping toxicities. No treatment interruptions due to AEs occurred and no overlapping toxicities were observed. All CRS events were grade 1 or 2. Infections were reported in 44 (67.7%) patients (grade ≥ 3: 27.7%). One patient (1.5%) had a grade 1 ICANS event that completely resolved within 1 day. The most common all-grade non-hematologic AEs were neutropenia (49.2% any grade, 41.5% grade 3 or 4), anemia (41.5% any grade, 27.7% grade 3 or 4), and thrombocytopenia (32.3% any grade, 24.6% grade 3 or 4). The most common all-grade hematological AEs were CRS (67.7% any grade, 0 grade 3 or 4), diarrhea (32.3% any grade, 1.5% grade 3 or 4), nausea (27.7% any grade, 0 grade 3 or 4), and asthenia (20.0% any grade, 1.5% grade 3 or 4). An overview of AEs in patients treated with teclistamab and daratumumab is shown in Table 14.

[0311] [Table 15] Daratumumab SC 1800mg + teclistamab SC (1.5mg / kg QW or 3mg / kg QW or 3mg / kg Q2W) QW, weekly: Q2W, every other week; SC = subcutaneous; CRS, cytokine release syndrome; ICAN, immune effector cell-associated neurotoxicity syndrome; AEs were graded by CTCAE v 5, CRS and ICANS events were graded according to the American Society for Transplantation and Cellular Therapy 2019 criteria. AE: adverse event.

[0312] Fifty-one patients were evaluable for response. Overall response rate (ORR) was improved with teclistamab monotherapy compared with the phase 2 recommended dose. The ORR for patients treated with daratumumab SC 1800 mg and teclistamab SC Q2W 3 mg / kg (n=27) was 74.1%. The ORR for patients treated with daratumumab SC 1800 mg and teclistamab SC Q2W 1.5 mg / kg (n=20) was 75.0%. The ORR for patients treated with daratumumab SC 1800 mg and teclistamab SC 3 mg / kg (n=4) was 100%. The median follow-up was 8.6 months (range: 0.3-19.6), and the median time to first confirmed response was 1 month (range: 0.9-3.5). Table 15 below summarizes the ORR.

[0313] [Table 16] a. Patients have received at least one line of study treatment and have at least one post-baseline response assessment by the investigator, including unconfirmed responses. b. PR or better in response-evaluable patients, including unconfirmed responses. CR, complete response; ORR, overall response rate; PR, partial response; QW, weekly; Q2W, every other week; SC, subcutaneous; SD, stable disease; PD, progressive disease; RP2D, recommended phase 2 dose; tec, teclistamab; VGPR, very good partial response.

[0314] Responses were durable and deepened over time as shown in Figure 2. Responses were observed in heavily pretreated patients, including those who were either CD38-exposed or refractory. Median follow-up of responders was 9.6 months (range 1.5-19.6), with 26 responses on ongoing treatment at the time of cut-off. In addition, one participant had an ongoing response at cut-off after discontinuing treatment due to an adverse event.

[0315] A detailed overview of the overall response rates for patients treated with daratumumab 1800 mg and teclistamab (1500 μg / kg or 3000 μg / kg weekly, and 300 mg and 3000 μg / kg every other week) in combination with daratumumab with or without pomalidomide is shown in Table 16. Sixty-three participants across all teclistamab dose levels had a post-dose disease assessment ≥1 (i.e., were evaluable for efficacy) as of April 6, 2022. Patients receiving 300 mg SC teclistamab every other week in combination with daratumumab 1800 mg SC were treated weekly from day 15 of cycle 1 through cycle 2, then every other week from day 1 of cycle 3 (C3D1). Patients receiving 3000 μg / kg SC teclistamab in combination with 1800 mg daratumumab every other week were treated every other week starting on day 15 of cycle 1. Patients receiving 720 μg / kg or 750 μg / kg SC teclistamab in combination with 1800 mg SC daratumumab and 2 or 4 mg pomalidomide every other week starting on day 15 of cycle 1.

[0316] [Table 17-1]

[0317] [Table 17-2]

[0318] For subjects receiving 3000 μg / kg SC teclistamab weekly in combination with 1800 mg SC daratumumab (n=4 evaluable subjects), responses included 2 subjects (50.0%) with CR / sCR and 2 subjects (50.0%) with VGPR.For subjects receiving 720 μg / kg SC teclistamab weekly in combination with 1800 mg SC daratumumab and 4 mg pomalidomide (n=9 response-evaluable subjects), responses included 2 subjects (22.2%) with sCR, 3 subjects (33.3%) with CR, 2 subjects (22.2%) with VGPR, 1 subject (11.1%) with PR, and 2 subjects (22.2%) with progressive disease. There was one response-evaluable subject receiving SC teclistamab 750 μg / kg weekly in combination with SC daratumumab 1800 mg and pomalidomide 2 mg with SD. For subjects receiving SC teclistamab 300 mg every other week in combination with SC daratumumab 1800 mg (n=2 response-evaluable subjects), responses included 2 subjects (100%) with VGPR.

[0319] Biomarker data showed that the pharmacodynamic profile of teclistamab in the presence of daratumumab is consistent with the mechanism of action of these agents and the profile observed in the teclistamab monotherapy trial (MajesTEC-1). As of the cutoff date for biomarker analysis (April 6, 2022), biomarkers were evaluated in 35 subjects [1500 μg / kg QW (n=21) and 3000 μg / kg QW (n=5); 3000 μg / kg Q2W (n=9)]. There was a transient decrease in T cell counts early after teclistamab and daratumumab dosing, followed by recovery of T cell counts within 1 week (Figure 3). There was also a two-fold expansion of T cell counts by day 1 of cycle 3 (C3D1). Furthermore, T activation was induced by teclistamab combination with daratumumab (Figure 4). Induction of proinflammatory cytokines occurred following daratumumab and teclistamab (escalated and full dose) treatment (Figure 5). In two subjects, the CD38+ T cell subset is decreased following the first dose of daratumumab.

[0320] Teclistamab + daratumumab administration resulted in peripheral T cell activation, as demonstrated by induction of CD38+ / CD8+ T cells (Figure 6). The percentage of CD38+ / CD8+ T cells decreased after the first daratumumab administration on day 1 of cycle 1 (C1D1), consistent with previous data, but notably teclistamab administration resulted in induction of CD38+ T cells after the first escalating dose of teclistamab (C1D2).

[0321] Teclistamab SC (6.0 mg / kg) + daratumumab SC cohort SC treatment with daratumumab and teclistamab was administered in 28-day cycles (with escalating dosing for teclistamab). Preliminary data as of April 6, 2022 included results for 12 subjects treated with SC daratumumab 1800 mg and teclistamab 6.0 mg / kg (6000 μg / kg). An overview of the teclistamab and daratumumab dosing cohorts is shown in Table 17.

[0322] [Table 18]

[0323] The median number of prior lines of therapy was 6.0 (range, 2-15 lines), and the median follow-up time was 5.39 months (range, 1.0-6.0 months). Participants had received a median of 2.0 cycles of Tec-Dara treatment (range, 1-4 cycles). Two participants discontinued treatment due to death. One of these participants died due to grade 5 hemophagocytic syndrome (related to both study drugs) and the other participant died due to COVID-19 pneumonia (unrelated to study drug). One participant discontinued study treatment due to a TEAE of grade 4 COVID-19 pneumonia and subsequently died due to grade 5 COVID-19 pneumonia.

[0324] All participants (100.0%) had ≥1 TEAE. Four participants (33.3%) had a TEAE with a maximum severity of grade 3. Five subjects (41.7%) had a TEAE with a maximum severity of grade 4. Two participants had a grade 5 TEAE. Seven participants (58.3%) reported serious TEAEs. One participant experienced a grade 5 DLT of fatal hemophagocytic syndrome.

[0325] The most frequently reported TEAEs (≥20% of subjects) were fatigue (75%; all grade 1 or 2), CRS (58.3%; all grade 1 or 2), and neutropenia (58.3%; grade 3 / 4: 50%), decreased appetite (50%, all grade 1 or 2), recurrent cytomegalovirus infection (41.7%; grade 3 / 4: 25%), fever, nausea, and diarrhea (all 41.7%; all grade 1 or 2), chills (33.3%; all grade 1 or 2), dry mouth, abnormal breathing, weight loss, vomiting, hypocalcemia, and dysgeusia (25%; all grade 1 or 2), hypokalemia (25%; grade 3 / 4, 8.3%), and anemia (25%, grade 3 / 4: 16.7%). No ICANS were reported. Four participants (33.3%) experienced local injection site reactions. No patients experienced systemic infusion / infusion-related reactions.

[0326] Overall, the phase 1b data were encouraging with preliminary efficacy data suggesting encouraging ORR (70-100%) in heavily pretreated patients. Furthermore, teclistamab-mediated induction of cytotoxic T cells (CD38+ / CD8+) in the presence of daratumumab supports the rationale for the combination regimen. As a result, further investigation of the combination of teclistamab and daratumumab in patients with RRMM is warranted. For example, the randomized phase 3 MajesTEC-3 trial (NCT05083169) evaluates RRMM patients treated with teclistamab and daratumumab SC (Tec-Dara) versus daratumumab SC, pomalidomide, and dexamethasone (DPd), or daratumumab, bortezomib, and dexamethasone (DVd).

[0327] Example 2 A Phase 3 Randomized Study Comparing Teclistamab in Combination with Daratumumab SC (Tec-Dara) with Daratumumab SC, Pomalidomide, and Dexamethasone (DPd) or Daratumumab SC, Bortezomib, and Dexamethasone (DVd) in Participants with RRMM We will conduct a phase 3 randomized trial comparing teclistamab in combination with daratumumab SC (Tec-Dara) with daratumumab SC, pomalidomide, and dexamethasone (DPd) or daratumumab SC, bortezomib, and dexamethasone (DVd) in participants with relapsed or refractory multiple myeloma (RRMM). Participants must have received 1-3 prior lines of therapy, including a PI and lenalidomide.

[0328] Objectives and Endpoints The primary objective of the study is to compare the efficacy of teclistamab in combination with daratumumab SC (Tec-Dara; group A, Figure 7) with investigator-selected DPd or DVd (group B; hereafter referred to as DPd / DVd) as assessed by PFS. Key secondary objectives include further comparison of efficacy as assessed by overall response (PR or better) rate, CR or better rate, MRD (minimal residual disease) negativity rate, PFS2 (progression-free survival in the next line of treatment), and OS (overall survival). The study will be conducted in three stages for each participant: screening (until 28 days), treatment (until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent, or end of study, whichever occurs first), and follow-up (until death, withdrawal of consent, loss to follow-up, or end of study, whichever occurs first). Participants who discontinue study treatment for any reason other than progressive disease or withdrawal of consent will continue to be followed for response assessments until progressive disease is confirmed or until initiation of subsequent antimyeloma treatment. After progressive disease is confirmed, participants will be followed every 16 weeks for survival status, subsequent antimyeloma treatment, and occurrence of second primary malignancies until the end of the study.

[0329] Target population The study will be conducted with multiple myeloma patients who have previously received 1-3 prior lines of therapy, including a PI and lenalidomide. If a participant has received only one prior line of therapy, his or her disease must be lenalidomide refractory. The inclusion and exclusion criteria for enrolling subjects in the study are described below.

[0330] Inclusion criteria 1. 18 years of age or older. 2. Documented multiple myeloma defined by the following criteria: a. Diagnosis of multiple myeloma according to IMWG diagnostic criteria b. Measurable disease at screening, defined as any of the following: 1) Serum M-protein level ≥ 0.5 g / dL (central laboratory); or 2) Urinary M-protein level ≥ 200 mg / 24 hours (central laboratory); or 3) Serum immunoglobulin free light chain ≥ 10 mg / dL (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio. NOTE: All attempts should be made to determine participant eligibility based on central laboratory results of screening blood and urine M-protein measurements. In exceptional circumstances, after discussion with and written approval by the sponsor, local laboratory results of blood and urine M-protein measurements may be used to determine initial eligibility, but only if the results are >25% above the measurability threshold. In such cases, central laboratory results should still be obtained prior to the start of administration of study treatment to establish baseline central laboratory values ​​and to confirm results from the local laboratories. 3. Received 1-3 prior lines of anti-myeloma therapy including a PI and lenalidomide. Participants who have received only one prior line of anti-myeloma therapy must be lenalidomide refractory (i.e., have demonstrated progressive disease by IMWG criteria during treatment or within 60 days of completion of a lenalidomide-containing regimen). Progression on or within 60 days of the last dose of lenalidomide administered as maintenance meets this criterion. NOTE: Participants must have received at least one complete treatment cycle of each regimen unless progressive disease is the best response to a regimen. A single line of treatment may consist of one or more agents and may include induction, hematopoietic stem cell transplantation, and maintenance therapy. Radiation therapy, bisphosphonates, or a single short course of steroids (i.e., the equivalent of dexamethasone 40 mg / day or less for 4 days) are not considered prior lines of treatment. 4. Documented evidence of progressive disease based on investigator's assessment of response by IMWG criteria at or thereafter the last regimen. 5. Have an ECOG performance status score of 0, 1, or 2 at screening and immediately prior to the start of study treatment. 6.Has laboratory values ​​that meet the following criteria during the screening phase and at the start of study treatment:

[0331] [Table 19] ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor; RBC = red blood cells; ULN = upper limit of normal. In addition, these tests should be reevaluated within 72 hours. Prior to the first dose, participants must also meet all criteria. If the criteria are not met within 72 hours prior to dosing, one repeat of the laboratory test is permitted. If more than one repeat laboratory test is required, the sponsor must be consulted prior to dosing. 7. Females of childbearing potential must have a negative high-sensitivity serum pregnancy test at screening and again within 24 hours of initiating study treatment, and must consent to further serum or urine pregnancy tests during the study. 8. A woman must fulfil the following conditions: a. There is no possibility of pregnancy, or b. Have childbearing capacity, and 1) Practice true abstinence, or 2) Two effective methods of birth control (at least one must be a highly effective method such as tubal ligation, intrauterine device (IUD), or hormonal (birth control pill, hormonal patch, injectable patch, injection, etc.)). NOTE: Participants must agree to continue as above throughout the study and for 90 days after the last dose of study treatment. NOTE: If a woman has any possibility of becoming pregnant after the start of the study, she must follow item (b.) above. NOTE: Interactions between hormonal contraception and teclistamab have not been formally tested. Therefore, women randomized to group A were given hormone If contraceptives are being used, an additional barrier method should be used. NOTE: Sexual abstinence is considered a highly effective strategy only if it is defined as abstaining from heterosexual intercourse for the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be assessed in relation to the duration of the study and the participants' preferred and usual life patterns. 9. Women must agree not to donate or freeze eggs (eggs, oocytes) for future use for purposes of assisted reproduction during the study and for 90 days after receiving the last dose of study treatment. 10. Men must wear condoms (with spermicidal foam / gel / film / cream / suppository) when engaging in activities that allow passage of ejaculated semen to another person, throughout the study and for a minimum of 90 days after the last dose of study treatment. If the female partner is of childbearing potential, she must practice highly effective contraception. NOTE: If a male participant has had a vasectomy, he must continue to use condoms (with spermicidal foam / gel / film / cream / suppository), but his female partner does not need to use any contraception. 11. Male participants must agree not to donate sperm for reproductive purposes during the study and for a minimum of 90 days after the last dose of study treatment. 12. Be willing and able to adhere to the lifestyle restrictions specified in this protocol. 13. Participants must sign (or their legally acceptable representative must sign) an ICF indicating that the subject understands the purpose of the study and the procedures it will entail, and is willing to take part in the study.

[0332] Exclusion criteria Potential subjects meeting any of the following criteria will be excluded from participating in the study: 1. Contraindication or life-threatening allergy, hypersensitivity, or intolerance to the investigational product or its excipients (see teclistamab investigator's pamphlet and applicable package insert). Additional exclusion criteria for specific study drugs include: a. Participants are not eligible to receive DPd as a control therapy if any of the following are present: 1) Contraindication or life-threatening allergy, hypersensitivity, or intolerance to pomalidomide (intolerance defined as discontinuation of previous treatment due to any AE related to pomalidomide) 2)Disease considered refractory to pomalidomide by IMWG (progression during or within 60 days of completing pomalidomide treatment) b. Participants are not eligible to receive DVd as a control therapy if any of the following are present: 1) Contraindication or life-threatening allergy, hypersensitivity, or intolerance to bortezomib (intolerance defined as discontinuation of prior therapy due to any AE related to bortezomib) 2) Painful grade 1 peripheral neuropathy or grade 2 or greater peripheral neuropathy as defined by NCI-CTCAE version 5.0 3)Disease considered refractory to bortezomib by IMWG (progression during or within 60 days of completing bortezomib treatment) 4) Received a strong CYP3A4 inducer within 5 half-lives prior to randomization. c. Participants are not eligible for this study if they are refractory to both pomalidomide and bortezomib. 2. Received any prior BCMA-directed therapy. 3.Disease considered refractory to anti-CD38 monoclonal antibody by IMWG (progression during treatment with anti-CD38 monoclonal antibody or within 60 days of completion of treatment). 4. Received the following prior anti-myeloma therapy in the specified time frame prior to randomization: Treatment with targeted therapy, epigenetic therapy, or investigational drug or invasive investigational medical device within 21 days or at least 5 half-lives, whichever is shorter b. Investigational vaccines within the past 4 weeks c. Monoclonal antibody therapy within 21 days d. Cytotoxic therapy within 21 days e. PI therapy within 14 days f. IMiD therapy within 14 days g. Radiotherapy within 14 days or focal radiation within 7 days h. Genetically modified adoptive cell therapy (e.g., chimeric antigen receptor modified T cells, NK cells) within the past 3 months 5. Stem cell transplant: Allogeneic stem cell transplant within 6 months. Participants receiving an allogeneic transplant must be off all immunosuppressive medications for at least 42 days without evidence of graft-versus-host disease. b. Autologous stem cell transplant within 12 weeks prior to randomization. 6. Received a cumulative dose of corticosteroids equivalent to 140 mg prednisone or greater within 14 days prior to randomization. 7. Received a live attenuated vaccine within 4 weeks prior to randomization. 8. Myelodysplastic syndrome or active malignancy other than relapsed / refractory multiple myeloma (i.e., has progressed in the last 24 months or required a change in therapy). The only permitted exceptions are as follows: Non-muscle invasive bladder cancer that has been treated within the last 24 months and is considered to be completely cured b. Skin cancer (non-melanoma or melanoma) treated within the last 24 months that is considered to be cured c. Non-invasive cervical cancer that has been treated within the last 24 months and is considered to be completely cured d. Localized Prostate Cancer (N0M0): 1) Gleason score ≤ 6 and either treated within the last 24 months or untreated and under surveillance 2) Gleason score 3+4, treated ≥6 months prior to full study screening, and considered at very low risk of recurrence, or 3) Patients have a history of localized prostate cancer, have undergone androgen deprivation therapy, and are considered to be at very low risk of recurrence. e. Breast cancer: Adequately treated lobular carcinoma in situ or non-invasive breast cancer, or a history of localized breast cancer and treatment with anti-hormonal drugs, and considered to be at very low risk of recurrence. f. Other malignancies considered cured with minimal risk of recurrence. 9. Plasma cell leukemia, Waldenstrom macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathies, M-protein, and skin changes), or primary amyloid light chain amyloidosis at the time of screening. 10. Patients have clinical signs of CNS involvement or meningeal involvement of multiple myeloma. If either is suspected, a negative whole brain MRI and lumbar cytology are required. 11. Stroke or seizure within 6 months prior to signing the ICF. 12.Participant is pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 90 days after the last dose of study medication. 13. The participant plans to father a child while enrolled in this study or within 90 days after the last dose of study intervention. 14. Presence of any of the following cardiac conditions: New York Heart Association stage III or IV heart failure b. Myocardial infarction or coronary artery bypass graft within 6 months prior to randomization c. Clinically significant ventricular arrhythmias or a history of unexplained asphyxia not thought to be due to vasovagal natural or dehydration d. Uncontrolled cardiac arrhythmia or clinically significant ECG abnormalities 15. Any of the following: A. Seropositive for human immunodeficiency virus. b Hepatitis B infection (i.e., HBsAg or HBV-DNA positive). If the infection status is unknown, a quantitative level is required to determine the infection status. c. Active hepatitis C infection was measured by a positive HCV-RNA test. Subjects with a history of HCV antibody positivity must undergo HCV-RNA testing. Participants with a history of chronic hepatitis C infection (defined as both HCV antibody and HCV-RNA positive) are eligible for the study if they complete antiviral therapy and have undetectable HCV-RNA 12 weeks after completion of therapy. d. COPD with FEV1 less than 50% of predicted normal. Note that FEV1 testing is required for participants known or suspected to have COPD or asthma and participants must be excluded if FEV1 is less than 50% of predicted normal. e. Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Please note that FEV1 testing is required for participants known or suspected to have asthma, and participants must be excluded if FEV1 is less than 50% of predicted normal. Note: Please note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study. 16. May interfere with the test procedure or results; or any concomitant medical or psychiatric condition or disease which, in the opinion of the Investigator, poses the following risk to participating in the Study: A. Uncontrolled diabetes B. Acute diffuse infiltrative pulmonary disease c. Evidence of an active systemic viral, fungal, or bacterial infection requiring systemic antimicrobial therapy d. Active autoimmune disease or documented history of autoimmune disease, except for vitiligo, type I diabetes, and previous autoimmune thyroiditis that is now euthyroid based on clinical symptoms and laboratory tests. e. Mental health disorder (e.g., alcohol or drug abuse), dementia, or abnormal mental state f. Any other issue that may impair the participant's ability to receive or tolerate the planned treatment at the treatment center, or that may impair the participant's ability to provide informed consent or any conditions under which, in the investigator's judgment, participation would not be in the subject's best interest (e.g., impairing quality of life), or that may interfere with, limit, or confuse the evaluations specified in the protocol. g. History of non-compliance with recommended medical treatments 17.Has undergone major surgery within 2 weeks of the first dose, or is not scheduled to fully recover from surgery, or has surgery scheduled at the time the subject is expected to participate in the study or within 2 weeks after the last dose of test medication. NOTE: Participants who are scheduled for a surgical procedure performed under local anesthesia are eligible to participate. Kyphoplasty or vertebroplasty are not considered major surgery. If there are questions about these criteria, investigators should consult with the appropriate sponsor personnel and resolve the issue before enrolling the participant in the study.

[0333] Study intervention Approximately 560 participants will be randomized in a 1:1 ratio to Tec-Dara (Group A) or investigator's choice of DPd / DVd (Group B). Study treatment will be administered in 28-day cycles for Tec-Dara (Group A) and DPd (Group B). For DVd (Group B), study treatment will be administered in 21-day cycles for cycles 1-8 and 28-day cycles for cycles 9+. Participants in Groups A and B will be treated with the dosing regimens shown in Table 19.

[0334] [Table 20]

[0335] The teclistamab SC dosing schedule is a RP2D dose consisting of two escalating doses (0.06 and 0.3 mg / kg) followed by a weekly treatment dose of 1.5 mg / kg.

[0336] Randomization will be stratified by investigator's choice of DPd or DVd, screening stage per ISS (I vs. II vs. III), prior anti-CD38 monoclonal antibody exposure, and number of prior lines of therapy (1 vs. 2 or 3).

[0337] Test evaluation Efficacy evaluation Efficacy assessments will be performed according to protocol-defined IMWG criteria (2016) using data from serum, urine, bone marrow, and imaging (when applicable). Response or progression will be assessed by the investigator, using a validated algorithm, and by an Independent Review Committee (IRC).

[0338] Pharmacokinetic and immunogenicity evaluation Sparse blood samples will be collected for measurement of serum concentrations of teclistamab (Arm A [Tec-Dara] only) and daratumumab (both treatment arms) for PK analysis. Population PK analyses may be performed and results reported separately. Detection and characterization of anti-drug antibodies to teclistamab and daratumumab will be performed using validated or appropriately qualified assay methods.

[0339] Pharmacodynamic and biomarker evaluation Peripheral blood and bone marrow aspirates will be collected from participants in both treatment arms. Biomarker assessment will focus on the following objectives: 1) to evaluate pharmacodynamic biomarkers indicative of mechanism of action of teclistamab and daratumumab; 2) to determine the ability of study treatment to induce and maintain MRD negativity; 3) to investigate biomarkers of response / resistance for myeloma cells (e.g., levels of BCMA, CD38, and PD-L1 expression) and immune cell response / resistance biomarkers (e.g., activation / exhaustion markers on T cells); 4) to determine clinical benefit of study treatment in participants with cytogenetic alterations or other high-risk molecular subtypes.

[0340] Safety assessment The safety of teclistamab in combination with daratumumab SC will be assessed by physical examination, neurological examination, ECOG performance status, clinical laboratory tests, vital signs, and AE monitoring. The severity of AEs will be assessed using NCI-CTCAE version 5.0, except for CRS and ICANS grading, which will be assessed based on ASTCT guidelines. Concomitant medications will be recorded.

[0341] statistical methods The primary population for efficacy analysis is the intention-to-treat (ITT) population, which includes all randomized participants. The safety set consists of all randomized participants who received any study treatment. Stratified log-rank tests, Kaplan-Meier methods, and stratified Cox regression with treatment as the only explanatory variable will be used to analyze the primary efficacy endpoint of PFS. For binary secondary endpoints (e.g., overall response, VGPR or better, CR, and MRD negativity), stratified Cochran-Mantel-Haenszel tests will be used. For secondary time-to-event endpoints (e.g., OS, PFS2, time to ProS deterioration, and time to next treatment), a similar methodology to PFS will be adopted. One interim analysis is planned for PFS after 218 PFS events (O'Brien & Fleming alpha consumption). The final analysis for PFS will be performed after 335 PFS events have been reported. The end of the study will be defined by a final OS (overall survival) analysis, which will be performed at the beginning of 335 events or 5 years after the last participant was randomized.

[0342] Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the present invention, and that such changes and modifications may be made without departing from the spirit of the present invention. It is therefore intended in the appended claims to cover all such equivalent variations that fall within the true spirit and scope of the present invention.

[0343] The disclosures of each patent, patent application, and publication cited or described in this specification are hereby incorporated by reference in their entirety.

Claims

1. 1. A pharmaceutical composition for use in treating multiple myeloma in a subject in need thereof, comprising a BCMAxCD3 bispecific antibody, said method comprising: (1) administering to the subject a BCMAxCD3 bispecific antibody at a dose of 200 μg / kg to 3 mg / kg every 1 to 4 weeks; (2) administering to the subject an anti-CD38 antibody at a dose of 1200 mg to 2400 mg every 1 to 4 weeks.

2. The method comprises: (1) subcutaneously administering the BCMAxCD3 bispecific antibody to the subject at a dose of 1 mg / kg to 3 mg / kg every 1 to 4 weeks; (2) subcutaneously administering the anti-CD38 antibody to the subject at a dose of 1600 mg to 2000 mg every 1 to 4 weeks.

3. The method, (i) administering to the subject 1.5 mg / kg of the BCMAxCD3 bispecific antibody subcutaneously once a week during weeks 1 through 8 of treatment, and 3.0 mg / kg of the BCMAxCD3 bispecific antibody subcutaneously every two weeks from week 8 onwards; and (ii) administering 1800 mg of the anti-CD38 antibody subcutaneously to the subject once a week during weeks 1 through 8 of treatment, every two weeks during weeks 9 through 24, and every four weeks from week 24 onward. Including, the BCMAxCD3 bispecific antibody (1) a BCMA-binding domain having heavy chain complementarity determining regions (HCDRs) 1, 2, and 3 of the amino acid sequences of SEQ ID NOs: 18, 19, and 20, respectively, and light chain complementarity determining regions (LCDRs) 1, 2, and 3 of the amino acid sequences of SEQ ID NOs: 21, 22, and 23, respectively; (2) a CD3-binding domain having HCDR1, 2, and 3 of the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively, and LCDR1, 2, and 3 of the amino acid sequences of SEQ ID NOs: 31, 32, and 33, respectively; The pharmaceutical composition according to claim 1 or 2, comprising:

4. The pharmaceutical composition of claim 3, further comprising subcutaneous administration of 0.06 mg / kg of the BCMAxCD3 bispecific antibody on the second day of treatment, and subcutaneous administration of 0.3 mg / kg of the BCMAxCD3 bispecific antibody on the fourth day, followed by an initial subcutaneous administration of 1.5 mg / kg of the BCMAxCD3 bispecific antibody.

5. The pharmaceutical composition of claim 2, further comprising subcutaneously administering the BCMAxCD3 bispecific antibody to the subject at a dose of less than 0.5 mg / kg, followed by subcutaneous administration of the BCMAxCD3 bispecific antibody at doses of 1 mg / kg to 3 mg / kg.

6. The pharmaceutical composition of claim 4, wherein the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody to the subject at a dose of 1.5 mg / kg weekly, 3.0 mg / kg weekly, or 3.0 mg / kg every other week.

7. The pharmaceutical composition of claim 6, wherein the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody to the subject at a dose of 1.5 mg / kg weekly.

8. The pharmaceutical composition of claim 6, wherein the method comprises subcutaneously administering the BCMAxCD3 bispecific antibody to the subject at a dose of 3 mg / kg weekly.

9. The pharmaceutical composition of any one of claims 1, 2, 5 to 8, wherein the method comprises subcutaneously administering the anti-CD38 antibody to the subject at a dose of 1800 mg once a week during weeks 1 to 8 of the treatment, once every two weeks during weeks 9 to 24 of the treatment, and once every four weeks after week 24 of the treatment.

10. The pharmaceutical composition of claim 10, wherein the anti-CD38 antibody is administered or provided for administration together with rHuPH20, e.g., about 30,000 U of rHuPH20.

11. the BCMAxCD3 bispecific antibody (1) A BCMA-binding domain comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (HCDRs) HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NOs: 18, 19, and 20, respectively, and a light chain variable region (VL) comprising light chain complementarity determining regions (LCDRs) LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NOs: 21, 22, and 23, respectively; and (2) A pharmaceutical composition according to any one of claims 1, 2, 5 to 8, comprising a CD3-binding domain comprising a VH comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 29, and SEQ ID NO: 30, respectively, and a VL comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 32, and SEQ ID NO: 33, respectively.

12. 9. The pharmaceutical composition of any one of claims 1, 2, 5 to 8, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) comprising the amino acid sequence of SEQ ID NO: 26, a first light chain (LC1) comprising the amino acid sequence of SEQ ID NO: 27, a second heavy chain (HC2) comprising the amino acid sequence of SEQ ID NO: 36, and a second light chain (LC2) comprising the amino acid sequence of SEQ ID NO:

37.

13. The pharmaceutical composition of any one of claims 1, 2, 5 to 8, wherein the anti-CD38 antibody comprises a VH having HCDR1, HCDR2, and HCDR3 of the amino acid sequences of SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively, and a VL having LCDR1, LCDR2, and LCDR3 of the amino acid sequences of SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13, respectively.

14. The pharmaceutical composition of claim 13, wherein the CD38 antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 6 and a VL comprising the amino acid sequence of SEQ ID NO:

7.

15. 9. The pharmaceutical composition of any one of claims 1, 2, 5 to 8, wherein the subject is refractory or relapsed to a treatment selected from the group consisting of an anti-CD38 antibody, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, ixazomib, isatuximab, melphalan and thalidomide, or any combination thereof, preferably the subject is lenalidomide refractory.

16. A pharmaceutical composition described in any one of claims 1, 2, 5 to 8, wherein the subject has undergone at least one previous treatment for multiple myeloma, or the subject is relapsed or refractory to said at least one previous treatment, and said previous treatment may include at least one of a proteasome inhibitor (PI) or an immunomodulatory agent (IMiD).

17. A pharmaceutical composition described in any one of claims 1, 2, 5 to 8, wherein the method further comprises administering an additional therapeutic agent, such as pomalidomide and / or dexamethasone, to the subject.

18. 9. The pharmaceutical composition of any one of claims 1, 2, 5 to 8, wherein the treatment results in T cell activation such as an increase in at least one of CD25, PD-1, CD38 on CD4 and CD8 T cells, or wherein the treatment results in an increase in the frequency of at least one of CD38+CD8+ T cells, CD38+CD4+ T cells, and Tregs T cells.

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