Methods for treating multiple myeloma

Abstract

Embodiments of the present invention relate to methods of treating multiple myeloma in a subject in need thereof comprising administering to the subject a BCMAxCD3 bispecific antibody on a novel dosing schedule.

Description

METHODS FOR TREATING MULTIPLE MYELOMACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of United States Provisional Application Serial No. 63 / 651,207, filed May 23, 2024, the entire contents of which is incorporated herein by reference in its entirety.SEQUENCE STATEMENT

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on April 19, 2025, is named JBI6907WOPCTl.xml and is 24,338 bytes in size.FIELD

[0003] Methods of treating multiple myeloma are disclosed.BACKGROUND

[0004] Multiple myeloma (MM) is a cancer of the plasma cells. Mechanistically, multiple myeloma is characterized by production of monoclonal proteins (M-proteins) comprised of pathological immunoglobulins or fragments of such, which have lost their function. The proliferation of multiple myeloma cells leads to subsequent displacement from the normal bone marrow niche, while overproduction of M-proteins causes characteristic osteolytic lesions, increased susceptibility to infections, hypercalcemia, renal insufficiency or failure, and neurological complications.

[0005] Treatment options for multiple myeloma have improved over time and vary depending on the aggressiveness of the disease, underlying prognostic factors, physical condition of the patient, and existing comorbidities. Therapeutic options include proteasome inhibitors (Pls), immunomodulatory drugs (IMiDs), alkylating agents, monoclonal antibodies (mAbs), antibody drug conjugate, histone deacetylase inhibitor, nuclear protein export inhibitor, chimeric antigen receptor (CAR) T cell therapy and stem cell transplantation.

[0006] Despite these therapeutic achievements, the disease recurs and is associated with additional risk factors (e.g., comorbidities or increasing age), thus warranting the need for novel therapeutic approaches, such as new dosage and treatment regimens. In particular in the elderly population, for which stem cell transplantation is often not a viable option, and inpatients with refractory disease who exhausted several therapies, multiple myeloma remains an incurable malignancy and an unmet medical need with significant morbidity and mortality. In particular, there remains a need for therapeutic regimens that achieve rapid, deep and durable clinical responses, while providing manageable safety profiles.SUMMARY

[0007] An embodiment of the present invention provides a method of treating relapsed or refractory multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject a BCMAxCD3 bispecific antibody (e.g., teclistamab) in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W).

[0008] According to certain embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.

[0009] According to certain embodiments, the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and theCD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0010] According to certain embodiments, the BCMAxCD3 bispecific antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.

[0011] According to certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0012] According to certain embodiments, the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

[0013] According to certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

[0014] According to certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).

[0015] According to certain embodiments, the Fc region of the BCMA-binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

[0016] According to certain embodiments, the Fc region of the CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).

[0017] According to certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0018] According to certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.

[0019] According to certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence ofSEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.

[0020] According to certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.

[0021] According to certain embodiments, the BCMAxCD3 bispecific antibody is teclistamab.

[0022] According to certain embodiments, the BCMAxCD3 bispecific antibody is administered as a monotherapy.

[0023] According to certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy.

[0024] According to certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy, including a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.

[0025] According to certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy, including lenalidomide and an anti-CD38 monoclonal antibody in any prior line.

[0026] According to certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy including a minimum of 2 consecutive cycles of an anti-CD38 monoclonal antibody in any prior line and 2 consecutive cycles of lenalidomide in any prior line.

[0027] According to certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy, including a minimum of 2 consecutive cycles each of a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.

[0028] According to certain embodiments, the treatment cycle # 1 comprises administering two step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW).

[0029] According to certain embodiments, the treatment cycle # 1 comprises administering a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody, then2-4 days later administering a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a first treatment dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody, and then administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1.5 mg / kg.

[0030] According to certain embodiments, the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 3; administering a treatment dose of 1.5 mg / kg on Days 5, 12 and 1, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.

[0031] According to certain embodiments, the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 4; administering a treatment dose of 1.5 mg / kg on Days 7, 14 and 21, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.

[0032] According to certain embodiments, the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer progression-free survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonalantibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

[0033] According to certain embodiments, the subject exhibits longer progression-free survival compared to the reference subject’s progression-free survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months

[0034] According to certain embodiments, the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer overall survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

[0035] According to certain embodiments, the subject exhibits longer overall survival compared to the reference subject’s overall survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

[0036] According to certain embodiments, the subject exhibits a partial response, a very good partial response, a complete response, or a stringent complete response, according to IMWG 2016 criteria.

[0037] According to certain embodiments, the subject exhibits a complete response or a stringent complete response, according to IMWG 2016 criteria.

[0038] According to certain embodiments, the antibody exhibits a pharmacokinetic (PK) profile that is equivalent or similar to (e.g., within about 2% or about 5% or about 10% or about 15% or about 20% or about 25% of) a PK profile of a reference antibody, wherein the antibody and the reference antibody have different glycosylation profiles. According to certain embodiments, the PK profile comprises one or more of the following PK parameters: (i) serumconcentration of the antibody during the treatment cycle #1, 2 or 3, (ii) Cmax of the first treatment dose, (iii) area under serum concentration versus time curve (AUCtau) of the first treatment dose, and (iv) Ctrough on Day 1 of the treatment cycle #3.

[0039] According to certain embodiments, the antibody comprises neutral N-linked oligosaccharides having less than about 75% GOF, greater than about 20% GIF, and greater than about 2% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having greater than about 70.0% GOF, less than about 15% GIF, and less than about 3% G2F.

[0040] According to certain embodiments, the antibody comprises neutral N-linked oligosaccharides having less than about 65% GOF, greater than about 25% GIF, and greater than about 4% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having greater than about 75.0% GOF, less than about 12% GIF, and less than about 2% G2F.

[0041] According to certain embodiments, the antibody comprises neutral N-linked oligosaccharides having about 40% to about 70% GOF, about 15% to about 35% GIF, and about 3% to about 7% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having about 75.0% to about 90% GOF, about 7% to about 12% GIF, and about 0.1% to about 2% G2F.

[0042] According to certain embodiments, the antibody comprises neutral N-linked oligosaccharides having about 50% to about 60% GOF, about 25% to about 30% GIF, and about 4% to about 6% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having about 75.0% to about 85% GOF, about 7.5% to about 10.5% GIF, and about 0.4% to about 1.2% G2F.

[0043] According to an embodiment, a method of increasing median progression-free survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, comprises: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response,administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median progression-free survival is relative to the median progression-free survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd). According to certain embodiments, the increase in the median progression-free survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

[0044] According to an embodiment, a method of increasing median overall survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, comprises: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median overall survival is relative to the median overall survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib anddexamethasone (Kd). According to certain embodiments, the increase in the median overall survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

[0045] According to an embodiment, a method of increasing a percentage of subjects that exhibit a complete response or stringent complete response (according to IMWG 2016 criteria) in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, comprises: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the percentage of subjects that exhibit a complete response or stringent complete response is relative to percentage of subjects that exhibit a complete response or stringent complete response in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

[0046] According to certain embodiments, the teclistamab is administered as a monotherapy.

[0047] All methods described herein, however expressed, may be described as corresponding uses, in particular medical uses.BRIEF DESCRIPTION OF THE DRAWINGS

[0048] The following figures form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these figures in combination with the description of specific embodiments presented herein.

[0049] FIG. 1 is a graph that illustrates teclistamab serum concentration: time profile of post-change versus pre-change following teclistamab administration at 0.06 / 0.3 / 1.5 mg / kg SC weekly. Data is shown as mean ± standard deviation for scheduled visits up to Cycle 4 Day 1. Post-change profile shows preliminary data from participants trated in SC cohort 20 and available as of 06 September 2023 (n<12 / timepoint), while pre-change profile represents the participants in Phase 1 of Maj eTEC- 1 who received RP2D (n<40 / timepoint).

[0050] FIG. 2 is a table of oligosaccharide mapping results for pre -change versus postchange batches of teclistamab drug substance (DS). Superscript a: G0F corresponds to a biantennary, core-fucosylated structure containing 4 N-acetylglucosamine (GN), 3 mannose (M) and 1 fucose (F); GIF and G2F are the same structure with an additional 1 and 2 galactose (G), respectively. GIF includes GIF and GIF’ (positional isomer of galactose of GIF). Mono- sialylated corresponds to either a GIF or G2F structure with one sialic acid (N- acetylneuraminic acid). Other Neutrals (non-fucosylated) include GO and GO-GlcNAc and high mannose structures (M5, M6, and M8). Other Neutrals (fucosylated) include G0F-GN, G0F+GN, and a biantennary, core-fucosylated structure with 2 GN and 3 mannose (M3F). Superscript b: The historical ranges are the actual minimum -maximum ranges (or one-sided limits), and the statistical process capability ranges are mean ±3SD ranges. These ranges were based on the release and characterization results from n = 17 DS batches from the pre-change process and included the head-to-head testing results for methods used in this study. The historical ranges for free thiol and intact mass (glycation) were based on 5 batches. For some attributes, the historical ranges were not available or not applicable. Superscript c: LOQ = 0.4%. Due to rounding, the total area percent may not equal 100.0%.DETAILED DESCRIPTION

[0051] The disclosed methods can be understood more readily by reference to the following detailed description. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is notintended to be limiting of the claimed methods. All patents, published patent applications and publications cited herein are incorporated by reference as if set fourth fully herein.

[0052] As used herein, the singular forms “a,” “an,” and “the” include the plural.

[0053] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0054] “About” when used in reference to numerical ranges, cutoffs, or specific values means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of an assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0055] “Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins can be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (K) and lambda (X), based on the amino acid sequences of their constant domains.

[0056] “Antigen binding fragment” or “antigen binding domain” refers to a portion of an immunoglobulin molecule that binds an antigen. Antigen binding fragments can be synthetic, enzymatically obtainable or genetically engineered polypeptides and include the VH, the VL, the VH and the VL, Fab, F(ab')2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1 , the LCDR2 and / or the LCDR3. VH and VL domains can be linked together via a synthetic linker to form various types of single chain antibody designs where the VH / VL domains can pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Int. Patent Publ. Nos. W01998 / 44001, WO1988 / 01649, WO1994 / 13804 and W01992 / 01047.

[0057] BCMA refers to human B-cell maturation antigen, also known as CD269 or TNFRSF17 (UniProt Q02223). The extracellular domain of BCMA encompasses residues 1-54 of Q02223. Human BCMA comprises the amino acid sequence of SEQ ID NO: 1.SEQ ID NO: 1MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTN AILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSR TGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTND YCKSLPAALSATEIEKSISAR

[0058] “Bispecific” refers to an antibody that specifically binds two distinct antigens or two distinct epitopes within the same antigen. The bispecific antibody can have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Maccicci cynomolgus (cynomolgus, cyno) or Pan troglodytes, or can bind an epitope that is shared between two or more distinct antigens.

[0059] “BCMAxCD3 bispecific antibody” refers to a bispecific antibody that specifically binds BCMA and CD3.

[0060] “Cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can alsometastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” can include a tumor.

[0061] CD3 refers to a human antigen which is expressed on T cells as part of the multimolecular T cell receptor (TCR) complex and which consists 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.SEQ ID NO: 2MQSGTHWRVLGLCLLSVGVWGQDGNEEMGGITQTPYKVSISGTTVILTCPQYP GSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPE DANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAK AKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRISEQ ID NO: 3DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIG SDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

[0062] “CH3 region” or “CH3 domain” refers to the CH3 region of an immunoglobulin. The CH3 region of human IgGl antibody corresponds to amino acid residues 341-446. However, the CH3 region can also be any of the other antibody isotypes as described herein.

[0063] “Combination” means that two or more therapeutics are administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0064] “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. CDRs can be defined using various delineations such as Kabat (Wu et al., J. Exp. Med. 132(2):211-250 (1970) and 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(4):901-917 (1987)),IMGT (Lefranc et al., Dev. Comp. Immunol. 27( 1): 55-77 (2003)) and AbM (Martin and Thornton, J. Mol. Biol. 263(5): 800-815 (1996)). The correspondence between the various delineations and variable region numbering are described (see, e.g., Lefranc et al., Dev. Comp. Immunol. 27(l):55-77 (2003); Honegger and Pluckthun, J. Mol. Biol. 309(3):657-670 (2001); International ImMunoGeneTics (IMGT®) database). Available programs such as abYsis byUCL Business PLC can be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification. Preferably, the term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR1”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by the method of Kabat.

[0065] “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 description and the claims, the words “comprise”, “comprising”, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0066] “Fc gamma receptor” (FcyR) refers to well-known FcyRI, FcyRIIa, FcyRIIb or FcyRIII. Activating FcyR includes FcyRI, FcyRIIa and FcyRIII.

[0067] “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. “Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, “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 an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, “human antibody” can contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., I. Mol. Biol. 296(l):57-86 (2000) or synthetic HCDR3incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., J. Mol. Biol. 397(2):385-396 (2010), and in Int. Patent Publ. No. W02009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”.

[0068] “Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody can include substitutions in the frameworks so that the frameworks can not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0069] “Identity” refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by aligning and comparing the sequences. “Percent (%) sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN (DNAStar, Inc.) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0070] “Isolated” refers to a homogenous population of molecules (such as synthetic polynucleotides or a protein such as an antibody) which have been substantially separated and / or purified away from other components of the system the molecules are produced in, such as a recombinant cell, as well as a protein that has been subjected to at least one purification or isolation step. “Isolated antibody” refers to an antibody that is substantially free of other cellular material and / or chemicals and encompasses antibodies that are isolated to a higher purity, such as to 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% purity.

[0071] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such asamino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibody can be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent.

[0072] “Mutation” refers to an engineered or naturally occurring alteration in a polypeptide or polynucleotide sequence when compared to a reference sequence. The alteration can be a substitution, insertion or deletion of one or more amino acids or polynucleotides.

[0073] “Negative minimal residual disease status” or “negative MRD status” or “MRD negative” refers to the PerMillionCount (i.e., a point estimate of malignant myeloma cells per million nucleated cells) in a patients on-study bone marrow sample relative to their reference bone marrow sample (i.e., Teclistamab treatment naive bone marrow sample). Based on this PerMillionCount, each sample is determined to be positive or negative. Samples are positive if the PerMillionCount is greater than or equal to the limit of sensitivity, otherwise they are negative. Negative minimal residual disease status can be determined at a sensitivity of 0.01% (IO-4), 0.001% (10-5) or 0.0001% (IO-6). Negative minimal residual disease status was determined using next generation sequencing (NGS).

[0074] “Pharmaceutical composition” refers to composition that comprises an active ingredient and a pharmaceutically acceptable carrier.

[0075] “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject.

[0076] “Recombinant” refers to DNA, antibodies and other proteins that are prepared, expressed, created or isolated by recombinant means when segments from different sources are joined to produce recombinant DNA, antibodies or proteins.

[0077] “Refractory” refers to a cancer that is not amendable to surgical intervention and is initially unresponsive to therapy.

[0078] “Relapsed” refers to a cancer that responded to treatment but then returns.

[0079] “Step-up dose” - refers to a dose of an active agent that is administered to a subject prior to a treatment dose. A step-up dose is lower than the treatment dose. To prevent or lessen certain toxicities, such as cytokine release syndrome (CRS), a “priming” dose strategy may include one or more lower step-up dose(s) followed by higher treatment doses.

[0080] “Subject” includes any human or nonhuman animal. “Nonhuman animal” includes all vertebrates, e.g., mammals and non-mammals, such as nonhuman primates, sheep,dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. Except when noted, the terms “patient” or “subject” are used interchangeably.

[0081] “T cell redirecting therapeutic” refers to a molecule containing two or more binding regions, wherein one of the binding regions specifically binds a cell surface antigen on a target cell or tissue and wherein a second binding region of the molecule specifically binds a T cell antigen. Examples of cell surface antigen include a tumor associated antigen, such as BCMA. Examples ofT cell antigen include, e.g., CD3. This dual / multi-target binding ability recruits T cells to the target cell or tissue leading to the eradication of the target cell or tissue.

[0082] “Therapeutically effective amount” refers to an amount effective, at doses and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient.

[0083] “Treat” or ‘ ‘treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder. Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0084] “Treatment dose” refers to a dose of the active agent that is administered to a subject to treat a disease. A treatment dose may be administered at a regular dosing interval on a repetitive basis (e.g. weekly, biweekly, monthly). A treatment dose may be preceded by one or more step-up doses.

[0085] A patient that is “triple-class exposed” refers to a multiple myeloma patient that has previously been treated with (at a minimum) a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.

[0086] “Tumor cell” or a “cancer cell” refers to a cancerous, pre-cancerous or transformed cell, either in vivo, ex vivo, or in tissue culture, that has spontaneous or induced phenotypic changes. These changes do not necessarily involve the uptake of new geneticmaterial. Although transformation can arise from infection with a transforming virus and incorporation of new genomic nucleic acid, uptake of exogenous nucleic acid or it can also arise spontaneously or following exposure to a carcinogen, thereby mutating an endogenous gene. Transformation / cancer is exemplified by morphological changes, immortalization of cells, aberrant growth control, foci formation, proliferation, malignancy, modulation of tumor specific marker levels, invasiveness, tumor growth in suitable animal hosts such as nude mice, and the like, in vitro, in vivo, and ex vivo.

[0087] The numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991), unless otherwise explicitly stated. Antibody constant chain numbering can be found for example at ImMunoGeneTics website, at IMGT Web resources at IMGT Scientific charts.

[0088] Conventional one and three-letter amino acid codes are used herein as shown in Table 1.Table 1.BCMAxCD3 Bispecific Antibodies and Uses Thereof

[0089] It is well-known in the art that drug development is an unpredictable field. The lack of predictability in the art is evidenced, for example, by health authority requirements (such as those of the Food and Drug Administration) to establish a safe and effective dosing regimen for each individual drug candidate in clinical trials. Over the last decade (2011-2020), only 7.9% of all developmental drug candidates achieved FDA approval from a Phase I clinical study. See Clinical Development Success Rates and Contributing Factors 2011-2020. The rate of success is even lower in oncology, such that only 5.3% of oncology drug candidates succeed.

[0090] In the field of oncology, even for a drug that already has an established dose in a particular indication, the Food and Drug Administration (FDA) recommends further clinical studies to identify an optimal dose for a new indication; otherwise, patients may be exposed to unreasonable and significant risk, among other potential deficiencies. See, e.g., Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases,' Draft Guidance for Industry; January 2023).

[0091] In patients with relapsed or refractory disease who have exhausted several therapies, multiple myeloma remains an incurable malignancy and an unmet medical need with significant morbidity and mortality. The present inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that provide improved safety profiles over currently approved regimens while maintaining deep and durable efficacy.

[0092] Teclistamab (also known as TECVAYLI®) is the first BCMA-directed bispecific antibody approved for the treatment of patients with relapsed or refractory multiple myeloma. Teclistamab is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least three or four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody. The efficacy of teclistamab is continuing to be evaluated in patients with relapsed or refractory multiple myeloma in a multi -center clinical study (MajesTEC-1, NCT03145181 [Phase 1] and NCT04557098 [Phase 2]). The study has included patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. In the MajesTEC-1 study, at 14. 1-month median followup, teclistamab demonstrated rapid, deep and durable responses, with an overall response rate (ORR) of 63% and median progression-free survival (mPFS) of 11.3 months (see, e.g., Usmaniet al., Lancet 398(10301):665-674 (2021) and Moreau et al., New Engl. J. Med. 387(6):495- 505 (2022), which are incorporated by reference herein).

[0093] Patients with relapsed or refractory multiple myeloma (RRMM) are already at increased risk of infection, and bispecific antibodies targeting B-cell maturation antigen (BCMA) may contribute to increased infection risk, due to on-target, off-tumor toxicity. In the MajesTEC-1 clinical study, patients (N=165) received subcutaneous teclistamab 1.5 mg / kg weekly following a step-up dosing schedule (0.06 mg / kg and 0.3 mg / kg, each separated by 2-4 days). At a median follow-up of 21.6 months (range 0.26-32.69), infections were reported in 129 patients (78.2%). Overall, grade 3 / 4 infections occurred in 86 patients (52.1%), most commonly pneumonia (20.6%), COVID-19 (18.8%), sepsis (6.1%), and urinary tract infection (6.1%). Grade 3 / 4 neutropenia occurred in 65.5% of patients. Thus, there remains a need for optimized dosing regimens of BCMAxCD3 bispecific antibodies with improved safety profdes. The inventors have developed optimized dosing regimens based, at least in part, on emerging clinical data,that reduce infection rates in patients, while still achieving rapid, deep and durable clinical responses. For example, it is believed that a BCMAxCD3 dosing schedule that comprises 28-day treatment cycles and 1.5 mg / kg weekly dosing during treatment cycles 1-2, followed by 3 mg / kg biweekly (Q2W) dosing for treatment cycles 3-6, and a switch to 3 mg / kg teclistamab monthly (Q4W) dosing from Cycle 7 onward, or an earlier switch to 3 mg / kg teclistamab monthly (Q4W) dosing at any of cycles 3-6 if a subject has achieved VGPR or better, will have comparable safety and efficacy with the 1.5 mg / kg teclistamab QW dose schedule, while further increasing the convenience and flexibility for patients, caregivers, and healthcare providers.

[0094] In addition, teclistamab is manufactured by mammalian cell culture, and it was discovered that changes to the manufacturing process for teclistamab result in post-change teclistamab having differences in the glycosylation profile of the Fc region compared with prechange teclistamab. It is believed that the differences in glycosylation profile does not impact the pharmacokinetic profile of teclistamab in subjects.Antibodies of the Present Invention

[0095] Any suitable BCMAxCD3 bispecific antibody known to those skilled in the art in view of the present disclosure can be used in the invention.

[0096] Various bispecific antibody formats include formats described herein and recombinant IgG-like dual targeting molecules, wherein the two sides of the molecule each contain the Fab fragment or part of the Fab fragment of at least two different antibodies; IgGfusion molecules, wherein full length IgG antibodies are fused to an extra Fab fragment or parts of Fab fragment; Fc fusion molecules, wherein single chain Fv molecules or stabilized diabodies are fused to heavy-chain constant-domains, Fc-regions or parts thereof; Fab fusion molecules, wherein different Fab-fragments are fused together; ScFv- and diabody-based and heavy chain antibodies (e.g., domain antibodies, nanobodies) wherein different single chain Fv molecules or different diabodies or different heavy-chain antibodies (e.g. domain antibodies, nanobodies) are fused to each other or to another protein or carrier molecule, or bispecific antibodies generated by arm exchange. Exemplary bispecific formats include dual targeting molecules include Dual Targeting (DT)-Ig (GSK / Domantis), Two-in-one Antibody (Genentech) and mAb2 (F-Star), Dual Variable Domain (DVD)-Ig (Abbott), DuoBody (Genmab), Ts2Ab (Medlmmune / AZ) and BsAb (Zymogenetics), HERCULES (Biogen Idee) and TvAb (Roche), ScFv / Fc Fusions (Academic Institution), SCORPION (Emergent BioSolutions / Trubion, Zymogenetics / BMS) and Dual Affinity Retargeting Technology (Fc- DART) (MacroGenics), F(ab)2 (Medarex / AMGEN), Dual-Action 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 Diabody (Academic), TCR-like Antibodies (AIT, ReceptorLogics), Human Serum Albumin ScFv Fusion (Merrimack) and COMBODY (Epigen Biotech), dual targeting nanobodies (Ablynx), dual targeting heavy chain only domain antibodies. Various formats of bispecific antibodies have been described, for example in Chames and Baty, Curr. Opin. Drug Disc. Dev. 12(2):276-283 (2009) and in Nunez-Prado et al., Drug Discovery Today 20(5):588-594 (2015), which are incorporated by reference herein.

[0097] In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMA binding domains described in WO2017 / 031104, the entire content of which is incorporated herein by reference. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the CD3 binding domains described in W02017 / 031104. In some embodiments, the BCMAxCD3 bispecific antibody comprises any one of the BCMAxCD3 bispecific antibodies described in WO2017 / 031104.

[0098] In some embodiments, the BCMAxCD3 bispecific antibody is chimeric, humanized or human.

[0099] In some embodiments, the bispecific antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype. In preferred embodiments, the bispecific antibody is an IgG4 isotype. An exemplary wild-type IgG4 comprises an amino acid sequence of SEQ ID NO: 24.SEQ ID NO: 24:ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPS CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDG VEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQK SLSLSLGK

[0100] The bispecific antibody can be of any allotype. It is expected that allotype has no influence on properties of the bispecific antibodies, such as binding or Fc-mediated effector functions. Immunogenicity of therapeutic antibodies is associated with increased risk of infusion reactions and decreased duration of therapeutic response (Baert et al., N. Engl. J. Med. 348(7):601-608 (2003)). The extent to which therapeutic antibodies induce an immune response in the host can be determined in part by the allotype of the antibody (Stickler et al., Genes Immun. 12(3):213-221 (2011)). Antibody allotype is related to amino acid sequence variations at specific locations in the constant region sequences of the antibody. Table 2 shows select IgGl, IgG2 and IgG4 allotypes.Table 2.

[0101] In some embodiments, the bispecific antibody comprises one or more Fc substitutions that reduces binding of the bispecific antibody to a Fey receptor (FcyR) and / or reduces Fc effector functions such as Clq binding, complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis (ADCP). The specific substitutions can be made in comparison to the wild-type IgG4 of SEQ ID NO: 24.

[0102] Fc positions that can be substituted to reduce binding of the Fc to the activating FcyR and subsequently to reduce effector function are substitutions L234A / L235A on IgGl, 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-deleted / A327G / P331A / D365E / L358M on IgGl, H268Q / V309L / A330S / P331S on IgG2, S267E / L328F on IgGl, L234F / L235E / D265A on IgGl, L234A / L235A / G237A / P238S / H268A / A330S / P331S on IgGl, S228P / F234A / L235A / G237A / P238S on IgG4, and S228P / F234A / L235A / G236- deleted / G237A / P238S on IgG4, wherein residue numbering is according to the EU index.

[0103] Fc substitutions that can be used to reduce CDC are a K322A substitution.

[0104] Well-known S228P substitution can further be made in IgG4 antibodies to enhance IgG4 stability.

[0105] In some embodiments, the bispecific antibody comprises one or more asymmetric substitutions in a first CH3 domain or in a second CH3 domain, or in both the first CH3 domain and the second CH3 domain.

[0106] In some embodiments, the one or more asymmetric substitutions is selected from the group consisting of F405L / K409R, wild-type / F405L_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_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F and T350V_L351 Y_F405 A_Y407V / T350V_T366L_K392L_T394W.

[0107] In some embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises phenylalanine at position 405 and arginine at position 409 in a first heavy chain (HC1) and leucine at position 405 and lysine at position 409 in a second heavy chain (HC2), wherein residue numbering is according to the EU Index.

[0108] In some embodiments, the BCMAxCD3 bispecific antibody further comprises proline at position 228, alanine at position 234 and alanine at position 235 in both the HC1 and the HC2.

[0109] Table 3 and Table 4 provide sequences of an exemplary embodiment of a BCMAxCD3 bispecific antibody, according to the Kabat numbering system.Table 3. Exemplary Sequences of a BCMA Binding ArmTable 4. Exemplary sequences of a CD3 binding arm

[0110] In some embodiments, the BCMAxCD3 bispecific antibody is CC-93269, BI 836909, JNJ-64007957 (teclistamab), or PF-06863135. In preferred embodiments, the BCMAxCD3 bispecific antibody is Teclistamab (also referred to herein as Tec).[oni] Teclistamab and its methods of use are described, for example, in WO2017 / 031104, WO 2019 / 220369 and WO 2021 / 228783, which are incorporated by reference herein. According to particular embodiments, the BCMAxCD3 bispecific antibody has an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequence of teclistamab.

[0112] In certain embodiments, the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.

[0113] In certain embodiments, the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

[0114] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.

[0115] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype.

[0116] In certain embodiments, the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

[0117] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

[0118] In certain embodiments, the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).

[0119] In certain embodiments, the Fc region of the BCMA -binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

[0120] In certain embodiments, the Fc region of the CD3 CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).

[0121] In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

[0122] In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.

[0123] In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.

[0124] In certain embodiments, the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.

[0125] In certain embodiments, the BCMAxCD3 bispecific antibody is teclistamab.Patient Populations with Multiple Myeloma

[0126] The BCMAxCD3 bispecific antibodies disclosed herein are for use in treating multiple myeloma in a subject, for example a human subject, wherein the subject is relapsed or refractory to treatment with one or more prior anti -cancer treatments. Relapsed disease means acancer has come back. Refractory disease means a cancer has not improved with treatment or has stopped responding to treatment.

[0127] In some embodiments, the subject is relapsed or refractory to treatment with a therapeutic used to treat multiple myeloma or other hematological malignancies.

[0128] In certain embodiments, the subject has received one prior line of antimyeloma therapy.

[0129] In certain embodiments, the subject has received 2 prior lines of antimyeloma therapy.

[0130] In certain embodiments, the subject has received 3 prior lines of antimyeloma therapy.

[0131] In certain embodiments, the subject has received at least 3 prior lines of antimyeloma therapy.

[0132] In certain embodiments, the subject has received at least 4 prior lines of antimyeloma therapy.

[0133] In certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy.

[0134] In certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy, including a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.

[0135] In certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy, including lenalidomide and an anti-CD38 monoclonal antibody in any prior line.

[0136] In certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy, including a minimum of 2 consecutive cycles each of a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody (or minimum of 6 doses if anti-CD38 monoclonal antibody was only part of a maintenance regimen) in any prior line.

[0137] In certain embodiments, the subject has received 1 to 3 prior lines of antimyeloma therapy including a minimum of 2 consecutive cycles of an anti-CD38 monoclonal antibody (or minimum of 6 doses if anti-CD38 monoclonal antibody was only part of a maintenance regimen) in any prior line and 2 consecutive cycles of lenalidomide in any prior line.

[0138] In particular embodiments, the patients are relapsed or refractory or intolerant to the last line of therapy (LOT); were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy; and had measurable disease.

[0139] In some embodiments, the subject has received three anti -cancer therapies prior to administration of the BCMAxCD3 bispecific antibody. In one embodiment, the three prior anti -cancer therapies are a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody. In certain such embodiments, the proteasome inhibitor is bortezomib, carfilzomib or ixazomib, the immunomodulatory drug (IMiD) is lenalidomide, pomalidomide or thalidomide and the anti-CD38 antibody is daratumumab or isatuximab.

[0140] In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is bortezomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.

[0141] In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is carfilzomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.

[0142] In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is lenalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, theimmunomodulatory drug (IMiD) is pomalidomide and the anti-CD38 antibody is isatuximab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is daratumumab. In one embodiment, the proteasome inhibitor is ixazomib, the immunomodulatory drug (IMiD) is thalidomide and the anti-CD38 antibody is isatuximab.

[0143] In some embodiments, the subject is refractory or relapsed to treatment with one or more treatments or therapies, such as THALOMID® (thalidomide), REVLIMID® (lenalidomide), POMALYST® (pomalidomide), VELCADE® (bortezomib), NINLARO (ixazomib), KYPROLIS® (carfilzomib), FARAD YK® (panobinostat), AREDIA® (pamidronate), ZOMETA® (zoledronic acid), DARZALEX® (daratumumab), elotozumab or melphalan, Xpovio ® (Selinexor), Venclexta ® (Venetoclax), GSK 916, CAR-T therapies, or other BCMA-directed therapies.

[0144] Various qualitative and / or quantitative methods can be used to determine relapse or refractory nature of the disease. Symptoms that can be associated are for example a decline or plateau of the well-being of the patient or re-establishment or worsening of various symptoms associated with solid tumors, and / or the spread of cancerous cells in the body from one location to other organs, tissues or cells.

[0145] In some embodiments, the multiple myeloma is relapsed or refractory to treatment with an anti-CD38 antibody, selinexor, venetoclax, lenalinomide, bortezomib, pomalidomide, carfilzomib, elotozumab, ixazomib, melphalan or thalidomide, or any combination thereof.

[0146] In one embodiment, the anti-CD38 antibody is daratumumab.

[0147] In another embodiment, the anti-CD38 antibody is isatuximab

[0148] In some embodiments, the multiple myeloma is a 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 is they have one or more of the following cytogenetic abnormalities: t(4; 14)(p 16;q32), t( 14; 16)(q32;q23), dell7p, IqAmp, t(4; 14)(p 16;q32) and t(14; 16)(q32;q23), t(4; 14)(p 16;q32) and dell7p, t(14; 16)(q32;q23) and dell7p, or t(4; 14)(p 16;q32), t(14; 16)(q32;q23) and dell7p. In some embodiments, the subject having the high-risk multiple myeloma has one or more chromosomal abnormalities comprising: t(4; 14)(p 16;q32), t( 14; 16)(q32;q23), dell7p, IqAmp, t(4; 14)(pl6;q32) and t(14; 16)(q32;q23), t(4; 14)(p 16;q32) and dell7p, t( 14; 16)(q32;q23) and dell7p; ort(4;14)(pl6;q32), t( 14; 16)(q32;q23) and dell7p, or any combination thereof.

[0149] The cytogenetic abnormalities can be detected for example by fluorescent in situ hybridization (FISH). In chromosomal translocations, an oncogene is translocated to the IgH region on chromosome 14q32, resulting in dysregulation of these genes. t(4;14)(pl6;q32) involves translocation of fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain containing protein (MMSET) (also called WHSC1 / NSD2), and t(14;16)(q32;q23) involves translocation of the MAF transcription factor C-MAF. Deletion of 17p (dell7p) involves loss of the p53 gene locus.

[0150] Chromosomal rearrangements can be identified using well known methods, for example fluorescent in situ hybridization, karyotyping, pulsed field gel electrophoresis, or sequencing.Administration of a BCMAxCD3 Bispecific Antibody

[0151] The inventors have developed novel dosing regimens for BCMAxCD3 bispecific antibodies that provide improved safety profiles over currently approved regimens while maintaining deep and durable clinical responses overtime. For example, it is believed that a BCMAxCD3 dosing schedule that comprises 28-day treatment cycles and 1.5 mg / kg weekly dosing during treatment cycles 1-2, followed by 3 mg / kg biweekly (Q2W) dosing for treatment cycles 3-6, and a switch to 3 mg / kg teclistamab monthly (Q4W) dosing from Cycle 7 onward, or an earlier switch to 3 mg / kg teclistamab monthly (Q4W) dosing at any of cycles 3- 6 if a subject has achieved VGPR or better, has comparable safety and efficacy with the 1.5 mg / kg teclistamab QW dose schedule, while further increasing the convenience and flexibility for patients, caregivers, and healthcare providers.

[0152] As used herein, “weight-based” refers to administration of a dose amount that is based on the subject’s specific body weight; for example, 3 mg / kg refers to a dose of 3 milligrams of antibody per kilogram of the subject’s body weight. Unless otherwise specified herein, when a dose is described in a unit of “mg / kg” or “pg / kg,” weight-based dosing is being employed.

[0153] Unless otherwise specified herein, a BCMAxCD3 bispecific antibody, such as teclistamab, is administered on a dosing schedule based on sequential 28-day treatment cycles, for example, Cycle 1 starts on Day 1 of Cycle 1 and ends on Day 28 of Cycle 1, and then Day 1 of Cycle 2 starts the day after Day 28 of Cycle 1 and ends on Day 28 of Cycle 2, and then Day 1 of Cycle 3 starts the day after Day 28 of Cycle 2 and ends on Day 28 of Cycle 3, and so on.

[0154] As used herein “Q4W” means once every four weeks, “Q2W” (also referred to as “bi-weekly” or “biweekly”) means once every two weeks, and “QW” (also referred to as “weekly”) means once weekly. Q4W is sometimes referred to herein as “monthly” but technically refers to once every 4 weeks or once every 28 days (e.g., in 28-day cycles, a first treatment dose occurs on Day 1 of Cycle 1, a second treatment dose occurs on Day 1 of Cycle 2, etc.). Administration of a treatment dose once weekly (QW) is also referred to herein as a weekly dosing schedule. Administration of a treatment dose once every two weeks (Q2W) is also referred to herein as a bi-weekly dosing schedule. Administration of a treatment dose once every four weeks (Q4W) is also referred to herein as a monthly dosing schedule.

[0155] Additional abbreviations used herein include the following: CR, complete response; PR, partial response; Q2W, once every 2 weeks; Q4W, once every 4 weeks; QW, once weekly; RP2D, recommended phase 2 dose; SUD, step-up dose.

[0156] According to certain embodiments, the BCMAxCD3 bispecific antibody (e.g., teclistamab) is subcutaneously administered in sequential 28-day treatment cycles, as follows:Cycle 1 : 0.06 mg / kg step-up dose on Day 1, 0.3 mg / kg step-up dose (e.g., on Day 3 or Day 4), and 1.5 mg / kg weekly (QW) treatment doses thereafter (e.g., on Days 5, 12 and 19; or on Days 7, 14 and 21);Cycle 2: 1.5 mg / kg weekly (QW) (e.g., Days 1, 8, 15 and 22);Cycles 3-6: 3 mg / kg biweekly (Q2W) (e.g., Days 1 and 15), and may optionally change to monthly (Q4W) dosing (on Day 1 of a cycle) when in confirmed VGPR or better prior to Cycle 7;Cycle 7 and subsequent cycles: 3 mg / kg monthly (Q4W) (e.g., Day 1).

[0157] According to certain embodiments, the BCMAxCD3 bispecific antibody (e.g., teclistamab) is subcutaneously administered in sequential 28-day treatment cycles, as shown in Table A:Table A

[0158] According to certain embodiments, the BCMAxCD3 bispecific antibody (e.g., teclistamab) is subcutaneously administered in sequential 28-day treatment cycles, as shown inTable B:Table BaMay optionally change to Q4W dosing when in confirmed VGPR or better prior to Cycle 7.bA subject is not required to receive Q2W dosing of teclistamab prior to Q4W dosing if a response ofVGPR or better is confirmed by C3D1. No subject should switch to less frequent dosing before C3D1.cAll subjects should change to Q4W dosing (Day 1 only) from Cycle 7. In exceptional cases, participants can continue Q2W dosing (Day 1 and Day 15) from Cycle 7. Participants on Q4W dosing can optionally switch back to Q2W dosing.

[0159] According to embodiments of the present invention, methods of treating multiple myeloma are effective in eliciting a clinical response in a subject as determined by International Myeloma Working Group (IMWG) response criteria. According to particular embodiments, the methods of treatment are effective in eliciting a partial response, a very good partial response, a complete response or a stringent complete response, as determined by IMWG response criteria. As used herein, overall response rate (ORR) refers to the percentage of patients in a population that achieve a partial response (PR) or better, i.e., a partial response,very good partial response, complete response or stringent complete response. IMWG criteria for response to Multiple Myeloma treatment are provided in Table C below.Table CCR=complete response; FLC=free light chain; IMWG=Intemational Myeloma Working Group; M-protein=monoclonal paraprotein; MR=minimal response; PC=plasma cell; PD=progressive disease; PR=partial response; sCR=stringent complete response; SD=stable disease; VGPR=very good partial responseaPresence / absence of clonal cells is based upon the kappa / lambda ratio. An abnormal kappa / lambda ratio by immunohistochemistry or immunofluorescence requires a minimumof 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa / lambda of >4: 1 or <1:2.* Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the only measurable disease is by serum FLC levels: CR in such subjects indicates a normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such subjects requires a >90% decrease in the difference between involved and uninvolved FLC levels.

[0160] IMWG criteria for response to Multiple Myeloma treatment are also described, for example, in Durie et al., Kumar et al., and Rajkumar et al., which are incorporated by reference herein: Durie BG, Harousseau JL, Miguel JS, et al., “International Uniform Response Criteria for Multiple Myeloma,” Leukemia. 20(9): 1467-1473 (2006); Kumar S, Paiva B, Anderson KC, et al., “International Myeloma Working Group Consensus Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma,” Lancet Oncol. 17(8):e328- 346 (2016); Rajkumar SV, Harousseau JL, Durie B, et al., “Consensus Recommendations for the Uniform Reporting of Clinical Trials: Report of the International Myeloma Workshop Consensus Panel 1, ’’ Blood. 117(18):4691-4695 (2011).

[0161] Additional embodiments of dosing regimens of the present invention are described below.

[0162] An embodiment of the present invention provides a method of treating relapsed or refractory multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject a BCMAxCD3 bispecific antibody (e.g., teclistamab) in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; andtreatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W). According to certain embodiments, the BCMAxCD3 bispecific antibody (e.g., teclistamab) is administered as a monotherapy.

[0163] According to certain embodiments, the treatment cycle #1 comprises administering two step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW).

[0164] According to certain embodiments, the treatment cycle #1 comprises administering a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a first treatment dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody, and then administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1.5 mg / kg.

[0165] According to certain embodiments, the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 3; administering a treatment dose of 1.5 mg / kg on Days 5, 12 and 1, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.

[0166] According to certain embodiments, the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 4; administering a treatment dose of 1.5 mg / kg on Days 7, 14 and 21, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises:administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.

[0167] According to certain embodiments, the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer progression-free survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

[0168] According to certain embodiments, the subject exhibits longer progression-free survival compared to the reference subject’s progression-free survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months

[0169] According to certain embodiments, the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer overall survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

[0170] According to certain embodiments, the subject exhibits longer overall survival compared to the reference subject’s overall survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

[0171] According to certain embodiments, the subject exhibits a partial response, a very good partial response, a complete response, or a stringent complete response, according to IMWG 2016 criteria.

[0172] According to certain embodiments, the subject exhibits a complete response or a stringent complete response, according to IMWG 2016 criteria.Differences in Glycosylation Profile

[0173] Changes to the teclistamab manufacturing process increased the amount of teclistamab produced per batch: teclistamab made using the initial manufacturing process is termed “pre-change” teclistamab herein, and teclistamab made using the new process is termed “post-change” teclistamab herein. Teclistamab is manufactured by mammalian cell culture, and changes in the manufacturing process result in post-change teclistamab having differences in the glycosylation profde of the Fc region compared with pre-change teclistamab.

[0174] As described herein, carbohydrate structures for drug substances (e.g., prechange and post-change teclistamab drug substance batches) are evaluated by oligosaccharide mapping of the PNGase F released N-glycans using hydrophilic interaction liquid chromatography (HILIC) with fluorescence detection. Glycans labeled with the 2- aminobenzamide (2 -AB) fluorophore are quantitated by peak area integration of the HPLC chromatograms and expressed as a percentage of the total glycan peak area. As used herein, G0F corresponds to a biantennary, core-fucosylated structure containing 4 N- acetylglucosamine (GN), 3 mannose (M) and 1 fucose (F); GIF and G2F are the same structure with an additional 1 and 2 galactose (G), respectively. GIF includes GIF and GIF’ (positional isomer of galactose of GIF). Mono-sialylated corresponds to either a GIF or G2F structure with one sialic acid (N-acetylneuraminic acid). Other Neutrals (non-fucosylated) include GO and GO-GlcNAc and high mannose structures (M5, M6, and M8). Other Neutrals (fucosylated) include G0F-GN, G0F+GN, and a biantennary, core-fucosylated structure with 2 GN and 3 mannose (M3F).

[0175] According to certain embodiments, HILIC chromatograms for pre-change and post-change teclistamab drug substance (DS) batches are highly similar by visual inspection of the peak profde. According to certain embodiments, G0F is the major species in pre-change and post-change teclistamab, but GIF, G2F, and high mannose peaks are higher in the postchange DS. For example, FIG. 2 provides a table of oligosaccharide mapping results for prechange versus post-change batches of teclistamab drug substance, in which the post-change DS had higher levels of N-glycans with terminal galactose (GIF and G2F) and a decrease in N-glycans with no galactose (GOF) (FIG. 2); the high mannose (M5, M6, and M8) N-glycans were also slightly higher in the post-change DS.

[0176] According to certain embodiments, the antibody (e.g., post-change teclistamab) exhibits a pharmacokinetic (PK) profde that is equivalent or substantially similar to a PK profde of a reference antibody (e.g., pre-change teclistamab), wherein the antibody and the reference antibody have different glycosylation profdes in their Fc regions. According to certain embodiments, the PK profde comprises one or more of the following PK parameters: (i) serum concentration of the antibody during treatment cycle #1, 2 or 3, (ii) Cmax of the first treatment dose, (iii) area under serum concentration versus time curve (AUCtau) of the first treatment dose, and (iv) Ctrough on Day 1 of the treatment cycle #3.

[0177] According to certain embodiments, the antibody (e.g., post-change teclistamab) comprises neutral N-linked oligosaccharides having less than about 75% GOF, greater than about 20% GIF, and greater than about 2% G2F, and the reference antibody (e.g., pre-change teclistamab) comprises neutral N-linked oligosaccharides having greater than about 70.0% GOF, less than about 15% GIF, and less than about 3% G2F.

[0178] According to certain embodiments, the antibody (e.g., post-change teclistamab) comprises neutral N-linked oligosaccharides having less than about 65% GOF, greater than about 25% GIF, and greater than about 4% G2F, and the reference antibody (e.g., pre-change teclistamab) comprises neutral N-linked oligosaccharides having greater than about 75.0% GOF, less than about 12% GIF, and less than about 2% G2F.

[0179] According to certain embodiments, the antibody (e.g., post-change teclistamab) comprises neutral N-linked oligosaccharides having about 40% to about 70% GOF, about 15% to about 35% GIF, and about 3% to about 7% G2F, and the reference antibody (e.g., prechange teclistamab) comprises neutral N-linked oligosaccharides having about 75.0% to about 90% GOF, about 7% to about 12% GIF, and about 0.1% to about 2% G2F.

[0180] According to certain embodiments, the antibody (e.g., post-change teclistamab) comprises neutral N-linked oligosaccharides having about 50% to about 60% GOF, about 25% to about 30% GIF, and about 4% to about 6% G2F, and the reference antibody (e.g., prechange teclistamab) comprises neutral N-linked oligosaccharides having about 75.0% to about 85% GOF, about 7.5% to about 10.5% GIF, and about 0.4% to about 1.2% G2F.

[0181] According to an embodiment, a method of increasing median progression-free survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, comprises: administering to the population of subjects teclistamab,wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median progression-free survival is relative to the median progression-free survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd). According to certain embodiments, the increase in the median progression-free survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

[0182] According to an embodiment, a method of increasing median overall survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, comprises: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved avery good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median overall survival is relative to the median overall survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd). According to certain embodiments, the increase in the median overall survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

[0183] According to an embodiment, a method of increasing a percentage of subjects that exhibit a complete response or stringent complete response (according to IMWG 2016 criteria) in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, comprises: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the percentage of subjects that exhibit a complete response or stringent complete response is relative to percentage of subjects that exhibit a completeresponse or stringent complete response in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

[0184] According to certain embodiments, the teclistamab is administered as a monotherapy.

[0185] According to an embodiment, a method of treating multiple myeloma in a subject in need thereof comprises subcutaneously administering to the subject teclistamab in sequential 28-day treatment cycles, wherein the teclistamab comprises neutral N-linked oligosaccharides, and wherein: about 50% to about 90% of the neutral N-linked oligosaccharides comprise GOF, about 5% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 0.1% to about 10% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 83.8% of the neutral N-linked oligosaccharides comprise GOF, about 8.2% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 85.6% of the neutral N-linked oligosaccharides comprise GOF, about 7.7% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 82.3% of the neutral N-linked oligosaccharides comprise GOF, about 8.6% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.7% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or less than about 75% of the neutral N-linked oligosaccharides comprise GOF, greater than about 20% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 2% of the neutral N-linked oligosaccharides comprise G2F, or less than about 65% of the neutral N-linked oligosaccharides comprise GOF, greater than about 25% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 4% of the neutral N-linked oligosaccharides comprise G2F, or about 40% to about 70% of the neutral N-linked oligosaccharides comprise GOF, about 15% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 2% to about 8% of the neutral N-linked oligosaccharides comprise G2F, or about 45% to about 65% of the neutral N-linked oligosaccharides comprise GOF, about 18% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 3% to about 7% of the neutral N-linked oligosaccharides comprise G2F, orabout 50% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 4% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 55% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 4.5% to about 6.5% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 57.2% of the neutral N-linked oligosaccharides comprise GOF, about 28.4% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 5.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or greater than about 70.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 15% of the neutral N-linked oligosaccharides comprise GIF, and less than about 3% of the neutral N-linked oligosaccharides comprise G2F, or greater than about 75.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 12% of the neutral N-linked oligosaccharides comprise GIF, and less than about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 75.0% to about 90% of the neutral N-linked oligosaccharides comprise GOF, about 7% to about 12% of the neutral N-linked oligosaccharides comprise GIF, and about 0. 1% to about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 78.0% to about 85.6% of the neutral N-linked oligosaccharides comprise GOF, about 7.7% to about 10.9% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 1.1% of the neutral N-linked oligosaccharides comprise G2F, or about 79.9% to about 83.8% of the neutral N-linked oligosaccharides comprise GOF, about 8.2% to about 10.0% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 0.9% of the neutral N-linked oligosaccharides comprise G2F.

[0186] According to an embodiment, a method of treating multiple myeloma in a subject in need thereof comprises subcutaneously administering to the subject teclistamab in sequential 28-day treatment cycles, wherein the teclistamab comprises neutral N-linked oligosaccharides, and wherein: less than about 75% of the neutral N-linked oligosaccharides comprise GOF, greater than about 20% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 2% of the neutral N-linked oligosaccharides comprise G2F, or less than about 65% of the neutral N-linked oligosaccharides comprise GOF, greater than about 25% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 4% of the neutral N-linked oligosaccharides comprise G2F, orabout 40% to about 70% of the neutral N-linked oligosaccharides comprise GOF, about 15% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 2% to about 8% of the neutral N-linked oligosaccharides comprise G2F, or about 45% to about 65% of the neutral N-linked oligosaccharides comprise GOF, about 18% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 3% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 50% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 4% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 55% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 4.5% to about 6.5% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 57.2% of the neutral N-linked oligosaccharides comprise GOF, about 28.4% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 5.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F.

[0187] According to an embodiment, a method of treating multiple myeloma in a subject in need thereof comprises subcutaneously administering to the subject teclistamab in sequential 28-day treatment cycles, wherein the teclistamab comprises neutral N-linked oligosaccharides, and wherein: greater than about 70.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 15% of the neutral N-linked oligosaccharides comprise GIF, and less than about 3% of the neutral N-linked oligosaccharides comprise G2F, or greater than about 75.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 12% of the neutral N-linked oligosaccharides comprise GIF, and less than about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 75.0% to about 90% of the neutral N-linked oligosaccharides comprise GOF, about 7% to about 12% of the neutral N-linked oligosaccharides comprise GIF, and about 0. 1% to about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 78.0% to about 85.6% of the neutral N-linked oligosaccharides comprise GOF, about 7.7% to about 10.9% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 1.1% of the neutral N-linked oligosaccharides comprise G2F, or about 79.9% to about 83.8% of the neutral N-linked oligosaccharides comprise GOF, about 8.2% to about 10.0% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 0.9% of the neutral N-linked oligosaccharides comprise G2F.EXEMPLARY EMBODIMENTS

[0188] Provided below are enumerated embodiments of the present invention. These embodiments are illustrative only and do not limit the scope of the present disclosure or of the claims attached hereto.1. A method of treating relapsed or refractory multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject a BCMAxCD3 bispecific antibody (e.g., teclistamab) in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W).2. The method of embodiment 1, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.3. The method of embodiment 1 or 2, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) having the amino acidsequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.4. The method of any of embodiments 1-3, wherein the BCMAxCD3 bispecific antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.5. The method of any of embodiments 1-4, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype.6. The method of any of embodiments 1-5, wherein the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.7. The method of any of embodiments 1-6, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).8. The method of any of embodiments 1-7, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).9. The method of any of embodiments 1-8, wherein the Fc region of the BCMA- binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).10. The method of any of embodiments 1-9, wherein the Fc region of the CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).11. The method of any of embodiments 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.12. The method of any of embodiments 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity tothe amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.13. The method of any of embodiments 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.14. The method of any of embodiments 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.15. The method of any of embodiments 1-14, wherein the BCMAxCD3 bispecific antibody is teclistamab.16. The method of any of embodiments 1-15, wherein the BCMAxCD3 bispecific antibody is administered as a monotherapy.17. The method of any of embodiments 1-16, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy.18. The method of any of embodiments 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy, including a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.19. The method of any of embodiments 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy, including lenalidomide and an anti-CD38 monoclonal antibody in any prior line.20. The method of any of embodiments 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy including a minimum of 2 consecutive cycles of an anti- CD38 monoclonal antibody in any prior line and 2 consecutive cycles of lenalidomide in any prior line.21. The method of any of embodiments 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy, including a minimum of 2 consecutive cycles each of a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.22. The method of any of embodiments 1-21, wherein the treatment cycle #1 comprises administering two step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW).23. The method of any of embodiments 1-22, wherein the treatment cycle #1 comprises administering a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a first treatment dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody, and then administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1.5 mg / kg.24. The method of any of embodiments 1-23, wherein: the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 3; administering a treatment dose of 1.5 mg / kg on Days 5, 12 and 1, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.25. The method of any of embodiments 1-23, wherein: the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 4;administering a treatment dose of 1.5 mg / kg on Days 7, 14 and 21, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.26. The method of any of embodiments 1-25, wherein: the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti- CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer progression-free survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).27. The method of embodiment 26, wherein the subject exhibits longer progression-free survival compared to the reference subject’s progression-free survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months28. The method of any of embodiments 1-27, wherein: the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti- CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer overall survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and insteadcomprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).29. The method of embodiment 28, wherein the subject exhibits longer overall survival compared to the reference subject’s overall survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.30. The method of any of embodiments 1-29, wherein the subject exhibits a partial response, a very good partial response, a complete response, or a stringent complete response, according to IMWG 2016 criteria.31. The method of any of embodiments 1-30, wherein the subject exhibits a complete response or a stringent complete response, according to IMWG 2016 criteria.32. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 50% to about 90% of the neutral N-linked oligosaccharides comprise G0F, about 5% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 0. 1% to about 10% of the neutral N-linked oligosaccharides comprise G2F.33. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 56.7% to about 83.8% of the neutral N-linked oligosaccharides comprise G0F, about 8.2% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F.34. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 56.7% to about 85.6% of the neutral N-linked oligosaccharides comprise G0F, about 7.7% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F.35. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 56.7% to about 82.3% of the neutral N-linkedoligosaccharides comprise GOF, about 8.6% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.7% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F.36. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein less than about 75% of the neutral N-linked oligosaccharides comprise GOF, greater than about 20% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 2% of the neutral N-linked oligosaccharides comprise G2F.37. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein less than about 65% of the neutral N-linked oligosaccharides comprise GOF, greater than about 25% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 4% of the neutral N-linked oligosaccharides comprise G2F.38. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides , and wherein about 40% to about 70% of the neutral N-linked oligosaccharides comprise GOF, about 15% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 2% to about 8% of the neutral N-linked oligosaccharides comprise G2F.39. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides , and wherein about 45% to about 65% of the neutral N-linked oligosaccharides comprise GOF, about 18% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 3% to about 7% of the neutral N-linked oligosaccharides comprise G2F.40. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides , and wherein about 50% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 4% to about 7% of the neutral N-linked oligosaccharides comprise G2F.41. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides , and wherein about 55% to about 60% of the neutral N-linkedoligosaccharides comprise GOF, about 25% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 4.5% to about 6.5% of the neutral N-linked oligosaccharides comprise G2F.42. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 56.7% to about 57.2% of the neutral N-linked oligosaccharides comprise GOF, about 28.4% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 5.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F.43. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein greater than about 70.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 15% of the neutral N-linked oligosaccharides comprise GIF, and less than about 3% of the neutral N-linked oligosaccharides comprise G2F.44. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein greater than about 75.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 12% of the neutral N-linked oligosaccharides comprise GIF, and less than about 2% of the neutral N-linked oligosaccharides comprise G2F.45. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 75.0% to about 90% of the neutral N-linked oligosaccharides comprise GOF, about 7% to about 12% of the neutral N-linked oligosaccharides comprise GIF, and about 0. 1% to about 2% of the neutral N-linked oligosaccharides comprise G2F.46. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 78.0% to about 85.6% of the neutral N-linked oligosaccharides comprise GOF, about 7.7% to about 10.9% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 1. 1% of the neutral N-linked oligosaccharides comprise G2F.47. The method of any of embodiments 1-31, wherein the antibody comprises neutral N-linked oligosaccharides, and wherein about 79.9% to about 83.8% of the neutral N-linked oligosaccharides comprise GOF, about 8.2% to about 10.0% of the neutral N-linkedoligosaccharides comprise GIF, and about 0.5% to about 0.9% of the neutral N-linked oligosaccharides comprise G2F.48. The method of any of embodiments 1-31, wherein the antibody exhibits a pharmacokinetic (PK) profde that is equivalent or similar to (e.g., within about 2% or about 5% or about 10% or about 15% or about 20% or about 25% of) a PK profde of a reference antibody, wherein the antibody and the reference antibody have different glycosylation profdes.49. The method of embodiment 48, wherein: the antibody comprises neutral N-linked oligosaccharides having less than about 75% GOF, greater than about 20% GIF, and greater than about 2% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having greater than about 70.0% GOF, less than about 15% GIF, and less than about 3% G2F.50. The method of embodiment 48, wherein: the antibody comprises neutral N-linked oligosaccharides having less than about 65% GOF, greater than about 25% GIF, and greater than about 4% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having greater than about 75.0% GOF, less than about 12% GIF, and less than about 2% G2F.51. The method of embodiment 48, wherein: the antibody comprises neutral N-linked oligosaccharides having about 40% to about 70% GOF, about 15% to about 35% GIF, and about 3% to about 7% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having about 75.0% to about 90% GOF, about 7% to about 12% GIF, and about 0.1% to about 2% G2F.52. The method of embodiment 48, wherein: the antibody comprises neutral N-linked oligosaccharides having about 50% to about 60% GOF, about 25% to about 30% GIF, and about 4% to about 6% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having about 75.0% to about 85% GOF, about 7.5% to about 10.5% GIF, and about 0.4% to about 1.2% G2F.53. The method of any of embodiments 48-52, wherein the PK profde comprises one or more of the following PK parameters: (i) serum concentration of the antibody during thetreatment cycle #1, 2 or 3, (ii) Cmax of the first treatment dose, (iii) area under serum concentration versus time curve (AUCtau) of the first treatment dose, and (iv) Ctrough on Day 1 of the treatment cycle #3.54. A method of increasing median progression-free survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, the method comprising: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median progression-free survival is relative to the median progression-free survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).55. The method of embodiment 54, wherein the increase in the median progression-free survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.56. A method of increasing median overall survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyelomatherapy including an anti-CD38 monoclonal antibody and lenalidomide, the method comprising: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median overall survival is relative to the median overall survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).57. The method of embodiment 56, wherein the increase in the median overall survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.58. A method of increasing a percentage of subjects that exhibit a complete response or stringent complete response (according to IMWG 2016 criteria) in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, the method comprising: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein:treatment cycle #1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the percentage of subjects that exhibit a complete response or stringent complete response is relative to percentage of subjects that exhibit a complete response or stringent complete response in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).59. The method of any of embodiments 54-58, wherein the teclistamab is administered as a monotherapy.60. A method of treating multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject teclistamab in sequential 28-day treatment cycles, wherein the teclistamab comprises neutral N-linked oligosaccharides, and wherein: about 50% to about 90% of the neutral N-linked oligosaccharides comprise GOF, about 5% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 0.1% to about 10% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 83.8% of the neutral N-linked oligosaccharides comprise GOF, about 8.2% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 85.6% of the neutral N-linked oligosaccharides comprise GOF, about 7.7% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, orabout 56.7% to about 82.3% of the neutral N-linked oligosaccharides comprise GOF, about 8.6% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 0.7% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or less than about 75% of the neutral N-linked oligosaccharides comprise GOF, greater than about 20% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 2% of the neutral N-linked oligosaccharides comprise G2F, or less than about 65% of the neutral N-linked oligosaccharides comprise GOF, greater than about 25% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 4% of the neutral N-linked oligosaccharides comprise G2F, or about 40% to about 70% of the neutral N-linked oligosaccharides comprise GOF, about 15% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 2% to about 8% of the neutral N-linked oligosaccharides comprise G2F, or about 45% to about 65% of the neutral N-linked oligosaccharides comprise GOF, about 18% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 3% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 50% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 4% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 55% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 4.5% to about 6.5% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 57.2% of the neutral N-linked oligosaccharides comprise GOF, about 28.4% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 5.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F, or greater than about 70.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 15% of the neutral N-linked oligosaccharides comprise GIF, and less than about 3% of the neutral N-linked oligosaccharides comprise G2F, or greater than about 75.0% of the neutral N-linked oligosaccharides comprise GOF, less than about 12% of the neutral N-linked oligosaccharides comprise GIF, and less than about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 75.0% to about 90% of the neutral N-linked oligosaccharides comprise GOF, about 7% to about 12% of the neutral N-linked oligosaccharides comprise GIF, and about 0. 1% to about 2% of the neutral N-linked oligosaccharides comprise G2F, orabout 78.0% to about 85.6% of the neutral N-linked oligosaccharides comprise GOF, about 7.7% to about 10.9% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 1.1% of the neutral N-linked oligosaccharides comprise G2F, or about 79.9% to about 83.8% of the neutral N-linked oligosaccharides comprise GOF, about 8.2% to about 10.0% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 0.9% of the neutral N-linked oligosaccharides comprise G2F.61. A method of treating multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject teclistamab in sequential 28-day treatment cycles, wherein the teclistamab comprises neutral N-linked oligosaccharides, and wherein: less than about 75% of the neutral N-linked oligosaccharides comprise GOF, greater than about 20% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 2% of the neutral N-linked oligosaccharides comprise G2F, or less than about 65% of the neutral N-linked oligosaccharides comprise GOF, greater than about 25% of the neutral N-linked oligosaccharides comprise GIF, and greater than about 4% of the neutral N-linked oligosaccharides comprise G2F, or about 40% to about 70% of the neutral N-linked oligosaccharides comprise GOF, about 15% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 2% to about 8% of the neutral N-linked oligosaccharides comprise G2F, or about 45% to about 65% of the neutral N-linked oligosaccharides comprise GOF, about 18% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 3% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 50% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 35% of the neutral N-linked oligosaccharides comprise GIF, and about 4% to about 7% of the neutral N-linked oligosaccharides comprise G2F, or about 55% to about 60% of the neutral N-linked oligosaccharides comprise GOF, about 25% to about 30% of the neutral N-linked oligosaccharides comprise GIF, and about 4.5% to about 6.5% of the neutral N-linked oligosaccharides comprise G2F, or about 56.7% to about 57.2% of the neutral N-linked oligosaccharides comprise GOF, about 28.4% to about 28.5% of the neutral N-linked oligosaccharides comprise GIF, and about 5.4% to about 5.6% of the neutral N-linked oligosaccharides comprise G2F.62. A method of treating multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject teclistamab in sequential 28-day treatment cycles, wherein the teclistamab comprises neutral N-linked oligosaccharides, and wherein: greater than about 70.0% of the neutral N-linked oligosaccharides comprise G0F, less than about 15% of the neutral N-linked oligosaccharides comprise GIF, and less than about 3% of the neutral N-linked oligosaccharides comprise G2F, or greater than about 75.0% of the neutral N-linked oligosaccharides comprise G0F, less than about 12% of the neutral N-linked oligosaccharides comprise GIF, and less than about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 75.0% to about 90% of the neutral N-linked oligosaccharides comprise G0F, about 7% to about 12% of the neutral N-linked oligosaccharides comprise GIF, and about 0. 1% to about 2% of the neutral N-linked oligosaccharides comprise G2F, or about 78.0% to about 85.6% of the neutral N-linked oligosaccharides comprise G0F, about 7.7% to about 10.9% of the neutral N-linked oligosaccharides comprise GIF, and about 0.4% to about 1.1% of the neutral N-linked oligosaccharides comprise G2F, or about 79.9% to about 83.8% of the neutral N-linked oligosaccharides comprise G0F, about 8.2% to about 10.0% of the neutral N-linked oligosaccharides comprise GIF, and about 0.5% to about 0.9% of the neutral N-linked oligosaccharides comprise G2F.

[0189] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

[0190] The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in their entirety.EXAMPLES

[0191] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments.Example 1: A Phase 3 Randomized Study Comparing Teclistamab Monotherapy versus Pomalidomide, Bortezomib, Dexamethasone (PVd) or Carfilzomib, Dexamethasone (Kd) in Participants with Relapsed or Refractory MultipleMyeloma who have Received 1 to 3 Prior Lines of Therapy, Including an Anti-CD38 Monoclonal Antibody and Lenalidomide (MajesTEC-9; 64007957MMY3006; NCT05572515)Antibodies

[0192] Anti-BCMA / anti-CD3 antibody teclistamab (also called Tec) (e.g., described in W02017031104A1, the content of which is incorporated herein by reference in its entirety) was made by Janssen Pharmaceuticals. Teclistamab comprises a BCMA binding arm BCMB69 and a CD3 binding arm CD3B219, the amino acid sequences of which are shown in Table 5 and Table 6, respectively.Table 5. Sequences of BCMA Binding Arm of TeclistamabTable 6. Sequences of CD3 Binding Arm of TeclistamabStudy Rationale:

[0193] This is a Phase 3 Randomized Study Comparing Teclistamab Monotherapy versus Pomalidomide, Bortezomib, Dexamethasone (PVd) or Carfilzomib, Dexamethasone (Kd) in participants with Relapsed or Refractory Multiple Myeloma who have received 1 to 3 prior lines of therapy, including an Anti-CD38 Monoclonal Antibody and Lenalidomide.

[0194] Based on the results of Study 64007957MMY 1001 (MajesTEC-1), teclistamab monotherapy has demonstrated a high rate of deep and durable response in heavily pre-treated patients. As teclistamab relies on the immune system of the patient, receiving teclistamab monotherapy at earlier lines of therapy could lead to improved antimyeloma effects. The study population for Study 64007957MMY3006 (MajesTEC-9) has a high unmet medical need as allpatients will have relapsed or refractory myeloma and prior therapy will have included an anti- CD38 monoclonal antibody and lenalidomide, which limits future treatment options.Eligibility Criteria:

[0195] Inclusion Criteria include the following:• Documented diagnosis of multiple myeloma as defined by the criteria below: (a)Multiple myeloma diagnosis according to International Myeloma Working Group (IMWG) diagnostic criteria (b) Measurable disease at screening as defined by any of the following: (1) Serum M-protein level greater than or equal to (>=)0.5 grams per deciliter (g / dL) (central laboratory); or (2) Urine M-protein level >=200 milligrams (mg) / 24 hours (central laboratory); or (3) Serum immunoglobulin free light chain >=10 milligrams per deciliter (mg / dL) (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio• Relapsed or refractory disease as defined below: a. Relapsed disease is defined as an initial response to previous treatment, followed by confirmed progressive disease by IMWG criteria >60 days after cessation of treatment. b. Refractory disease is defined as failure to achieve a response or confirmed progressive disease by IMWG criteria during previous treatment or <60 days after cessation of treatment.• Received 1 to 3 prior lines of antimyeloma therapy including a minimum of 2 consecutive cycles of an anti- cluster of differentiation 38 (CD38) monoclonal antibody at the approved dosing schedule (or minimum of 6 doses if anti-CD38 monoclonal antibody was only part of a maintenance regimen) in any prior line and 2 consecutive cycles of lenalidomide in any prior line.• Documented evidence of progressive disease or failure to achieve a response to last line of therapy based on investigator's determination of response by International myeloma working group (IMWG) criteria.• Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2.• A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test within 10 to 14 days prior to C1D1 and again either serum or urine pregnancy test within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study.

[0196] Exclusion Criteria include the following:• Received any prior B cell maturation antigen (BCMA) -directed therapy• A participant is not eligible to receive PVd as control therapy if any of the following are present: (1) Received prior pomalidomide therapy, (2) Does not meet criteria for bortezomib retreatment (3) Contraindications or life-threatening allergies, hypersensitivity, or intolerance to pomalidomide or bortezomib, (4) Grade 1 peripheral neuropathy with pain or Grade greater than or equal to (>=) 2 peripheral neuropathy as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0, (5) Received a strong cytochrome P (CYP) 3A4 inducer within 5 half-lives prior to randomization; A participant is not eligible to receive Kd as control therapy if any of the following are present: (1) Received prior carfilzomib therapy, (2) Uncontrolled hypertension, defined as an average systolic blood pressure greater than (>) 159 millimeters of mercury (mmHg) or diastolic blood pressure >99 mmHg despite optimal treatment (3) Grade 2 peripheral neuropathy with pain or Grade >=3 peripheral neuropathy as defined by NCI-CTCAE Version 5.0, (4) Contraindications or life-threatening allergies, hypersensitivity, or intolerance to carfilzomib (intolerance defined as prior therapy discontinued due to any adverse event [AE] related to carfilzomib)• Central nervous system (CNS) involvement or clinical signs of meningeal involvement of multiple myeloma.• Received a live, attenuated vaccine within 4 weeks before randomization• Plasma cell leukemia at the time of screening, Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, M-protein (POEMS) syndrome and skin changes, or primary amyloid light chain amyloidosis• Received a maximum cumulative dose of corticosteroids of >=140 mg of prednisone or equivalent within 14 days prior to randomizationObjectives and Endpoints:

[0197] The primary objective of this study is to compare the efficacy of teclistamab monotherapy (Arm A) with that of an investigator’s choice of Pomalidomide, Bortezomib, Dexamethasone (PVd) or Carfilzomib, Dexamethasone (Kd) (Arm B: termed PVd / Kd hereafter) as assessed by progression-free survival (PFS). Key secondary objectives include comparisons of efficacy as assessed by the proportion of participants achieving CR or better response, OS, and time to worsening in the MySIm-Q total symptom score. The primaryhypothesis of this study is that teclistamab monotherapy will improve PFS compared with PVd or Kd in participants with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy and have been exposed to anti-CD38 monoclonal antibody therapy and lenalidomide.Overall Design:

[0198] This is a randomized, Phase 3, multicenter, open-label study to evaluate teclistamab monotherapy versus investigator’s choice of PVd or Kd. The study will be conducted in 3 phases: Screening (up to 28 days), Treatment (until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent, or end of the study, whichever occurs first), and Follow-up (until death, withdrawal of consent, loss to follow-up, or end of the study, whichever occurs first). Participants who discontinue study treatment for any reason other than progressive disease or withdrawal of consent for study participation will continue to be followed for response assessment until confirmed progressive disease or start of subsequent antimyeloma therapy.

[0199] After confirmed progressive disease, participants will be followed for survival status, subsequent antimyeloma therapies, and the occurrence of second primary malignancies every 16 weeks until the end of the study. An IDMC will be commissioned for this study to review cumulative safety data periodically and the results

[0200] from the prespecified interim analyses. Approximately 590 participants will be randomized in a 1 : 1 ratio to Arm A or Arm B. Randomization will be stratified by investigator’s choice of PVd or Kd, stage of disease at screening per ISS (I vs II / III), number of prior lines of therapy (1 vs 2 or 3), and anti-CD38 monoclonal antibody refractory status (yes vs no).Description of Study Treatment:

[0201] Study treatment will be administered on 28-day cycles for teclistamab (Arm A) and Kd (Arm B). For PVd (Arm B), study treatment will be administered on 21-day cycles. At the time of screening, the investigator must declare whether the participant will be treated with PVd or Kd should they be randomized to Arm B. The protocol includes eligibility criteria related to investigator’s choice of PVd or Kd.

[0202] Teclistamab monotherapy (Arm A) will be administered subcutaneously (SC) in 28-day cycles, as shown in the following table:PVd (Arm B) will be administered in 21 -day cycles, as shown in the following table:KD (Arm B) includes 2 dosing options, which will be administered in 28-day cycles, as shown in the following table:aThe use of either 20 / 56 mg / m2twice weekly or 20 / 70 mg / m2once weekly carfilzomib dosing schedule will depend on local clinical practice. For countries that do not have these carfilzomib dose schedules in their local prescribing information, the 20 / 56 mg / m2twice weekly schedule should be used.bParticipants who are >75 years of age may reduce the dose of dexamethasone by 50% after the first week.Justification for Teclistamab Dose:

[0203] For the first two treatment cycles, participants will receive the teclistamab SC monotherapy dose schedule comprising 2 step-up doses (0.06 and 0.3 mg / kg) followed by a weekly treatment dose of 1.5 mg / kg. This dose schedule was selected after review of safety, efficacy, PK, and pharmacodynamic data from participants with relapsed or refractory multiple myeloma treated with this regimen as a monotherapy in MajesTEC-1 . Participants will receive teclistamab SC Q2W starting on Cycle 3 Day 1 at a treatment dose of 3 mg / kg. Based on a population PK analysis, it is believed the 3 mg / kg teclistamab Q2W dose schedule in Cycle 3-6 will provide comparable exposure with the 1.5 mg / kg teclistamab QW dose schedule. The population PK analysis used serum teclistamab concentration data from MajesTEC-1 with the PK data cutoff of 01 December 2021. The final dataset included a total of 4,840 measurable serum teclistamab concentrations from 338 PK evaluable adult participants (n=83 received IV dose; n=255 received SC dose) with relapsed or refractory multiple myeloma. The weight distribution in this study population ranged from 41 to 139 kg, with a median body weight of 74 kg. The final population PK model was used to simulate teclistamab concentration-time profiles. The subjects for simulation were randomly sampled from the analysis dataset (n= 1,000). Based on the simulation, 3 mg / kg teclistamab SC Q2W dosing is calculated to result in the majority of participants having Ctrough above the maximum EC90 (target exposure), which was comparable with 1.5 mg / kg teclistamab SC QW dosing. Following 3 mg / kg teclistamab SC Q2W dosing on Week 20, the model estimated that Ctrough, Cmax, and AUCO-14 days will be comparable with those of 1.5 mg / kg teclistamab SC QWdosing. Consequently, the 3 mg / kg Q2W dose schedule in Cycle 3-6 is estimated to achieve comparable efficacy and tolerable safety.

[0204] For all participants, teclistamab SC will be administered at a reduced dosing frequency of 3 mg / kg Q4W from Cycle 7. Participants in confirmed VGPR or better may receive teclistamab SC at this reduced dosing frequency prior to Cycle 7 per investigator discretion. Following 3 mg / kg teclistamab SC Q4W dosing, the model estimated steady-state median Cmax,ss, and AUCss,o-28 day are lower than those of 1.5 mg / kg teclistamab SCQW dosing. However, the estimated median trough levels following 3 mg / kg Q4W are c alculated to be comparable to the max EC90. The model-calculated median steady state AUCo- 28day and Ctrough,ss following the 3 mg / kg Q4W dose are comparable to those of the 1.5 mg / kg Q2W SC dose. In the MajesTEC-1 study, at a follow up of 22.8 months, the median DOR has not been reached (95% CI: 24.0 to NE) for the 63 participants who switched to 1.5 mg / kg Q2W dosing after achieving a response, suggesting that response is maintained when switching to a less frequent dosing schedule. Additionally, in Majes-TEC-1, a majority of the responders (approximately 90%) are at VGPR or better (median time to VGPR or better: 2.2 months, range 0.2-18.5 months) by Cycle 7. Thus, the exposure achieved at 3 mg / kg Q4W dosing implemented per the timing in this study is believed to be sufficient to maintain efficacy. Furthermore, cumulative safety data from MajesTEC-1 remains consistent with that ofthe primary analysis but with a notable decrease of new high-grade infections over time.

[0205] Overall, the teclistamab SC dose schedule to be evaluated in MajesTEC-9 (1.5 mg / kg QW for Cycle 1-2, 3 mg / kg Q2W for Cycle 3-6, and 3 mg / kg teclistamab Q4W from Cycle 7 or per investigator discretion, prior to Cycle 7 for participants in confirmed VGPR or better) is anticipated to have comparable safety and efficacy with the 1.5 mg / kg teclistamab QW dose schedule, while further increasing the convenience and flexibility for patients, caregivers, and healthcare providers.Outcome Measures:

[0206] Efficacy assessments will occur per IMWG 2016 criteria. Responses or progression will be evaluated by investigators, use of a validated algorithm, and by an IRC; assessment by IRC will be used for determining the primary analysis.

[0207] The primary endpoint is progression-free survival (PFS), defined as the time from the date of randomization to the date of first documented disease progression, as defined in the IMWG 2016 criteria, or death due to any cause, whichever occurs first.

[0208] Key secondary endpoints include the following:

[0209] CR or better (sCR+CR) is defined as participants who achieve a CR or better response prior to subsequent antimyeloma therapy in accordance with the IMWG 2016 criteria.

[0210] Overall Survival (OS) is measured from the date of randomization to the date of the participant’s death due to any cause. If the participant is alive or the vital status is unknown, then the participant’s data will be censored at the date the participant was last known to be alive.

[0211] Time to worsening of symptoms is defined as the interval from the date of randomization to the start date of worsening in the MySIm-Q total symptom score. Worsening is defined as a decrease in score that is at least half of standard deviation from baseline values. Death due to disease progression will be considered as worsening. Participants who have not met the definition of worsening will be censored as of the last assessment date of the MySIm-Q prior to start of subsequent anticancer treatment.

[0212] Other secondary endpoints include the following:

[0213] Overall response (PR or better) is defined as participants who have a PR or better prior to subsequent antimyeloma therapy in accordance with the IMWG 2016 criteria.

[0214] VGPR or better (sCR+CR+VGPR) is defined as participants who achieve a VGPR or better response prior to subsequent antimyeloma therapy in accordance with the IMWG 2016 criteria.

[0215] Duration of response (DOR) will be calculated among responders (with a PR or better response). It is defined as the time interval between the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease according to the IMWG response criteria or death due to any cause, whichever occurs first. Participants who have not progressed and alive will be censored at the last disease evaluation before the start of subsequent antimyeloma therapy.

[0216] PFS2 is defined as the time interval between the date of randomization and date of event, which is defined as progressive disease as assessed by investigator on the first subsequent line of antimyeloma therapy, or death from any cause, whichever occurs first. Those who are alive and for whom a second disease progression has not been observed are censored at the last date of follow-up.

[0217] Time to next treatment is defined as the time from randomization to the start of subsequent antimyeloma treatment. Death due to disease progression without the start of any subsequent antimyeloma therapy will be considered as an event. Participants who withdraw consent to study, are lost to follow-up, or die due to causes other than disease progression will be censored at the date of death, or the last date known to be alive. Participants who are still continuing in the study at the time of analysis and have not started subsequent therapy will be censored at the date of their latest disease assessment.Example 2: A Phase 1 Randomized, Open-Label Pharmacokinetic Comparability Study Comparing Pre- and Post-change Teclistamab in Participants with Relapsed / Refractory Multiple Myeloma (MajesTEC-10;64007957MMY1008)Antibodies

[0218] Anti-BCMA / anti-CD3 antibody teclistamab (also called Tec) (e.g., described in W02017031104A1, the content of which is incorporated herein by reference in its entirety) was made by Janssen Pharmaceuticals. Teclistamab comprises a BCMA binding arm BCMB69 and a CD3 binding arm CD3B219, the amino acid sequences of which are shown in Table 5 and Table 6 above, respectively.Purpose:

[0219] The purpose of this study is to compare the pharmacokinetics (processes by which drugs are absorbed, distributed in the body, and excreted) between teclistamab made from the current commercial manufacturing process (pre-change) and the new manufacturing process (post-change).

[0220] Changes to the teclistamab manufacturing process were made, which have increased the amount of teclistamab produced per batch. Teclistamab is manufactured by mammalian cell culture, and changes to the manufacturing process for of teclistamab result in post-change teclistamab having differences in the glycosylation profile of the Fc region compared with pre-change teclistamab. This study will aim to evaluate PK comparability between teclistamab made from the initial commercial manufacturing process (pre-change) and the new manufacturing process (post-change).Eligibility Criteria:

[0221] Inclusion Criteria include the following:• Documented diagnosis of multiple myeloma as defined by the criteria below: (a)Multiple myeloma diagnosis according to International Myeloma Working Group (IMWG) diagnostic criteria (b) Measurable disease at screening as defined by any of the following: (1) Serum M-protein level greater than or equal to (>=)0.5 grams per deciliter (g / dL) (central laboratory); or (2) Urine M-protein level >=200 milligrams (mg) / 24 hours (central laboratory); or (3) Serum immunoglobulin free light chain >=10 milligrams per deciliter (mg / dL) (central laboratory) and abnormal serum immunoglobulin kappa lambda free light chain ratio• Relapsed or refractory disease as defined below:a. Relapsed disease is defined as an initial response to previous treatment, followed by confirmed progressive disease by IMWG criteria >60 days after cessation of treatment. b. Refractory disease is defined as failure to achieve a response or confirmed progressive disease by IMWG criteria during previous treatment or <60 days after cessation of treatment.• Received 1 to 3 prior lines of antimyeloma therapy, including a minimum of 2 consecutive cycles each of a PI, lenalidomide, and an anti-CD38 monoclonal antibody (or minimum of 6 doses if anti-CD38 monoclonal antibody was only part of a maintenance regimen) in any prior line.• Documented evidence of progressive disease or failure to achieve a response to last line of therapy based on investigator’s determination of response by IMWG criteria.• Have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2• A female participant of childbearing potential must have a negative highly sensitive serum pregnancy test at screening and within 24 hours of the start of study treatment and must agree to further serum or urine pregnancy tests during the study.

[0222] Exclusion Criteria include the following:• Received any bispecific antibody and / or CAR-T cell therapy.• Contraindications or life-threatening allergies, hypersensitivity, or intolerance to any study drug or its excipients.• Received a maximum cumulative dose of corticosteroids of >140 mg of prednisone or equivalent within 14 days prior to randomization.• Received a live, attenuated vaccine within 4 weeks before the first dose of study drug. Non-live or non-replicating vaccines authorized for emergency use (eg, COVID-19) by local health authorities are allowed• Received the following prior antimyeloma therapy, within the specified time frame prior to randomization: a. Targeted therapy, epigenetic therapy, or treatment with an investigational drug or an invasive investigational medical device within 21 days or >5 half-lives, whichever is less b. Investigational vaccine within 4 weeks c. Monoclonal antibody therapy within 21 days d. Cytotoxic therapy within 21 dayse. PI therapy within 14 days f. IMiD agent therapy within 14 days g. Radiotherapy within 14 days or focal radiation within 7 days h. Gene-modified adoptive cell therapy (eg, chimeric antigen receptor modified T cells, NK cells) within 3 months i. Plasmapheresis within 28 daysStudy Arms:

[0223] Arm A (Pre-Change Teclistmab): Participants will receive teclistamab monotherapy (made from the pre-change manufacturing process) for all step-up and treatment doses until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent to treatment, or end of the study, whichever occurs first.

[0224] Arm B (Post-Change Teclistamab): Participants will receive teclistamab monotherapy (made from the post-change manufacturing process) for all step-up and treatment doses until confirmed progressive disease, death, intolerable toxicity, withdrawal of consent to treatment, or end of the study, whichever occurs first.Overall Design:

[0225] The study will enroll participants with relapsed / refractory multiple myeloma who have received 1 to 3 prior lines of therapy, including an anti-CD38 monoclonal antibody, lenalidomide, and a proteosome inhibitor, a population who have high unmet medical need.

[0226] Multiple myeloma patients who are exposed to an anti-CD38 monoclonal antibody, lenalidomide, and a PI in early lines are particularly challenging to treat at subsequent lines, especially if they are refractory to any of these classes of drugs. Less than 40% of patients with multiple myeloma receive a third line of therapy. This high attrition rate highlights the need to move effective therapy into earlier lines. Therefore, there remains a significant and critical unmet need for new effective therapeutic options in earlier lines for patients who have previously been exposed to an anti-CD38 monoclonal antibody, lenalidomide, and a PI, especially those who are refractory to both drug classes.

[0227] Several factors suggest that teclistamab may address the above unmet need. First, since the degree of benefit of bispecific antibody therapy is partially dependent on a patient’s immune fitness, it is possible that there will be greater efficacy and durability of response when administered to patients earlier in their disease course, prior to exposure to therapies that may further compromise their immune fitness. Therefore, investigations of teclistamab in early lines of treatment are warranted to determine the ability to enhanceefficacy and increase depth of response. Second, a subgroup analysis of the pivotal RP2D population in MajesTEC-1 suggests that teclistamab may be more effective in earlier lines of therapy. Specifically, with a median follow-up of 22.8 months, the HR of PFS for 43 participants who received 2 to 3 prior lines of therapy versus 122 participants who received >3 prior lines of therapy was 0.72 (95% CI: 0.45 to 1.15). Median PFS for these 2 subgroups were 18.1 months (95% CI: 13.8 to 26.9) and 9.7 months (95% CI: 6.4 to 13.1), respectively. There were no participants with 1 prior line of treatment in MajesTEC-1.

[0228] Given these factors, MajesTEC-10 will evaluate teclistamab monotherapy in participants with relapsed / refractory multiple myeloma who have received 1 to 3 prior lines of therapy, including an anti-CD38 monoclonal antibody, lenalidomide, and a PI. Notably, this is a similar population as the ongoing Study 64007957MMY3006 (MajesTEC-9, described above), in which teclistamab monotherapy is being compared with investigator’s choice of PVd or Kd in participants with a prior anti-CD38 monoclonal antibody and lenalidomide.

[0229] This is a Phase 1, randomized, open-label, multicenter study to evaluate PK comparability between teclistamab from the pre-change manufacturing process (Arm A) versus post-change manufacturing process (Arm B). Participant involvement will include a Screening Phase (up to 28 days), a Treatment Phase, and a Follow-up Phase. The end of study / study completion is considered as 24 months after the last participant is randomized. Participants who discontinue study treatment for any reason other than progressive disease or withdrawal of consent for study participation will continue to be followed for response assessment until confirmed progressive disease or start of subsequent antimyeloma therapy, whichever occurs earlier. After confirmed progressive disease, participants will be followed for survival status, subsequent antimyeloma therapies, and the occurrence of second primary malignancies every 16 weeks until the end of the study unless the participant has died, is lost to follow-up, or has withdrawn consent. Contact will be made during the 30-day follow-up to collect adverse event information unless the participant has died, is lost to follow-up, has withdrawn consent, or until the start of subsequent systemic antimyeloma treatment, if earlier. A DRC will be commissioned for this study to ensure the continuing safety of the participants enrolled in this study. Approximately 100 participants will be randomized in a 1: 1 ratio to Arm A (pre-change teclistamab) or Arm B (post-change teclistamab).Description of Study Treatment:

[0230] Teclistamab will be administered subcutaneously (SC) in 28-day cycles in both arms, as shown in the following table:aParticipants may change to Q4W dosing when in confirmed VGPR or better prior to Cycle 7 per investigator discretion.bA participant is not required to receive Q2W dosing of teclistamab prior to Q4W dosing if a response ofVGPR or better is confirmed by C3D1. No subject should switch to less frequent dosing before C3D1.cAll participants should change to Q4W dosing (Day 1 only) from Cycle 7. In exceptional cases, participants can continue Q2W dosing (Day 1 and Day 15) from Cycle 7 after Sponsor consultation and approval. Participants on Q4W dosing can switch back to Q2W dosing after consultation with the Sponsor.Justification for Teclistamab Dose:

[0231] Teclistamab monotherapy will be administered SC using the same weight-based dosing schedule in both treatment arms (pre- and post-change teclistamab). The dose used for this study is optimized to allow robust evaluation of PK in the first 2 treatment cycles using weekly administration of treatment doses while increasing convenience and flexibility starting on Cycle 3 Day 1. The “Justification for Teclistamab Dose” described above for the MajesTEC-9 trial (Example 1) is also applicable to dosing schedule for this MajesTEC-10 trial.Objectives and Endpoints:

[0232] The pharmacokinetic (PK) parameters to be calculated will include, but are not limited to:• Cmax Maximum observed serum concentration of drug administration (after first treatment dose)• Tmax Time to the maximum observed serum concentration (after first treatment dose)• AUCtau Area under the concentration-time curve during dosing interval (after first treatment dose)• Grough Observed serum concentration immediately prior to the next study treatment administration• Additional PK parameters may be determined, as appropriate.

[0233] The co-primary PK endpoints are Cmax and AUCtau after the first treatment dose and Ctrough at Cycle 3 Day 1.

[0234] The following will serve to assess comparability of pre-change and post-change teclistamab:Cmax and AUCtau after the first treatment dose and Ctrough at Cycle 3 Day 1 were selected as co-primary endpoints.

[0235] Early PK metrics (Cmax and AUCtau following the first treatment dose) have been used in small cohorts in the MajesTEC-1 study to provide clinical experience to establishPK comparability. Based on this prior experience, the early PK metrics (Cmax and AUCtau following the first treatment dose) in a randomized comparability study are expected to provide a robust evaluation of teclistamab PK between pre-change and post-change teclistamab. Additionally, Ctrough at Cycle 3 Day 1 is a co-primary endpoint and will represent Ctrough before participants switch to Q4W dosing, which is calculated to result in lower exposure. Based on a PK simulation, the Ctrough will in general be stable after a participant starts Q2W dosing at Cycle 3 Day 1 and / or before they switch to Q4W dosing.Preliminary Data from Participants Treated with Post-change Teclistamab in MajesTEC-1:

[0236] Teclistamab monotherapy is approved in the US, EU, and other regions for the treatment of patients with relapsed or refractory multiple myeloma who have received at least 3 or 4 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody. The current approvals for teclistamab are based on data from Study 64007957MMY 1001 (MajesTEC-1), an ongoing Phase 1 / 2 dose escalation / dose expansion study evaluating teclistamab monotherapy in which participants in the pivotal population had relapsed or refractory multiple myeloma and were triple-class exposed (PI, IMiD, anti-CD38 monoclonal antibody). In MajesTEC-1, the regimen for teclistamab monotherapy included step-up doses of 0.06 and 0.3 mg / kg followed by weekly treatment doses of 1.5 mg / kg teclistamab SC administered. Per protocol, participants were allowed to switch to Q2W dosing upon meeting pre-defined response criteria.

[0237] Changes to the teclistamab manufacturing process increased the amount of teclistamab produced per batch: teclistamab made using the initial manufacturing process is termed pre-change teclistamab (Arm A) and teclistamab made using the new process is termed post-change teclistamab (Arm B). Teclistamab is manufactured by mammalian cell culture, and changes in the manufacturing process result in post-change teclistamab having differences in the glycosylation profile of the Fc region compared with pre-change teclistamab.

[0238] One of the Phase 1 cohorts in MajesTEC-1 evaluated post-change teclistamab. Preliminary data are summarized below for 12 participants treated with post-change teclistamab. In this cohort, teclistamab monotherapy was administered at 1.5 mg / kg weekly for Cycles 1 to 3, 3 mg / kg Q2W for Cycles 4 to 6, and 3 mg / kg Q4W from Cycle 7+.Study Population

[0239] As of 22 August 2023, all 12 participants enrolled in the post-change teclistamab cohort were triple-class exposed (PI, IMiD, and anti-CD38 monoclonal antibody)and 6 (50.0%) were penta-exposed (at least 2 Pls, at least 2 IMiDs, and an anti-CD38 monoclonal antibody). Nine participants (75.0%) were triple-class refractory and none were penta-refractory. The median number of prior lines of therapy was 4.0 (range: 2 to 7). The median age was 69.5 years (range: 49 to 82). Most participants (7 [58.3%]) had an ECOG score of 1 at baseline. A total of 3 participants (25.0%) treated in this cohort had Stage III ISS multiple myeloma at baseline and 8 (66.7%) had IgG-type multiple myeloma. Median followup in these participants was 2.4 months (range: 1 [participant died due to progressive disease] to 3.3) as of the data extract. Nine participants (75.0%) remained on treatment.Preliminary PK Analysis / Immunogenicity

[0240] Preliminary PK data available as of 06 September 2023 are summarized below for the 12 participants treated with post-change teclistamab. The PK profile of post-change teclistamab generally overlapped with that of pre-change teclistamab collected previously in Phase 1 of MajesTEC-1 (data cutoff of 09 August 2021) following teclistamab administration at 1.5 mg / kg SC weekly (FIG. 1). Non-compartmental analysis using nominal time was employed to preliminarily evaluate PK parameters of post-change teclistamab in Cycle 1 and Cycle 3. Mean exposures tended to be lower post-change but generally within the range of individual values. Early ADA data do not suggest increased immunogenicity risk in participants treated at 1.5 mg / kg SC weekly with post-change teclistamab compared with prechange teclistamab.

[0241] As of 22 August 2023, 11 participants were response evaluable. ORR (PR or better), as assessed by investigator based on IMWG 2011 criteria, was 63.6% (95% CI: 30.8%, 89.1%), with 27.3% of participants having a VGPR or better. One participant in the cohort was not evaluable for response because they did not have measurable disease at baseline; the participant currently has stable disease. Median time to first response was 1 month (range: 0.9 to 1.0). Historically, responses to teclistamab monotherapy have deepened overtime and the participants will continue to be monitored per protocol.

[0242] The preliminary PK data evaluated in Phase 1 of MajesTEC-1 for post-change teclistamab were generally within the range observed for participants treated at RP2D with prechange teclistamab in Phase 1 of MajesTEC-1. Clinical data observed in the 12 participants were generally consistent with pivotal data from MajesTEC-1 with the exception of a higher incidence of Grade 1 CRS (66.7% versus 49.7%, respectively). Incidence of Grade 2 CRS was similar in the 2 groups (25.0% for participants treated with post-change teclistamab and 21.2% in the pivotal population). No Grade >3 CRS was observed in the post-change teclistamabgroup. Given the small sample size, limited conclusions can be made and additional data are needed to assess the comparability of prechange and post-change teclistamab. MajesTEC-10 is designed to evaluate comparability of PK, safety, and efficacy of pre-change teclistamab versus post-change teclistamab in the randomized setting to preclude potential confounding factors of the comparison.Carbohydrate Structure of Pre-Change and Post-Change Teclistamab

[0243] The carbohydrate structures for pre-change and post-change teclistamab drug substance (DS) batches were evaluated by oligosaccharide mapping of the PNGase F released N-glycans using hydrophilic interaction liquid chromatography (HILIC) with fluorescence detection. Glycans labeled with the 2-aminobenzamide (2 -AB) fluorophore were quantitated by peak area integration of the HPLC chromatograms and expressed as a percentage of the total glycan peak area. The HILIC chromatograms for the pre-change and post-change DS batches were highly similar by visual inspection of the peak profile. GOF was the major species in both batches, but GIF, G2F, and high mannose peaks were higher in the post-change DS. No new peaks were detected in the post-change DS batch. FIG. 2 provides a table of oligosaccharide mapping results for pre-change versus post-change batches of teclistamab drug substance. Consistent with the visual inspection of the chromatograms, the post-change DS had higher levels of N-glycans with terminal galactose (GIF and G2F) and a decrease in N-glycans with no galactose (GOF) (FIG. 2). The high mannose (M5, M6, and M8) N-glycans were also slightly higher in the post-change DS. The GOF, GIF, G2F, high mannose, other neutrals - non-fucosylated, and the total neutral N-glycans were outside of the historical and statistical ranges, and there was increase in charged glycans. No impact of galactosylation on circulation half-life (PK) has been observed based on serum clearance studies. These results indicated that the carbohydrate structures of the post-change D S batch showed some differences in neutral N- glycan structures by oligosaccharide mapping, and the differences do not impact activity.

Claims

1. CLAIMSWhat is claimed is:

1. A method of treating relapsed or refractory multiple myeloma in a subject in need thereof, comprising subcutaneously administering to the subject a BCMAxCD3 bispecific antibody in sequential 28-day treatment cycles, wherein: treatment cycle # 1 comprises administering one or more step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the BCMAxCD3 bispecific antibody in an amount of 3 mg / kg monthly (Q4W).

2. The method of claim 1, wherein the BCMAxCD3 bispecific antibody comprises a BCMA binding domain comprising the HCDR1 of SEQ ID NO: 4, the HCDR2 of SEQ ID NO: 5, the HCDR3 of SEQ ID NO: 6, the LCDR1 of SEQ ID NO: 7, the LCDR2 of SEQ ID NO: 8 and the LCDR3 of SEQ ID NO: 9, and a CD3 binding domain comprising the HCDR1 of SEQ ID NO: 14, the HCDR2 of SEQ ID NO: 15, the HCDR3 of SEQ ID NO: 16, the LCDR1 of SEQ ID NO: 17, the LCDR2 of SEQ ID NO: 18 and the LCDR3 of SEQ ID NO: 19.

3. The method of claim 1 or 2, wherein the BCMA binding domain comprises a heavy chain variable region (VH) having the amino acid sequence of SEQ ID NO: 10 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 11, and the CD3 binding domain comprises a heavy chain variable region (VH) havingthe amino acid sequence of SEQ ID NO: 20 and a light chain variable region (VL) having the amino acid sequence of SEQ ID NO: 21.

4. The method of any of claims 1-3, wherein the BCMAxCD3 bispecific antibody is an IgGl, an IgG2, an IgG3 or an IgG4 isotype.

5. The method of any of claims 1-4, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype.

6. The method of any of claims 1-5, wherein the BCMAxCD3 bispecific antibody comprises one or more substitutions in its Fc region.

7. The method of any of claims 1-6, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

8. The method of any of claims 1-7, wherein the BCMAxCD3 bispecific antibody is an IgG4 isotype and comprises S228P, F234A, L235A F405L and R409K substitutions in its Fc region (according to EU numbering).

9. The method of any of claims 1-8, wherein the Fc region of the BCMA-binding arm comprises S228P, F234A and L235A substitutions in its Fc region (according to EU numbering).

10. The method of any of claims 1-9, wherein the Fc region of the CD3-binding arm comprises S228P, F234A, L235A, F405L, and R409K substitutions in its Fc region (according to EU numbering).

11. The method of any of claims 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having the amino acid sequence of SEQ ID NO: 23.

12. The method of any of claims 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 90% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 90% identity to the amino acid sequence of SEQ ID NO: 23.

13. The method of any of claims 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 95% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 95% identity to the amino acid sequence of SEQ ID NO: 23.

14. The method of any of claims 1-10, wherein the BCMAxCD3 bispecific antibody comprises a first heavy chain (HC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 12, a first light chain (LC1) having at least 98% identity to the amino acid sequence of SEQ ID NO: 13, a second heavy chain (HC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 22 and a second light chain (LC2) having at least 98% identity to the amino acid sequence of SEQ ID NO: 23.

15. The method of any of claims 1-14, wherein the BCMAxCD3 bispecific antibody is teclistamab.

16. The method of any of claims 1-15, wherein the BCMAxCD3 bispecific antibody is administered as a monotherapy.

17. The method of any of claims 1-16, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy.

18. The method of any of claims 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy, including a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.

19. The method of any of claims 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy, including lenalidomide and an anti-CD38 monoclonal antibody in any prior line.

20. The method of any of claims 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy including a minimum of 2 consecutive cycles of an anti-CD38 monoclonal antibody in any prior line and 2 consecutive cycles of lenalidomide in any prior line.

21. The method of any of claims 1-17, wherein the subject has received 1 to 3 prior lines of antimyeloma therapy, including a minimum of 2 consecutive cycles each of a proteasome inhibitor (PI), lenalidomide, and an anti-CD38 monoclonal antibody in any prior line.

22. The method of any of claims 1-21, wherein the treatment cycle #1 comprises administering two step-up doses of the BCMAxCD3 bispecific antibody and then administering treatment doses of 1.5 mg / kg weekly (QW).

23. The method of any of claims 1-22, wherein the treatment cycle #1 comprises administering a first step-up dose of 0.06 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a second step-up dose of 0.3 mg / kg of the BCMAxCD3 bispecific antibody, then 2-4 days later administering a first treatment dose of 1.5 mg / kg of the BCMAxCD3 bispecific antibody, and then administering the BCMAxCD3 bispecific antibody on a weekly dosing schedule (QW) at a treatment dose of 1.5 mg / kg.

24. The method of any of claims 1-23, wherein: the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 3;administering a treatment dose of 1.5 mg / kg on Days 5, 12 and 1, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.

25. The method of any of claims 1-23, wherein: the treatment cycle #1 comprises: administering a step-up dose of 0.06 mg / kg on Day 1; administering a step-up dose of 0.3 mg / kg on Day 4; administering a treatment dose of 1.5 mg / kg on Days 7, 14 and 21, the treatment cycle #2 comprises: administering a treatment dose of 1.5 mg / kg QW on Days 1, 8, 15, and 22, each of the treatment cycles #3-#6 comprises: administering a treatment dose of 3 mg / kg Q2W on Days 1 and 15, with an optional change to administering the treatment dose of 3 mg / kg Q4W (starting on Day 1 of treatment cycle #3, #4, #5 or #6) if the subject has achieved a very good partial response, a complete response or a stringent complete response (according to 2016 IMWG criteria), the treatment cycle #7 and each of the subsequent treatment cycles comprises: administering a treatment dose of 3 mg / kg Q4W on Day 1.

26. The method of any of claims 1-25, wherein: the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer progression-free survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfdzomib and dexamethasone (Kd).

27. The method of claim 26, wherein the subject exhibits longer progression-free survival compared to the reference subject’s progression-free survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months28. The method of any of claims 1-27, wherein: the subject has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the subject exhibits longer overall survival compared to a reference subject that has received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, and the reference subject was administered a therapeutically effective regimen that does not include a BCMAxCD3 bispecific antibody and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfdzomib and dexamethasone (Kd).

29. The method of claim 28, wherein the subject exhibits longer overall survival compared to the reference subject’s overall survival by at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

30. The method of any of claims 1-29, wherein the subject exhibits a partial response, a very good partial response, a complete response, or a stringent complete response, according to IMWG 2016 criteria.

31. The method of any of claims 1-30, wherein the subject exhibits a complete response or a stringent complete response, according to IMWG 2016 criteria.

32. The method of any of claims 1-31, wherein the antibody exhibits a pharmacokinetic (PK) profile that is equivalent or similar to a PK profile of a reference antibody, wherein the antibody and the reference antibody have different glycosylation profiles in their Fc regions.

33. The method of claim 32, wherein: the antibody comprises neutral N-linked oligosaccharides having less than about 75% GOF, greater than about 20% GIF, and greater than about 2% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having greater than about 70.0% GOF, less than about 15% GIF, and less than about 3% G2F.

34. The method of claim 32, wherein: the antibody comprises neutral N-linked oligosaccharides having less than about 65% GOF, greater than about 25% GIF, and greater than about 4% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having greater than about 75.0% GOF, less than about 12% GIF, and less than about 2% G2F.

35. The method of claim 32, wherein: the antibody comprises neutral N-linked oligosaccharides having about 40% to about 70% GOF, about 15% to about 35% GIF, and about 3% to about 7% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having about 75.0% to about 90% GOF, about 7% to about 12% GIF, and about 0. 1% to about 2% G2F.

36. The method of claim 32, wherein: the antibody comprises neutral N-linked oligosaccharides having about 50% to about 60% GOF, about 25% to about 30% GIF, and about 4% to about 6% G2F, and the reference antibody comprises neutral N-linked oligosaccharides having about 75.0% to about 85% GOF, about 7.5% to about 10.5% GIF, and about 0.4% to about 1.2% G2F.

37. The method of any of claims 32-36, wherein the PK profile comprises one or more of the following PK parameters: (i) serum concentration of the antibody during the treatment cycle #1, 2 or 3, (ii) Cmax of the first treatment dose, (iii) area under serum concentration versus time curve (AUCtau) of the first treatment dose, and (iv) Ctrough on Day 1 of the treatment cycle #3.

38. A method of increasing median progression-free survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, the method comprising: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle # 1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median progression-free survival is relative to the median progression-free survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

39. The method of claim 38, wherein the increase in the median progression-free survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or atleast about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

40. A method of increasing median overall survival in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, the method comprising: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle # 1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the median overall survival is relative to the median overall survival in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

41. The method of claim 40, wherein the increase in the median overall survival is at least about 2 months, or at least about 4 months, or at least about 6 months, or at least about 8 months, or at least about 10 months, or at least about 12 months, or at least about 14 months, or at least about 16 months, or at least about 18 months, or at least about 20 months, or at least about 22 months, or at least about 24 months.

42. A method of increasing a percentage of subjects that exhibit a complete response or stringent complete response (according to IMWG 2016 criteria) in a population of subjects with relapsed or refractory multiple myeloma that have received 1 to 3 prior line(s) of antimyeloma therapy including an anti-CD38 monoclonal antibody and lenalidomide, the method comprising: administering to the population of subjects teclistamab, wherein the teclistamab is subcutaneously administered in sequential 28-day treatment cycles, wherein: treatment cycle # 1 comprises administering one or more step-up doses of the teclistamab and then administering treatment doses of 1.5 mg / kg weekly (QW); treatment cycle #2 comprises administering a treatment dose of the teclistamab in an amount of 1.5 mg / kg weekly (QW); each of treatment cycles #3-#6 comprises either (i) administering a treatment dose of the teclistamab in an amount of 3 mg / kg biweekly (Q2W), or (ii) if the subject has achieved a very good partial response, a complete response or a stringent complete response, administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W) beginning on Day 1 of treatment cycle #3, #4, #5 or #6; and treatment cycle #7 and each subsequent treatment cycle comprises administering a treatment dose of the teclistamab in an amount of 3 mg / kg monthly (Q4W), wherein the increase in the percentage of subjects that exhibit a complete response or stringent complete response is relative to percentage of subjects that exhibit a complete response or stringent complete response in a reference population of subjects, the reference population having been administered a therapeutically effective regimen that does not include teclistamab and instead comprises (i) pomalidomide, bortezomib and dexamethasone (PVd) or (ii) carfilzomib and dexamethasone (Kd).

43. The method of any of claims 38-42, wherein the teclistamab is administered as a monotherapy.

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