Treating multiple myeloma with Anti-CD3 / BCMA bispecific antibody in combination with an Anti-CD38 antibody

Abstract

Methods of treating relapsed or refractory multiple myeloma by administering (a) a bispecific antibody that binds to CD3 and BCMA. and (b) an anti-CD38 antibody (e.g., daratumumab) to a patient in need are provided.

Description

ATTORNEY DOCKET NO.: 13371-343-228 METHODS OF TREATING MULTIPLE MYELOMA INVOLVING AN ANTI- CD3 / BCMA BISPECIFIC ANTIBODY IN COMBINATION WITH AN ANTI-CD38 ANTIBODY CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Serial No.63 / 677,995 filed July 31, 2024, and U.S. Serial No.63 / 729,151 filed December 6, 2024, the disclosure of each of which is incorporated by reference herein in its entirety. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0001] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “13371-343-228_SEQLISTING.xml”, was created on July 23, 2025, and is 8,718 bytes in size. 1. FIELD

[0002] The present application pertains to, among other things, methods of treating multiple myeloma (MM) by administering a bispecific antibody that binds to CD3 and BCMA (a CD3xBCMA bispecific antibody) in combination with an anti-CD38 antibody (e.g., daratumumab). 2. BACKGROUND

[0003] Multiple myeloma (MM) is a plasma cell malignancy and the second most frequent hematopoietic cancer with an annual incidence of ~30,000 in the United States (US). The disease is characterized by the proliferation of clonal plasma cells in the bone marrow and frequently accompanied by the production of a monoclonal immunoglobulin. More than 80% of patients are > 60 years of age, with a median age of onset of 68 years; approximately 2% of cases are diagnosed prior to the age of 40 (Jemal A et al., Cancer Statistics, 2008; 58(2):71-96.; Waxman AJ et al., Blood.2010; 116(25):5501-6; Pulte D et al., The Oncologist.2011; 16(11):1600-3.). The disease primarily localizes to the bones and bone marrow, with resultant cytopenias, bone pain, fractures, infections, hypercalcemia, and renal failure. In addition, serious neurological sequelae can result from pathological fractures in the vertebral bodies. 1 NAI-5002116038v1

[0004] Current therapies for MM often cause remissions, but nearly all patients eventually relapse and die. Although some monoclonal antibodies have shown promise for treating MM in preclinical studies and early clinical trials, consistent clinical efficacy of any monoclonal antibody therapy for MM has not been conclusively demonstrated. Bispecific antibodies represent a new class of therapeutic agents that combine the target specificity and safety profile of monoclonal antibodies with the potency of T-cell mediated cellular toxicity. Use of bispecific antibodies, however, to treat MM poses the risks of dose-limiting toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or both. In fact, per the label on certain CD3xBCMA bispecific antibodies (e.g., teclistamab and elranatamab) patient accessibility may be limited because of the boxed warnings for CRS and ICANS.

[0005] Etentamig (previously known as ABBV-383) is a CD3xBCMA bispecific T-cell redirecting antibody incorporating a unique anti-CD3 moiety that preferentially activates effector over regulatory T-cells and uncouples cytokine release from anti-tumor activity, as well as two heavy-chain-only anti-BCMA moieties for a 2:1 tumor associated antigen (TAA) to CD3 stoichiometry. Etentamig is composed of a bivalent BCMA-binding domain with high avidity, a low-affinity CD3-binding domain designed to mitigate cytokine release, and a present but silenced Fc tail resulting in an extended half-life. These characteristics potentially result in a manageable safety profile with more convenient dosing intervals and robust efficacy.

[0006] Daratumumab is a monoclonal antibody (mAb) directed against CD38 that is approved in multiple combinations and multiple lines of treatment for MM. Use of a CD3xBCMA bispecific antibody (e.g., etentamig), in combination with an anti-CD38 antibody (e.g., daratumumab) has the potential to increase efficacy of the bispecific antibody while reducing instances of adverse events such as CRS. Accordingly, the present disclosure provides methods for treating MM using a combination of a CD3xBCMA bispecific antibody and an anti- CD38 antibody, while reducing instances of adverse events such as CRS. 3. SUMMARY

[0007] Provided herein is a method for treating relapsed or refractory (R / R) multiple myeloma (MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 20 mg or 40 mg or 60 mg of a 2 NAI-5002116038v1bispecific antibody once per a four-week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, wherein the bispecific antibody is etentamig, thereby treat said R / R MM.

[0008] In one aspect, provided herein is a method for safely and effectively treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 60 mg of etentamig once per a four-week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, thereby treating said R / R MM. In embodiments, the anti-CD38 monoclonal antibody is daratumumab. In embodiments, the etentamig is administered intravenously. In embodiments, the anti-CD38 monoclonal antibody is administered subcutaneously. In embodiments, the anti-CD38 monoclonal antibody dose is about 1800 mg.

[0009] In embodiments, the anti-CD38 monoclonal antibody is administered weekly during cycles 1 and 2. In embodiments, the anti-CD38 monoclonal antibody is administered about every 2 weeks during cycle 3 to cycle 6. In embodiments, the anti-CD38 monoclonal antibody is administered every 4 weeks after cycle 6. In embodiments, the method comprises administering the etentamig on day 1 of cycle 1. In embodiments, the method comprises administering the anti- CD38 monoclonal antibody on day 2 of cycle 1.

[0010] In embodiments, the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the etentamig.

[0011] In embodiments, the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the anti-CD38 monoclonal antibody in cycle 1.

[0012] In embodiments, the method comprises administering the etentamig and the anti- CD38 monoclonal antibody on day 1 of each cycle after cycle 1.

[0013] In embodiments, the method further comprises administering dexamethasone weekly.

[0014] In embodiments, the R / R MM has progressed after treatment with at least one prior line of therapy.

[0015] In embodiments, the administration of the etentamig and the anti-CD38 monoclonal antibody results in a partial response (PR) in the subject. In embodiments, the administration of 3 NAI-5002116038v1the etentamig and the anti-CD38 monoclonal antibody results in a stringent complete response (sCR) in the subject. In embodiments, the administration of the bispecific antibody and the anti- CD38 monoclonal antibody results in a very good partial response (VGPR) in the subject. In embodiments, the administration of the etentamig and the anti-CD38 monoclonal antibody provides an objective response rate that is greater than 50% or greater than 55%. In embodiments, the administration of the etentamig and the anti-CD38 monoclonal antibody results in less than 50% incidence of any grade of CRS in the subject.

[0016] In embodiments, the subject has received at least one prior line of therapy; the etentamig is administered intravenously; the subject achieves a VGPR; and the subject does not experience a Grade 1, Grade 2 or Grade 3 CRS.

[0017] In embodiments, administration of the etentamig and the anti-CD38 antibody results in a reduced incidence of at least one adverse event as compared to the administration of 60 mg of etentamig administered as a monotherapy in a four-week cycle. In embodiments, the adverse event is CRS.

[0018] In another aspect, provided herein is a method for safely and effectively treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 60 mg of etentamig once per a four-week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, wherein the subject does not experience a Grade 1, Grade 2 or Grade 3 CRS; and wherein the subject experiences at least a partial response.

[0019] In embodiments, the etentamig is administered intravenously. In embodiments, the method comprises administering the etentamig on day 1 of cycle 1.

[0020] In embodiments, the anti-CD38 monoclonal antibody is daratumumab. In embodiments, the anti-CD38 monoclonal antibody is administered subcutaneously. In embodiments, the anti-CD38 monoclonal antibody dose is about 1800 mg. In embodiments, the anti-CD38 monoclonal antibody is administered weekly during cycles 1 and 2. In embodiments, the anti-CD38 monoclonal antibody is administered about every 2 weeks during cycle 3 to cycle 6. In embodiments, the anti-CD38 monoclonal antibody is administered every 4 weeks after cycle 6. In embodiments, the method comprises administering the anti-CD38 monoclonal antibody on day 2 of cycle 1. 4 NAI-5002116038v1

[0021] In embodiments, the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the etentamig.

[0022] In embodiments, the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the anti-CD38 monoclonal antibody in cycle 1.

[0023] In embodiments, the method comprises administering the etentamig and the anti- CD38 monoclonal antibody on day 1 of each cycle after cycle 1.

[0024] In embodiments, the method further comprises administering dexamethasone weekly.

[0025] In embodiments, the R / R MM has progressed after treatment with at least one prior line of therapy.

[0026] In embodiments, the administration of the etentamig and the anti-CD38 monoclonal antibody results in a stringent complete response (sCR) in the subject. In embodiments, the administration of the bispecific antibody and the anti-CD38 monoclonal antibody results in a very good partial response (VGPR) in the subject. In embodiments, the administration of the etentamig and the anti-CD38 monoclonal antibody provides an objective response rate that is greater than 50% or greater than 55%. In embodiments, the administration of the etentamig and the anti-CD38 monoclonal antibody results in less than 50% incidence of any grade of CRS in the subject. In embodiments, the subject has received at least one prior line of therapy; the etentamig is administered intravenously; and the subject achieves a VGPR.

[0027] In embodiments, administration of the etentamig and the anti-CD38 antibody results in a reduced incidence of at least one adverse event as compared to the administration of 60 mg of etentamig administered as a monotherapy in a four-week cycle. In embodiments, the adverse event is CRS.

[0028] In another aspect, provided herein is a method for treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises: (A) administering to the subject on day one of cycle 1: (i) about 40 mg dexamethasone, and (ii) a therapeutically effective amount of about 60 mg of etentamig; and (B) administering to the subject on day two of cycle 1: (i) about 20 mg dexamethasone, and (ii) about 1800 mg daratumumab; thereby treating said R / R MM. 5 NAI-5002116038v1

[0029] In embodiments, the method further comprises: (C) administering to the subject on day 1 of each subsequent cycle: (i) about 40 mg dexamethasone, (ii) a therapeutically effective amount of about 60 mg of etentamig, and (iii) about 1800 mg of the daratumumab.

[0030] In embodiments, each cycle comprises about four weeks.

[0031] In embodiments, the etentamig is administered intravenously.

[0032] In embodiments, the daratumumab is administered subcutaneously. In embodiments, the daratumumab is administered weekly during cycles 1 and 2. In embodiments, the daratumumab is administered every two weeks during cycles 3 and 6. In embodiments, the daratumumab is administered once per cycle after cycle 6.

[0033] In embodiments, the dexamethasone is administered orally or intravenously. In embodiments, administration of about 40 mg dexamethasone is repeated once weekly per cycle. In embodiments, about 40 mg dexamethasone is administered on days 1, 8, 15, and 22 per cycle.

[0034] In embodiments, the R / R MM has progressed after treatment with at least one prior line of therapy.

[0035] In embodiments, the administration of the etentamig and the daratumumab results in a partial response (PR) in the subject. In embodiments, the administration of the etentamig and the daratumumab results in a stringent complete response (sCR) in the subject. In embodiments, the administration of the etentamig and the daratumumab results in a very good partial response (VGPR) in the subject. In embodiments, the administration of the etentamig and the daratumumab provides an objective response rate that is greater than 50% or greater than 55%. In embodiments, the administration of the etentamig and the daratumumab results in less than 50% incidence of any grade of CRS in the subject.

[0036] In embodiments, the subject has received at least one prior line of therapy; the etentamig is administered intravenously; the subject achieves a VGPR; and the subject does not experience Grade 1, Grade 2 or Grade 3 CRS.

[0037] In embodiments, the subject experiences a reduced incidence of at least one adverse event as compared to the administration of 60 mg of administered as a monotherapy in a four- week cycle. In embodiments, the adverse event is CRS. 6 NAI-5002116038v1

[0038] In another aspect, provided herein is a method for safely and effectively treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 60 mg of etentamig once per a four-week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, thereby treating said R / R MM, wherein when the method is used to treat a population of patients with R / R MM, a statistically significantly greater percentage of the patients achieve a reduced incidence of CRS and / or a greater objective response rate, compared to a control group of patients treated with about 60 mg etentamig monotherapy once per a four-week cycle. In embodiments, the anti-CD38 monoclonal antibody is daratumumab. In embodiments, the etentamig is administered intravenously. In embodiments, the anti-CD38 monoclonal antibody is administered subcutaneously. In embodiments, the anti- CD38 monoclonal antibody dose is about 1800 mg.

[0039] These and further aspects will be further explained in the rest of the disclosure, including the Examples. 4. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIG.1 illustrates an exemplary treatment schedule for R / R MM involving administering dexamethasone prior to intravenously administering 20 mg of etentamig and subcutaneously administering 1800 mg of daratumumab.

[0041] FIG.2 illustrates an exemplary treatment schedule for R / R MM involving administering dexamethasone prior to intravenously administering 40 mg of etentamig and subcutaneously administering 1800 mg of daratumumab.

[0042] FIG.3 illustrates an exemplary treatment schedule for R / R MM involving administering dexamethasone prior to intravenously administering 60 mg of etentamig and subcutaneously administering 1800 mg of daratumumab.

[0043] FIG.4 illustrates the objective response rate (combined partial response (PR) and VGPR) and VGPR of R / R MM patients that received etentamig and daratumumab in three dosing cohorts. PR rates are depicted within each column at the bottom and VGPR rates are depicted within each column at the top. 7 NAI-5002116038v15. DETAILED DESCRIPTION

[0044] All references cited throughout the disclosure, including patent applications and publications, are incorporated by reference herein in their entirety. 5.1 Terminology

[0045] Antibody residues herein are numbered according to the Kabat numbering system and the EU numbering system. The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest.5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody. Unless stated otherwise herein, references to residue numbers in the variable domain of antibodies mean residue numbering by the Kabat numbering system. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies mean residue numbering by the EU numbering system.

[0046] The term “BCMA” as used herein relates to human B-cell maturation antigen, also known as BCMA, CD269, and TNFRSF17 (UniProt Q02223), which is a member of the tumor necrosis receptor superfamily that is preferentially expressed in differentiated plasma cells. The extracellular domain of human BCMA consists, according to UniProt of amino acids 1-54 (or 5- 51).

[0047] The term “characterized by expression of BCMA” broadly refers to any disease or disorder in which BCMA expression is associated with or involved with one or more pathological processes that are characteristic of the disease or disorder. Such disorders include, but are not limited to, B-cell neoplasms, including MM.

[0048] The term “CD3” refers to the human CD3 protein multi-subunit complex. The CD3 protein multi-subunit complex is composed of 6 distinctive polypeptide chains. These include a CD3γ chain (SwissProt P09693), a CD3δ chain (SwissProtP04234), two CD3ε chains (SwissProt P07766), and one CD3ζ chain homodimer (SwissProt 20963), and a T-cell receptor (α / β or γ / δ) heterodimer. The term “CD3” includes any CD3 variant, isoform and species homolog that is 8 NAI-5002116038v1naturally expressed by cells (including T-cells) or can be expressed on cells transfected with genes or cDNA encoding those polypeptides, unless noted. In specific embodiments, the CD3 is human CD3δε.

[0049] A “CD3xBCMA bispecific antibody” is a bispecific antibody that comprises two different antigen-binding regions, one of which binds to the antigen human CD3 and one of which binds to human BCMA.

[0050] The term “CD38” refers to the human CD38 protein. The CD38 protein is a single chain glycoprotein with a single transmembrane segment.

[0051] “Complement dependent cytotoxicity” or “CDC” refers to the ability of a molecule to lyse a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g., an antibody) complexed with a cognate antigen. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), may be performed.

[0052] The term “Complete Response (“CR”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, has the meaning defined in Table 4.

[0053] The term “stringent Complete Response (“sCR”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, has the meaning defined in Table 4.

[0054] The term “cytokine release syndrome” or “CRS” (with or without neurotoxicity) is the primary toxicity associated with T-cell redirection therapy (e.g. T-cell engaging bispecific antibodies). CRS occurs due to hyper-activation of the immune system and is mediated predominantly by the secretion of pro-inflammatory cytokines (e.g. IL-6). Signs and symptoms are those of systemic inflammation like sepsis, anaphylaxis, and tumor lysis syndrome and include the following: high fever / rigors, hypotension, hypoxia, neurologic changes, pain, nausea, and headache. In addition, abnormalities of liver and kidney function tests have been reported. Meta- analyses show that clinical findings, e.g. fever, are usually the first indicators of CRS onset. Herein, CRS is graded according to American Society for Transplantation and Cellular Therapy (ASTCT) 9 NAI-5002116038v12019 Guidelines.

[0055] The term “daratumumab” refers to a mAb directed against CD38. In embodiments, daratumumab may refer to Darzalex® (Janssen Biotech, Inc.).

[0056] The term “Duration of Response (“DOR”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, means the number of days from the date of first response (sCR, CR, VGPR, or PR) to the earliest recurrence, progressive disease, or death, whatever occurs first. For subjects who never experience response, the subject's data is not included in the analysis of DOR. Duration of response is analyzed by Kaplan-Meier methodology.

[0057] The term “effector cell” refers to an immune cell which is involved in the effector phase of an immune response, as opposed to the cognitive and activation phases of an immune response. Some effector cells express specific Fc receptors and carry out specific immune functions. In embodiments, an effector cell such as a natural killer cell is capable of inducing antibody-dependent cellular cytotoxicity (ADCC). For example, monocytes and macrophages, which express FcR, are involved in specific killing of target cells and presenting antigens to other components of the immune system or binding to cells that present antigens. In embodiments, an effector cell may phagocytose a target antigen or target cell.

[0058] Antibody “effector functions” refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody. Examples of antibody effector functions include C1q binding; complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B-cell receptor; BCR), etc.

[0059] The term “immune cell” is used herein in the broadest sense, including, without limitation, cells of myeloid or lymphoid origin, for instance lymphocytes (such as B-cells and T- cells including cytolytic T-cells (CTLs)), killer cells, natural killer (NK) cells, macrophages, monocytes, eosinophils, polymorphonuclear cells, such as neutrophils, granulocytes, mast cells, and basophils.

[0060] The term “human effector cells” refers to leukocytes that express receptors such as T- 10 NAI-5002116038v1cell receptors or FcRs and perform effector functions. Preferably, the cells express at least FcγRIII and perform ADCC effector function. Examples of human leukocytes which mediate ADCC include natural killer (NK) cells, monocytes, cytotoxic T-cells and neutrophils. The effector cells may be isolated from a native source thereof, e.g., from blood or PBMCs as described herein.

[0061] The term “Immune Effector Cell-Associated Neurotoxicity Syndrome” or “ICANS” refers to neurotoxicity that arises from unclear etiology but has been postulated to stem from endothelial activation / microangiopathy, possibly downstream of IL-1 secretion by monocytes / macrophages. Onset usually occurs with or after CRS. Symptoms of neurotoxicity include delirium, headache, agitation, aphasia, central nervous system bleed, ataxia, confusion, seizure, somnolence, and tremor. Herein, ICANS is graded according to American Society for Transplantation and Cellular Therapy (ASTCT) 2019 Guidelines.

[0062] The term “Infusion Related Reactions” or “IRR” have been associated with monoclonal antibody therapies, including bispecific antibody therapies (e.g. T-Cell engaging bispecific antibodies) and are thought to have multiple mechanisms, including type I and IV hypersensitivity reactions as well as cytokine release triggered by antibody-antigen interactions. IRRs usually occur within 2 hours of the first or second exposure to an antibody therapy and are characterized by fever / chills, flushing / itching, changes in vital signs, pain, nausea / vomiting, and / or rashes. Anaphylaxis may rarely occur.

[0063] The term “line of therapy” means at least one complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of regimens.

[0064] The term “Minimal Residual Disease (“MRD”)” negativity by next-generation sequencing (NGS), as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, means the proportion of subjects who achieve MRD negative status (< 10‑5) (threshold as assessed by NGS Adaptive Clonoseq) with ≥ CR (per IMWG response criteria) prior to the initiation of new myeloma therapy. The point estimate and the 95% confidence interval based on Clopper-Pearson method is calculated for MRD negativity rate. For the analysis of MRD, subjects with missing or unevaluable MRD status is considered as MRD positive. 11 NAI-5002116038v1

[0065] A “new line of therapy” means at least one of the following: (a) start of a new line of treatment after discontinuation of a previous line; (b) the unplanned addition or substitution of 1 or more drugs in an existing regimen; (c) in subjects undergoing > 1 stem cell transplant (SCT), except in the case of a planned tandem SCT with a predefined interval (such as 3 months), each SCT (autologous or allogeneic) should be considered a new line of therapy regardless of whether the conditioning regimen used is the same or different. A regimen is considered to have been discontinued if all the drugs in that given regimen have been stopped. A regimen is not considered to have been discontinued if only some, but not all, of the drugs of the regimen have been discontinued.

[0066] The term “Overall Response Rate (“ORR”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, means the proportion of subjects who achieved a PR or better (PR + VGPR + CR + sCR). The point estimate and the 95% confidence interval based on Clopper-Pearson method is calculated for ORR. For the analysis of response rates, subjects without any postbaseline response assessments is considered as non-responders.

[0067] The term “Partial Response (“PR”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, has the meaning defined in Table 4.

[0068] The term “prior line of therapy” means a course of therapy (comprising at least 1 cycle) that was administered and discontinued before a new line of therapy.

[0069] The term “Progression-free Survival (“PFS”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, means the number of days from the date of first dose to the date of earliest disease progression or death. All disease progression is included regardless of whether the event occurred while the subject was taking etentamig or had previously discontinued etentamig. Progression-free survival is analyzed by Kaplan-Meier methodology.

[0070] The term “relapsed” means previously treated multiple myeloma that progresses and requires initiation of salvage therapy, but does not meet criteria for refractory myeloma. 12 NAI-5002116038v1

[0071] The term “refractory” means disease that is nonresponsive (failure to achieve minimal response [MR] or development of progressive disease) while on primary or salvage therapy, or progresses within 60 days of last therapy.

[0072] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a human being assessed for treatment and / or being treated.

[0073] The term “Time-to-Progression (“TTP”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, means the number of days from the date of first dose to the date of earliest disease progression. All disease progression is included regardless of whether the event occurred while the subject was taking etentamig or had previously discontinued etentamig. Time-to-progression is analyzed by Kaplan-Meier methodology.

[0074] The terms “treatment,” “treating” and the like are used herein to generally mean obtaining a desired pharmacologic and / or physiologic effect. “Treatment” as used herein covers any treatment of a disease in a human and includes: inhibiting the disease, i.e., arresting its development; or relieving the disease, i.e., causing regression of the disease. The treatment of ongoing disease, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment is desirably performed prior to complete loss of function in the affected tissues. The subject therapy may be administered during the symptomatic stage of the disease.

[0075] A “therapeutically effective amount” is an amount of active agent that imparts therapeutic benefit to a subject as part of a course of treatment. Therapeutic benefit may be a safety or efficacy benefit. For example, a “therapeutically effective amount” is an amount that induces, ameliorates or otherwise causes an improvement in the pathological symptoms, disease progression, or physiological conditions associated with a disease. In embodiments, the term “therapeutically effective amount” is an amount of active agent that obtains a desired pharmacological and / or physiological effect.

[0076] The term “Very Good Partial Response (“VGPR”),” as defined by the International Myeloma Working Group (IMWG) 2016 criteria for Multiple Myeloma, has the meaning defined in Table 4. 13 NAI-5002116038v1

[0077] Abbreviations used herein include the following: β (Terminal phase elimination rate constant); Ab (antibody); ADA (Antidrug antibody); ADCC (Antibody-dependent cell cytotoxicity); AE (Adverse event); ALT (alanine aminotransferase); ANC (Absolute neutrophil count); APRIL (A proliferation inducing ligand); aPTT (activated partial thromboplastin time); ASCT (autologous stem cell transplantation); AST (Aspartate aminotransferase); AUC (Area under the concentration-time curve); AUCt (Area under the serum concentration-time curve from time zero to time of last measurable concentration); BCMA (B-cell maturation antigen (also called TNFRSF17)); BUN (Blood urea nitrogen); CAR (Chimeric antigen receptor); CBR (Clinical benefit rate); CI (Confidence interval); CL (Clearance); Cmax (Maximum observed serum concentration); CNS (Central nervous system); CR (Complete response); CRAB features (calcium elevation, renal failure, anemia, lytic bone lesions); CRS (Cytokine release syndrome); Css (Steady state concentration); CT (Computed tomography); CTCAE (Common Terminology Criteria for Adverse Events); DARA (daratumumab); DEX (dexamethasone); DLT (Dose limiting toxicity); DNA (Deoxyribonucleic acid); DOR (Duration of Response); ECG (Electrocardiogram); ECHO (Echocardiogram); ECOG (Eastern Cooperative Oncology Group); eCRF (Electronic Case Report Form); EDC (Electronic Data Capture); EE (Efficacy Evaluable); EEG (electroencephalogram); ELISA (Enzyme-linked immunosorbent assay); EOT (End of treatment); FCM (flow cytometry); 18F-FDG PET (18F-fluorodeoxyglucose PET); FFPE (Formalin-fixed paraffin embedded); FIH (First-in-human); FISH (Fluorescence in situ hybridization); FLC (Free light chain); GCP (Good Clinical Practice); GGT (gamma- glutamyltransferase); HAV-IgM (Hepatitis A virus immunoglobulin M); HBsAg (Hepatitis B surface antigen); HBV (Hepatitis B virus); HCV (Hepatitis C virus); HCV Ab (Hepatitis C virus antibody); HIV (Human immunodeficiency virus); IB (Investigator’s Brochure); ICH (International Conference on Harmonization); ICU (intensive care unit); IEC (Independent Ethics Committee); IFN (interferon); IL (interleukin); IMiD (Immunomodulatory imide); IMWG (International Myeloma Working Group); INR (International normalized ratio); IRB (Institutional Review Board); IV (Intravenous); LDH (Lactate dehydrogenase); LP (lumbar puncture); mAb (Monoclonal antibody); MABEL (Minimal anticipated biological effect level); MCH (mean corpuscular hemoglobin); MCHC (mean corpuscular hemoglobin concentration); MCV (mean corpuscular volume); MedDRA (Medical Dictionary for Regulatory Activities); MFC (multiparameter flow cytometry); MM (Multiple myeloma); M-protein (myeloma protein); 14 NAI-5002116038v1MR (Minor response); MRD (minimal residual disease); MRI (Magnetic Resonance Imaging); MTD (Maximum tolerated dose); MUGA (Multiple gated acquisition scan); NCI (National Cancer Institute); NC (Noncompartmental analysis); NGF (next-generation flow); NGS (next- generation sequencing); ORR (Objective response rate); OS (Overall survival); PBMC (Peripheral blood mononuclear cells); PC (Positive control); PET (Positron emission tomography); PI (Proteasome inhibitor); PD (Pharmacodynamic); PK (Pharmacokinetic); PFS (Progression-free Survival); PR (Partial response); PT (Prothrombin time); Q3W (Once every 3 weeks); Q4W (Once every 4 weeks); QTc (QT interval corrected for heart rate); RBC (red blood cell); RNA (Ribonucleic acid); RP2D (Recommended phase 2 dose); SAE (Serious adverse event); sCR (Stringent complete response); SFLC (serum free light chain); SIFE (Serum immunofixation electrophoresis); SMG (Safety monitoring group); SPD (sum of the products of the maximal perpendicular diameters of measured lesions); SPEP (Serum protein electrophoresis); SUVmax (maximum standardized uptake value); t1 / 2(Terminal phase elimination half-life); T-BsAbs (T-cell engaging bispecific antibodies); TEAE (Treatment emergent adverse event); Tmax (Time to maximum observed serum concentration); TNF (tumor necrosis factor); Treg cells (Regulatory T cells); TTP (Time to progression); TTR (Time to response); UIFE (Urine immunofixation electrophoresis); ULN (Upper limit of normal); UPEP (Urine protein electrophoresis); US (United States); V1 (Central compartment volume); VGPR (Very good partial response); WBC (white blood cell). 5.2 CD3xBCMA bispecific antibody

[0078] The present disclosure relates to methods of treating R / R MM by administering to a subject a bispecific antibody that binds to CD3 (e.g., human CD3) and BCMA (e.g., human BCMA) (i.e., a CD3xBCMA bispecific antibody). In embodiments, the CD3xBCMA bispecific antibody used in the methods provided herein is etentamig (previously known as TNB-383B and ABBV-383). In embodiments, the bispecific CD3xBCMA antibody comprises: an anti-CD3 heavy chain variable (VH) domain that is paired with a light chain variable (VL) domain, wherein the VH domain and the VL domain together have binding affinity for CD3; a heavy chain variable domain of a heavy chain-only antibody having binding affinity to BCMA, in a bivalent configuration; and a variant human IgG4 Fc domain comprising a first heavy chain constant region sequence comprising an S228P mutation, an F234A mutation, an L235A 15 NAI-5002116038v1mutation, and a T366W mutation (knob), and a second heavy chain constant region sequence comprising an S228P mutation, an F234A mutation, an L235A mutation, a T366S mutation, an L368A mutation, and a Y407V mutation (hole).

[0079] Etentamig is a human, monoclonal IgG4 bispecific antibody, comprising: (a) a first binding arm specific for human CD3, wherein the first binding arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:1; and a light chain comprising the amino acid sequence of SEQ ID NO:2; and (b) a second binding arm specific for human BCMA, wherein the second binding arm comprises: a heavy chain-only variable region in a bivalent configuration and comprising the amino acid sequence of SEQ ID NO:3 (Table 1). Table 1: Etentamig CD3xBCMA Bispecific Antibody Sequences Anti-CD3 full EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLL length light IYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNW P K W Y T L P V K Y G W Y S V Q P S L L L16 NAI-5002116038v1Anti-CD3 full EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEW length heavy VSGISWNSGSIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALY h i VH F2B YCAKDSRGYGDYRLGGAYWG GTLVTVSSASTKGPSVFPLAPCSRST L P V K Y G W Y S V Q P S L L Lc antibody is etentamig and consists of a first polypeptide consisting of SEQ ID NO:1, a second polypeptide consisting of SEQ ID NO:2, and a third polypeptide consisting of SEQ ID NO:3. In embodiments, SEQ ID NO:2 of etentamig has the C-terminal lysine removed (SEQ ID NO:4). In embodiments, SEQ ID NO:3 of etentamig has the C-terminal lysine removed (SEQ ID NO:5). In embodiments, SEQ ID NO:2 and SEQ ID NO:3 of etentamig each have the C-terminal lysine removed (SEQ ID NO:4 and SEQ ID NO:5, respectively).

[0081] In embodiments, the CD3xBCMA bispecific antibody binds to human CD3δε. In embodiments, the CD3xBCMA bispecific antibody binds to human BCMA. In embodiments, the CD3xBCMA bispecific antibody binds to human CD3δε and human BCMA. In embodiments, the CD3xBCMA bispecific antibody binds to human CD3δε and binds to human BCMA. In embodiments, the CD3xBCMA bispecific antibody is a monoclonal antibody.

[0082] In embodiments, the CD3xBCMA bispecific antibodies herein are formulated into 17 NAI-5002116038v1pharmaceutical compositions comprising the CD3xBCMA bispecific antibodies that are suitable for intravenous administration. The pharmaceutical compositions are generally formulated as sterile and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration. In embodiments of the methods described hereinbelow, the bispecific antibody is administered intravenously. 5.3 Methods of Treatment

[0083] In embodiments, the method comprises treating R / R MM in a human subject comprising administering a CD3xBCMA bispecific antibody (e.g., etentamig) and an anti-CD38 monoclonal antibody (mAb) (e.g., daratumumab).

[0084] In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for one or more treatment cycles, wherein each treatment cycle is about 4 weeks or 28 days. As used herein, a four-week or 28-day cycle may be referred to as “Q4W.” In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for one 4-week or 28-day treatment cycle. In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for two treatment cycles. In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for three treatment cycles. In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for four treatment cycles. In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for five treatment cycles. In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for six treatment cycles. In embodiments, the CD3xBCMA bispecific antibody and the anti-CD38 antibody are administered for more than six treatment cycles. In embodiments, the last dose of treatment is considered as the dose when the treatment is stopped either due to disease progression or to meeting other discontinuation criteria as defined herein. In embodiments, the CD3xBCMA antibody is etentamig. In embodiments, etentamig is administered IV. In embodiments, the anti-CD38 monoclonal antibody is daratumumab. In embodiments, the anti- CD38 monoclonal antibody is administered subcutaneously.

[0085] In embodiments, the method comprises treating relapsed or refractory MM in a human subject comprising administering a CD3xBCMA bispecific antibody (e.g., etentamig) and an anti-CD38 monoclonal antibody (mAb) (e.g., daratumumab). In embodiments, the subject 18 NAI-5002116038v1previously has been exposed to at least one prior line of therapy. In embodiments, the subject has received at least two prior lines of therapy. In embodiments, the subject has received at least three prior lines of therapy. In embodiments, the prior line of therapy includes treatment with a proteasome inhibitor (PI). In embodiments, the prior line of therapy includes treatment with an immunomodulatory imide (IMiD) (e.g., pomalidomide, lenalidomide). In embodiments, the prior line of therapy includes treatment with an anti-CD38 mAb (e.g., daratumumab). In specific embodiments, the prior line of therapy includes treatment with an anti-CD38 mAb (e.g., daratumumab) not within 90 days of first dose of the CD3xBCMA bispecific antibody. In embodiments, the prior line of therapy includes treatment with a PI and an IMID. In embodiments, the bispecific antibody is a monoclonal antibody. In embodiments, the method of treating relapsed or refractory MM comprises administering a CD3xBCMA bispecific antibody and an anti-CD38 monoclonal antibody (mAb) (e.g., daratumumab) as a fourth line therapy to patients who have previously been exposed to treatment with a PI and an IMiD.

[0086] In embodiments, the method for treating R / R MM in a human subject comprises administering a therapeutically effective amount of about 20 mg to about 60 mg per cycle of etentamig, and an anti-CD38 monoclonal antibody, thereby treating said MM. In embodiments, the dose of etentamig is a therapeutically effective amount of about 20 mg per cycle. In embodiments, the dose of etentamig is a therapeutically effective amount of about 40 mg per cycle. In embodiments, the dose of etentamig is a therapeutically effective amount of about 60 mg per cycle.

[0087] In embodiments, each cycle in which etentamig is administered is about four weeks. In embodiments, the subject is administered a therapeutically effective amount of 20 mg of etentamig once every four weeks or 28 days. In embodiments, the subject is administered a therapeutically effective amount of 40 mg of etentamig once every four weeks or 28 days. In embodiments, the subject is administered a therapeutically effective amount of 60 mg of etentamig once every four weeks or 28 days.

[0088] In embodiments, etentamig is administered intravenously (IV). In embodiments, etentamig infusion is given over 2 hours (± 10 minutes). If no infusion reactions occur during the first dose of etentamig (e.g. the dose of etentamig in cycle 1), the duration of infusion for subsequent doses of etentamig (in subsequent cycles) may be shortened. In embodiments, 19 NAI-5002116038v1subjects are monitored for 4 hours after the first infusion in cycle 1, and for 2 hours after each subsequent infusion in cycles after cycle 1. For clarity, the 4 hours of close observation post- infusion in Cycle 1 should occur during the subject’s hospitalization after the first dose of etentamig. In embodiments, a subject is hospitalized for a total of 48 hours, from day 1 to day 3, following the first dose of etentamig.

[0089] In embodiments, the anti-CD38 monoclonal antibody is daratumumab.

[0090] In embodiments, the anti-CD38 monoclonal antibody is administered subcutaneously.

[0091] In specific embodiments, the anti-CD38 monoclonal antibody is administered at a dose of about 1800 mg.

[0092] In embodiments, about 1800 mg of daratumumab is administered subcutaneously. In embodiments, daratumumab (1800 mg) is administered by subcutaneous injection by manual push over approximately 3-5 minutes by a healthcare professional. On subsequent cycles, in embodiments, when etentamig and daratumumab dosing coincide, daratumumab is administered at least 1 hour after end of etentamig infusion, and on the same day.

[0093] In embodiments, the anti-CD38 monoclonal antibody is administered weekly during cycles 1 and 2. In embodiments, the anti-CD38 monoclonal antibody is administered about every 2 weeks during cycle 3 to cycle 6. In embodiments, the anti-CD38 monoclonal antibody is administered every 4 weeks after cycle 6. In embodiments, the method does not require prior step-up dosing with the CD3xBCMA bispecific antibody (e.g., etentamig).

[0094] In embodiments, the method for treating R / R MM in a human subject comprises administering to the subject as a combination therapy comprising: a therapeutically effective amount about 20 mg, 40 mg, or 60 mg of etentamig once every four weeks and administering about 1800 mg of daratumumab weekly for the first eight weeks, thereby treating said R / R MM. In embodiments, the method comprises continuing to administer to the subject the same dose of about 20 mg, 40 mg, or 60 mg of etentamig once every four weeks and administering about 1800 mg of daratumumab every two weeks for the next 16 weeks. In embodiments, the method further comprises continuing to administer to the subject the same dose of about 20 mg, 40 mg, or 60 mg of etentamig once every four weeks and further administering about 1800 mg of daratumumab once every four weeks. In embodiments, the method comprises administering to the subject a 20 NAI-5002116038v1dose of about 20 mg or 40 mg of etentamig once every four weeks and administering about 1800 mg of daratumumab every two weeks for the next 16 weeks. In embodiments, the method further comprises administering to the subject a dose of about 20 mg or 40 mg of etentamig once every four weeks and further administering about 1800 mg of daratumumab once every four weeks. In embodiments, etentamig is administered intravenously and daratumumab is administered subcutaneously. In embodiments, the combination therapy is administered as a fourth line therapy to patients who have previously been exposed to treatment with a PI and an IMiD. In embodiments, the combination therapy is administered as a third line therapy to patients who have previously been exposed to treatment with a PI and an IMiD.

[0095] In embodiments, the method for treating R / R MM in a human subject comprises administering to the subject as a combination therapy comprising: a therapeutically effective amount about 60 mg of etentamig once every four weeks and administering about 1800 mg of daratumumab weekly for the first eight weeks, thereby treating said R / R MM. In embodiments, the method comprises continuing to administer to the subject the same dose of about 60 mg of etentamig once every four weeks and administering about 1800 mg of daratumumab every two weeks for the next 16 weeks. In embodiments, the method further comprises continuing to administer to the subject the same dose of about 60 mg of etentamig once every four weeks and further administering about 1800 mg of daratumumab once every four weeks. In embodiments, etentamig is administered intravenously and daratumumab is administered subcutaneously. In embodiments, the combination therapy is administered as a fourth line therapy to patients who have previously been exposed to treatment with a PI and an IMiD. In embodiments, the combination therapy is administered as a third line therapy to patients who have previously been exposed to treatment with a PI and an IMiD.

[0096] In embodiments, etentamig is initially administered as an IV infusion once every four weeks starting on day 1 of cycle 1 and an anti-CD38 monoclonal antibody is initially administered subcutaneously weekly starting on day 2 of cycle 1. In embodiments, on day 1 of cycle 2, etentamig is administered as an IV infusion once every four weeks and the anti-CD38 monoclonal antibody is administered subcutaneously weekly. In embodiments, on day 1 of cycles 3 to 6, etentamig is administered as an IV infusion once every four weeks and the anti- CD38 monoclonal antibody is administered subcutaneously every other week. In embodiments, 21 NAI-5002116038v1on day 1 of cycle 7 and onwards, etentamig is administered as an IV infusion and the anti-CD38 monoclonal antibody is administered subcutaneously every four weeks. Subjects may continue to receive etentamig and the anti-CD38 monoclonal antibody as long as they do not meet any of the criteria for subject discontinuation.

[0097] In embodiments, the anti-CD38 monoclonal antibody is initially administered subcutaneously weekly starting on day 1 of cycle 1 and etentamig is initially administered as an IV infusion once every four weeks starting on day 2 of cycle 1 and. In embodiments, on day 1 of cycle 2, etentamig is administered as an IV infusion once every four weeks and the anti-CD38 monoclonal antibody is administered subcutaneously weekly. In embodiments, on day 1 of cycles 3 to 6, etentamig is administered as an IV infusion once every four weeks and the anti- CD38 monoclonal antibody is administered subcutaneously every other week. In embodiments, on day 1 of cycle 7 and onwards, etentamig is administered as an IV infusion and the anti-CD38 monoclonal antibody is administered subcutaneously every four weeks. Subjects may continue to receive etentamig and the anti-CD38 monoclonal antibody as long as they do not meet any of the criteria for subject discontinuation.

[0098] Aspects of the disclosure include methods for evaluating the safety, pharmacokinetic (PK), pharmacodynamic (PD) and clinical activity of a CD3xBCMA bispecific antibody in subjects with relapsed or refractory MM who have received at least 3 prior lines of therapy, including a PI, and an IMiD.

[0099] In embodiments, methods provided herein involve evaluating the safety, tolerability, PK and PD profiles of the CD3xBCMA bispecific antibody (e.g., etentamig) and anti-CD38 mAb (e.g., daratumumab) combination therapy, in patients with relapsed or refractory MM who have received at least 3 prior lines of therapy, including a PI, an IMiD and an anti-CD38 mAb (e.g., daratumumab).

[0100] In embodiments of the various methods provided herein, subjects are administered with one or more doses of an agent that reduces a risk or severity of an immune-mediated toxicity prior to administering etentamig and / or prior to administering the anti-CD38 monoclonal antibody. In embodiments, the agent is selected from the group consisting of dexamethasone, diphenhydramine, acetaminophen, ranitidine, famotidine, and any equivalents thereof, or any combination thereof. In embodiments, subjects are administered dexamethasone before 22 NAI-5002116038v1administration of about 20 mg to about 60 mg of etentamig. In embodiments, subjects are administered dexamethasone before administration of about 20 mg. about 40 mg, or about 60 mg of etentamig. In embodiments, subjects are administered dexamethasone before administration of about 20 mg of etentamig. In embodiments, subjects are administered dexamethasone before administration of about 40 mg of etentamig. In embodiments, subjects are administered dexamethasone before administration of about 60 mg of etentamig.

[0101] In embodiments, subjects are administered with dexamethasone (20-40 mg IV or orally) or equivalent, diphenhydramine (25 to 50 mg IV) or equivalent (e.g., Cetirizine 10 mg PO x 1), acetaminophen 650 to 1000 mg PO and ranitidine 150 mg PO / IV or equivalent about 15 to about 60 minutes prior to etentamig infusion to reduce the risk and severity of immune-mediated toxicities commonly observed with mAb therapy (e.g., CRS and / or ICANS). In embodiments, subjects are administered acetaminophen every six hours for the first 24 hours prior to infusion of etentamig. In embodiments, subjects are administered diphenhydramine and famotidine 15 to 60 minutes prior to infusion of etentamig. In embodiments, subjects are administered diphenhydramine and famotidine orally 15 to 60 minutes prior to infusion of etentamig. In embodiments, subjects are administered diphenhydramine and famotidine IV 15 to 60 minutes prior to infusion of etentamig.

[0102] In embodiments, subjects are administered dexamethasone before administration of the anti-CD38 antibody. In embodiments, the anti-CD38 antibody is daratumumab. In embodiments, daratumumab is administered subcutaneously. In embodiments, the total amount of dexamethasone administered before administration of the anti-CD38 antibody is about 20 mg. In embodiments, the total amount of dexamethasone administered before administration of the anti-CD38 antibody is about 40 mg.

[0103] In embodiments, subjects are administered about 20 mg dexamethasone about 15 to about 60 minutes before administration of the anti-CD38 antibody. In embodiments, subjects are administered about 40 mg dexamethasone about 15 to about 60 minutes before administration of the anti-CD38 antibody. In embodiments, subjects are administered 20 mg dexamethasone before administration of the anti-CD38 antibody on cycle 1 day 2. In embodiments, the anti- CD38 monoclonal antibody is daratumumab. In embodiments, the anti-CD38 monoclonal is administered at about 1800 mg of daratumumab. In embodiments, the anti-CD38 monoclonal 23 NAI-5002116038v1antibody is administered subcutaneously. In embodiments, the dexamethasone is administered intravenously or orally.

[0104] In embodiments, the method for treating R / R MM in a human subject in need thereof comprises administering to the subject on day one of cycle 1 a first dose of about 40 mg dexamethasone prior to administering etentamig at about 20 mg to about 60 mg, and then administering to the subject on day two of cycle 1 a second dose of about 20 mg dexamethasone prior to administering an anti-CD38 monoclonal antibody (e.g., daratumumab). In embodiments, etentamig is administered intravenously. In embodiments, the anti-CD38 monoclonal antibody is daratumumab. In specific embodiments, the anti-CD38 monoclonal is administered at about 1800 mg of daratumumab. In embodiments, the anti-CD38 monoclonal antibody is administered subcutaneously. In embodiments, the dexamethasone is administered intravenously or orally.

[0105] In embodiments, the method for treating R / R MM in a human subject in need thereof comprises administering to the subject on day one of cycle 1 a first dose of about 40 mg dexamethasone prior to administering about 60 mg etentamig, and then administering to the subject on day two of cycle 1 a second dose of about 20 mg dexamethasone prior to administering an anti-CD38 monoclonal antibody (e.g., daratumumab). In embodiments, the method further comprises administering to the subject on day 1 of each subsequent cycle: about 40 mg dexamethasone, about 60 mg etentamig, and the anti-CD38 monoclonal antibody. In embodiments, each cycle comprises about four weeks. In embodiments, etentamig is administered intravenously. In embodiments, the anti-CD38 monoclonal antibody is daratumumab. In embodiments, the anti-CD38 monoclonal is administered of about 1800 mg of daratumumab. In embodiments, the anti-CD38 monoclonal antibody is administered subcutaneously. In embodiments, the dexamethasone is administered intravenously or orally.

[0106] In one aspect, provided herein is a method for treating R / R MM in a human subject in need thereof, wherein the method comprises intravenously or orally administering to the subject dexamethasone prior to intravenously administering to the subject about 20 mg etentamig, and subcutaneously administering to the subject daratumumab of about 1800 mg, according to the treatment schedule illustrated in FIG.1.

[0107] In another aspect, provided herein is a method for treating R / R MM in a human 24 NAI-5002116038v1subject in need thereof, wherein the method comprises intravenously or orally administering to the subject dexamethasone prior to intravenously administering to the subject about 40 mg etentamig, and subcutaneously administering to the subject daratumumab of about 1800 mg, according to the treatment schedule illustrated in FIG.2.

[0108] In a further aspect, provided herein is a method for treating R / R MM in a human subject in need thereof, wherein the method comprises intravenously or orally administering to the subject dexamethasone prior to intravenously administering to the subject about 60 mg etentamig, and subcutaneously administering to the subject daratumumab of about 1800 mg, according to the treatment schedule illustrated in FIG.3.

[0109] In embodiments, the amount of dexamethasone is tapered in subsequent cycles if no CRS event occurred in a prior cycle. 5.4 Exemplary Subject Screening and Assessments

[0110] Certain aspects of the examples and other disclosure provided herein utilize the materials and methods below. 5.4.1 Exemplary Treatment Inclusion and Exclusion Criteria

[0111] In embodiments, patients undergo screening procedures within 28 days prior to initial drug administration. In embodiments, adult subjects who meet the inclusion criteria and who do not meet any of the exclusion criteria are eligible for treatment. Exemplary Inclusion Criteria: 1. Subject must be ≥ 18 years of age. 2. Three or more prior lines of therapy with exposure to a PI, and an IMiD. 3. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. 4. Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign informed consent. 5. Subject must have adequate bone marrow function, defined as: absolute neutrophil count (ANC) ≥ 1000 / mm3; platelets ≥ 50,000 / mm3; hemoglobin ≥ 8.0 g / dL. 25 NAI-5002116038v1Transfusion and / or growth factor support is permitted prior to assessment, but neutrophils, platelets, and hemoglobin must be stable for at least 72 hours after transfusion and / or growth factor administration prior to screening for the subject to be eligible. 6. Subject must have an eGFR ≥ 30 mL / min as estimated by the MDRD formula. 7. Subject must have total bilirubin ≤ 1.5 × upper limit of normal (ULN; except if the subject has a known diagnosis of Gilbert’s syndrome, in which case bilirubin must be < 3 × ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN. 8. Serum calcium (corrected for albumin) at or below the ULN range (subject may enroll in the setting of hypercalcemia IF hypercalcemia resolves with standard treatment by Cycle 1, Day 1) prior to study therapy initiation. 9. If female, subject must be either postmenopausal (for at least 12 consecutive months), OR permanently surgically sterile, OR for women of childbearing potential practicing at least 1 protocol specified method of female birth control AND one method of male birth control (vasectomy or condoms), starting at Cycle 1, Day 1 through at least 6 months after the last dose of study drug. 10. Measurable Disease: Subject has a diagnosis of MM and documented prior treatment with a PI, an IMiD, and an anti-CD38 mAb therapy (e.g., daratumumab) as part of 3 or more lines of therapy. There is no maximum number of prior regimens and prior bone marrow transplant is acceptable if subject is > 12 weeks (autologous) or > 1 year (allogeneic) status-post transplantation. In order to be eligible for this study subjects must not be candidates for treatment regimens known to provide clinical benefit in MM. Measurable disease is defined as at least 1 of the following: ₋ Serum M-protein ≥ 0.5 g / dL (≥ 5 g / L) ₋ Urine M-protein ≥ 200 mg / 24h ₋ Serum free light chain (FLC) assay: Involved FLC level ≥ 10 mg / dl (≥ 100 mg / L) and an abnormal serum FLC ratio (< 0.26 or > 1.65). 26 NAI-5002116038v111. Subject has confirmed evidence of relapse / progression from the immediately prior MM therapy, or subject is relapsed / refractory to the immediate prior MM therapy. (‘Relapsed / refractory’ is defined as subjects with a history of minimal response [MR] or better response to prior therapy, now with disease progression within 60 days of the last therapy. ‘Relapse’ is defined as previously treated myeloma that progresses and requires initiation of salvage therapy, without meeting International Myeloma Working Group [IMWG] uniform response criteria for relapsed / refractory.) 12. Subject has adequate archival tumor bone marrow sample if available or consents to a fresh pre-treatment bone marrow tumor biopsy. Exemplary Exclusion Criteria In embodiments, a subject will not be eligible for treatment if he / she meets any of the following criteria: 1. Subject has been diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of basal cell or squamous cell carcinoma of the skin, in situ malignancy, low-risk prostate carcinoma after curative therapy, or complete resection / curative therapy of an advanced malignancy. 2. Subject has a history of CNS involvement by their myeloma. 3. Subject has a history of ≥ Grade 3 peripheral neuropathy. 4. Subject has a history of plasma cell leukemia, POEMS syndrome, or amyloidosis. 5. Subject has received another investigational drug within 21 days of enrollment. 6. Subject has ever received BCMA-targeted therapy. Subjects who have received targeted therapy against non-BCMA targets will not be excluded. 7. Subject has received a peripheral autologous stem cell transplant within 12 weeks, or an allogeneic transplant within 1 year of the first dose of study drug treatment. 8. Subject has any medical or psychiatric condition which in the opinion of the investigator or Study Medical Monitor places the subject at an unacceptably high risk for toxicities, 27 NAI-5002116038v1could interfere with successful or safe delivery of therapy, or could interfere with evaluation of the investigational product or interpretation of subject safety or study results. Examples include history of significant mucosal / internal bleeding, major psychiatric illness, drug abuse (including active alcoholism), or known allergy or hypersensitivity to components of the study drug formulation. 9. Subject has received any therapy to treat cancer (including radiation, chemotherapy, biologics, cellular therapies, and / or steroids at doses > 20 mg) or undergone a major surgical procedure within 21 days, or within 5 half-lives of an anticancer drug, prior to the first dose of study treatment, whichever is shorter. 10. Subject has known active infection requiring parenteral anti-infective treatment. Upon completion of antibiotics and resolution of symptoms, the subject is considered eligible for the study from an infection standpoint. 11. Confirmed positive test results for human immunodeficiency virus (HIV), or subjects with chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV). Subjects who have a history of HBV or HCV who have documented cures (HBV: HBsAg negative; HCV: undetectable HCV ribonucleic acid (RNA) 24 weeks after the end of treatment) may be enrolled. 12. Major cardiac abnormalities, such as but not limited to the following: uncontrolled angina or unstable life-threatening arrhythmias, history of myocardial infarction < 12 weeks before Screening, Class ≥ 3 New York Heart Association congestive heart failure, severe cardiac insufficiency, or persistent QTc prolongation (> 480 msec, QTc Fridericia). 13. Subject has unresolved AEs ≥ Grade 2 (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE] v5.0) from prior anticancer therapy except for: ₋ Alopecia. ₋ Peripheral neuropathy (peripheral neuropathy ≥ Grade 3 excluded). ₋ Anemia or thrombocytopenia (thrombocytopenia must be Grade 4 to trigger exclusion, 28 NAI-5002116038v1Grade 3 with symptoms or bleeding, respectively, or return within 72 hours despite transfusion support). ₋ Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by any of the investigational products may be included (e.g., hearing loss) after consultation with the Study Medical Monitor. 5.4.2 Eastern Cooperative Oncology Group (ECOG) Performance Status

[0112] Aspects of the disclosure may include assessing an ECOG performance status of a subject at Screening, Day 1 of each cycle prior to dosing, at the EOT Visit or upon subject discontinuation, and at the 90-day follow-up visit after the last dose of the CD3xBCMA bispecific antibody. The ECOG performance status is documented using the scoring method in Table 2. Table 2: Eastern Cooperative Oncology Group (ECOG) Performance Score Grade ECOG tr. . y

[0113] Aspects of the disclosure may include obtaining samples for the clinical laboratory tests outlined in Table 3, at a minimum at Screening (by a central laboratory), and locally at subsequent visits, the EOT Visit, and the 90-day follow-up visit.

[0114] A certified laboratory can be utilized to process and provide results for the clinical 29 NAI-5002116038v1laboratory tests. Laboratory reference ranges are obtained prior to the initiation of the study. The baseline laboratory test results for clinical assessment for a particular test are defined as the last measurement prior to the initial dose of the CD3xBCMA bispecific antibody. Table 3: Clinical Laboratory Tests Laboratory TestParameter30 NAI-5002116038v1Laboratory TestParameterA5.4.4 Tumor Assessments

[0115] Aspects of the disclosure may involve performing a baseline skeletal survey with positron emission tomography (PET)-CT, contrast enhanced CT, or magnetic resonance imaging (MRI) for each patient within 28 days prior to administration of the first dose of the CD3xBCMA bispecific antibody; CT and / or MRI may also be performed for extramedullary disease assessment if clinically indicated. Imaging is repeated as clinically indicated. The same modality should be used for a subject at each visit where imaging is required, if possible. 5.4.5 Tumor Tissue

[0116] Aspects of the disclosure may involve collecting, at screening, adequate archival 31 NAI-5002116038v1tumor tissue (collected within the past 6 months prior to screening) and / or newly obtained biopsies for each subject; if no archival tumor tissue is available, a pre-treatment bone marrow biopsy is taken in embodiments. An “adequate” archival biopsy is defined as sufficient formalin- fixed paraffin embedded (FFPE) material (either block or slides) to perform and interpret 8 to 10 hematoxylin and eosin and / or immunohistochemical stains on the subject’s tumor and accompanied by a flow-cytometric report including plasma cell markers (at least CD38 and CD138). In embodiments, a bone marrow biopsy / aspirate is performed at cycle 3 day 1 (C3D1), in addition to IMWG mandated biopsies / aspirates at suspected CR, and when possible, at suspected progression.

[0117] In embodiments, both pre-treatment and progression biopsies are taken from the same lesion, or at least from the same anatomical location, of a patient. Collection of paired newly obtained tumor samples is used to assess the CD3xBCMA bispecific antibody PD in the tumor microenvironment. In embodiments, the bone marrow biopsies are analyzed by flow cytometry to quantitate BCMA density on the subject’s tumor cells. In embodiments, studies such as cytogenetics, fluorescence in situ hybridization (FISH), or sequencing studies of tumor cells, and evaluation of T-cell subsets by flow cytometry are also performed. In addition, the tumor mutation load is examined, in embodiments. 5.4.6 Activity Variables

[0118] In embodiments of the disclosure, activity may be measured by changes in SPEP, UPEP, and / or FLC (Kumar S et al., International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in MM, The Lancet Oncology. 2016;17(8):e328–46). In embodiments, the same parameter(s) used to meet eligibility criteria for treatment are used to evaluate response. In embodiments, a laboratory value that indicates clinical activity (Table 4) is verified by a second test, which may be conducted as soon as the results from the first test are available. In embodiments, activity endpoints (determined using IMWG uniform response criteria) include objective response rate (ORR, defined as stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]), clinical benefit rate (CBR; defined as CR + PR + MR for 24 weeks), overall survival (OS), progression-free survival (PFS), time to progression (TTP), time to response (TTR) and duration of objective response (DOR). 32 NAI-5002116038v1Table 4: Activity Measurements Response Criteria as ns D- ne or ith ch ds he m ry or of of tio00ny es on M- M- he ce ay ce as33 NAI-5002116038v1≥ 30%. In addition to these criteria, if present at baseline, a ≥ 50% reduction in the size (SPD) of soft tissue plasmacytomas is also required neat as se ot ial of 5 he se nd ell ≥ 1 1 of on ve n- or ns A ed34 NAI-5002116038v1Decrease in hemoglobin of ≥ 2 g / dL not related to therapy or other non- myeloma-related conditions; py or tic or or tic5.4.7 Dose Limiting Toxicity (DLT)

[0119] In embodiments of the disclosure, the DLT observation period is the first 21 days after the first dose of the CD3xBCMA bispecific antibody; dose limiting toxicities are determined on events that occur during the first observation period. A drug related event is defined as any adverse reaction that cannot be definitively attributed to the patient’s underlying disease, other medical condition, or a concomitant medication or procedure by the investigator or Medical Monitor. The NCI-CTCAE version 5.0 is used. DLT definitions are provided herein. Non-hematologic Dose-limiting Toxicity

[0120] A non-hematologic DLT is defined as any of the following TEAEs: • Non-hematological AEs Grade ≥ 3 with the following exceptions: ^ Grade 3 or 4 isolated electrolyte abnormalities (i.e., those occurring without clinical consequence) that resolve, with or without intervention, to Grade <2 within 72 hours. 35 NAI-5002116038v1^ Grade 3 hypo / hyperglycemia responsive to optimal medical management within 72 hours. ^ Grade 3 nausea / vomiting / diarrhea responsive to optimal medical management within 72 hours. ^ Alopecia or vitiligo of any grade. ^ Grade 3 fatigue lasting < 10 days. • Any AE that requires a delay in initiation of the next scheduled cycle by > 21 days. Hematologic Dose-limiting Toxicity

[0121] A hematologic DLT is defined as any of the following: • ≥ Grade 3 CRS. • Grade 4 neutropenia for > 5 days. • Grade 3 thrombocytopenia requiring platelet transfusion or Grade 4 thrombocytopenia. - During the course of the study, subjects with platelet counts < 10,000 / mm3should be monitored at least every 72 hours (or more often at investigator’s discretion) until recovery to > 50,000 / mm3. Platelet transfusions should be administered per Principal Investigator discretion and according to institutional guidelines. Recovery to > 50,000 / mm3is required to continue treatment. • Grade 3 anemia associated with clinically significant symptoms of hypoxia requiring red blood cell transfusion or Grade 4 anemia, unrelated to underlying disease. - Red cell transfusion in the absence of clinically significant hypoxic symptoms (i.e., tachypnea, decreased oxygen saturation, etc.) will not be considered a DLT. Moderate anemia is not an exclusion criterion for subjects entering the study and is an anticipated finding in subjects with MM. Nevertheless, subjects with hemoglobin < 8 g / dL should be monitored at least every 72 hours (or more often at investigator’s discretion) until recovery to ≥ 8 g / dL. Red cell transfusions should be administered according to institutional guidelines. Recovery to ≥ 8 g / dL is required to continue treatment. • Lymphopenia will not be considered a DLT. 36 NAI-5002116038v1• Any AE that requires a delay in initiation of the next scheduled cycle by > 21 days. CRS Dose-limiting Toxicity

[0122] Aspects of the disclosure involve monitoring for evidence of CRS in patients. CRS, with or without the presence of neurotoxicity, is the primary toxicity associated with T-cell redirection therapy (CARs and T-BsAbs / BiTEs). CRS occurs due to hyper-activation of the immune system and is mediated predominantly by the secretion of pro-inflammatory cytokines (most importantly IL-6). Signs and symptoms are those of systemic inflammation, like sepsis, anaphylaxis and tumor lysis syndrome, and include the following: high fever / rigors, hypotension, hypoxia, neurologic changes, pain, nausea, and headache. Meta-analyses show that clinical findings, specifically fever, are usually the first indicators of CRS onset (Hay KA et al., Blood, Jan 1:2017; Wang Z et al., Biomarker Research.2018;6(1):4.). CRS historically occurs within 14 days of first CAR / T-BsAb administration and does not usually occur in subsequent cycles. If CRS symptoms are suspected, Table 5 may be used to grade the toxicity. Table 5: Guidelines for CRS Grading CRS Grade 1 CRS Grade 2 CRS Grade 3 CRS Grade 4T m r t r graded according to NCI-CTCAE version 5.0 but they do not influence CRS grading.] 37 NAI-5002116038v1Neurological Dose-limiting Toxicity

[0123] Aspects of the disclosure involve monitoring for evidence of neurological toxicity (NT). Neurological toxicity (NT) arises from unclear etiology but has been postulated to stem from endothelial activation / microangiopathy, possibly downstream of IL-1 secretion by monocytes / macrophages (Gust J et al., Cancer Discovery, 2017; 7(12):1404-1419; Giavridis T et al., Nature Medicine, 201824(6):731-738.; Norelli M et al., Nature Medicine, 2018; 24(6):739-748.). Onset usually occurs with or after CRS (mostly CRS Grade ≥ 3). Isolated NT has been described after administration of anti-CD19 T-BsAbs (Velasquez MP et al., Blood. 2017; 131(1):30-38.). Symptoms of NT include delirium, headache, agitation, aphasia, CNS bleed, ataxia, confusion, seizure, somnolence, and tremor. Suggested guidelines for management of NTs are provided in Table 6. Table 6: Suggested Guidelines for Management of Neurological Toxicity AE Category Guidelines Neurologic AE after dosing C n lt n r l i t38 NAI-5002116038v15.4.8 Activity Analysis

[0124] Aspects of the disclosure may involve evaluating response and disease progression using IMWG uniform response criteria. In embodiments, objective response rate (ORR), DOR, PFS and CBR are determined. In embodiments, Kaplan-Meier estimates for PFS and associated CI of the median PFS, OS, and TTP are determined. 5.4.9 Objective Response Rate (ORR)

[0125] Aspects of the disclosure may involve determining an object response rate (ORR). Objective response rate is defined as the proportion of subjects with a confirmed partial or complete response to treatment. In embodiments, the ORR for each dose cohort is estimated with all testing sites pooled. In embodiments, the 2-sided 80% exact binomial CIs of ORR are also summarized using the Clopper-Pearson method along with the best overall response (CR, PR, SD, PD). 5.4.10 Progression-Free Survival (PFS)

[0126] Aspects of the disclosure may involve determining progression-free survival (PFS). Progression-free survival time is defined as the time from the first dose of the CD3xBCMA bispecific antibody to progression or death, whichever occurs first. In embodiments, subjects are censored at the date of last tumor assessment if neither event occurs. In embodiments, the Kaplan-Meier method is used to analyze PFS. 5.4.11 Duration of Objective Response (DOR)

[0127] Aspects of the disclosure may involve determining a duration of objective response (DOR). The duration of objective response for a subject is defined as the time from the initial objective response to disease progression or death, whichever occurs first. In embodiments, if a subject does not progress or die, then the subject is censored at the date of the last tumor assessment, similar to the censoring rules for the PFS analysis. In embodiments, the DOR is analyzed in the same fashion as for the PFS analysis. 5.4.12 Clinical Benefit Rate (CBR)

[0128] Aspects of the disclosure may involve determining a clinical benefit rate (CBR). 39 NAI-5002116038v1Clinical benefit rate is defined as the proportion of subjects with a confirmed complete, partial or minimal response for at least 24 weeks after responding to treatment. In embodiments, the CBR for each arm is estimated with all testing sites pooled. In embodiments, the 2-sided 80% exact binomial CIs of the CBR will also be summarized using the Clopper-Pearson method. 5.4.13 Safety Analysis

[0129] Aspects of the disclosure may involve conducting one or more safety analyses. In embodiments, at the end of a course of treatment, the safety of the CD3xBCMA bispecific antibody is assessed by evaluating the AEs, SUSARs / SAEs, changes in laboratory determinations, vital sign parameters and all other available relevant data. In embodiments, the methods involve providing descriptive statistics for the continuous variables and the frequencies / percentages for the discrete variables. In embodiments, the safety population allows for detection of SAEs occurring in as little as 21% of subjects with 80% confidence. 5.4.14 Adverse Events

[0130] Aspects of the disclosure may involve analyzing adverse events, including, but not limited to, treatment emergent adverse events (TEAEs). A treatment emergent adverse event (TEAE) is defined as an event that occurs or worsens on or after the first dose of the CD3xBCMA bispecific antibody until 90 days following discontinuation of drug administration have elapsed, or until subjects start another anticancer therapy, whichever occurs earlier.

[0131] In embodiments, TEAEs are summarized by dose cohort and overall including drug- related AEs, AEs by intensity, deaths, SAEs, and discontinuations due to AEs. In embodiments, DLTs for the dose cohorts in the Monotherapy Dose Escalation Phase are summarized similarly by cohort and overall. In embodiments, additional summaries and / or listings for AEs of special interest are also provided. 5.4.15 Clinical Laboratory Tests

[0132] Aspects of the disclosure may involve performing baseline laboratory tests for patients receiving treatment. In embodiments, disease response assessment laboratory tests from subsequent time points are also performed. In embodiments, changes from baseline in clinical laboratory results are analyzed and summarized by dose cohort and time point using descriptive 40 NAI-5002116038v1statistics. In embodiments, summaries of shifts from baseline to last available visit are provided. In embodiments, shifts are calculated as the proportion of subjects at baseline with values that are below, within, or above the normal range for a particular lab test, relative to the proportion of subjects at the Final Visit with values that are below, within, or above the normal range. In embodiments, lab abnormalities and treatment-emergent lab abnormalities meeting the NCI- CTCAE version 5.0 are summarized by treatment arm and overall. 5.4.16 Key Eligibility Criteria Tabulations and Summary Statistics

[0133] In embodiments, serum concentrations of the CD3xBCMA bispecific antibody and PK parameter values may be tabulated for each subject and each dose level, and summary statistics are computed for each sampling time and each parameter. Dose Proportionality Analysis:

[0134] In embodiments, pharmacokinetic parameters of the CD3xBCMA bispecific antibody from a particular dosing schedule may be assessed on Cycle 1 Day 1 are analyzed as follows. An analysis is performed for dose-normalized Cmax and dose-normalized AUC. The model used for the statistical analyses includes the dose level of the CD3xBCMA bispecific antibody as a categorical variable. In embodiments, covariates such as age, ethnicity, gender, and others that might explain some of the variability in the population are included in an initial model. In embodiments, a covariate may be dropped from the model if the regression coefficient is not significant at alpha level 0.10. In embodiments, a natural logarithmic transformation is employed for Cmax and the AUCs unless the data clearly indicate that other transformation or the untransformed variable provides more nearly symmetric probability distributions and / or more nearly homogenous variances across dose levels. When at least three dose levels of the CD3xBCMA bispecific antibody are studied, a test is performed on a contrast in the dose level effects chosen to be sensitive to an approximately linear function of dose or the logarithm of dose. Missing Values and Model Violations

[0135] In embodiments, all available data can be included in any dose proportionality analyses. In embodiments, one or more data points may be excluded from an analysis, provided 41 NAI-5002116038v1an appropriate justification is present. Normally, values of PK variables (Cmax, AUC, etc.) are determined without replacing missing individual concentration values, by simply using the available data. However, if a missing individual concentration results in a PK parameter value that may be too low or too high to a meaningful degree, the value of the PK parameter may tentatively be considered missing. In such cases, a value for the missing individual concentration may be imputed so that an appropriate value of the PK parameter can be included in an analysis. In embodiments, the imputed value is obtained using appropriate methodology that considers the individual characteristics of the subject.

[0136] If an outlier is identified and / or a pronounced non-normal probability distribution is observed (after logarithmic transformation for Cmax and AUC) then a non-parametric analysis may also be performed. Such a model violation may be identified by graphical methods, measures of non-normality (e.g., skewness, kurtosis) or other appropriate methods. If different dose levels have unequal variances to the extent that conclusions might be affected, then approximate methods that allow for unequal variances can be used. In embodiments, the possibility of bias from missing data of subjects who prematurely discontinued treatment due to an adverse event can be addressed. 6. EXAMPLES

[0137] The examples in this section are offered by way of illustration, and not by way of limitation. The following examples are presented as exemplary embodiments of the disclosure. They should not be construed as limiting the broad scope of the disclosure. 6.1 EXAMPLE 1. – Administration of Etentamig in Combination with Daratumumab-Dexamethasone (DARA-DEX) is Clinically Efficacious

[0138] Etentamig is a CD3xBCMA bispecific T-cell redirecting antibody incorporating a unique anti-CD3 moiety that preferentially activates effector over regulatory T-cells and uncouples cytokine release from anti-tumor activity, as well as 2 heavy-chain-only anti-BCMA moieties for a 2:1 TAA to CD3 stoichiometry. Etentamig is composed of a bivalent BCMA- binding domain with high avidity, a low-affinity CD3-binding domain designed to mitigate cytokine release, and a present but silenced Fc tail resulting in an extended half-life. These characteristics potentially result in a manageable safety profile with more convenient dosing 42 NAI-5002116038v1intervals and robust efficacy.

[0139] This Example details instances of dose limiting toxicities (DLT) and other adverse events in patients administered etentamig in combination with daratumumab-dexamethasone (DARA-DEX). The Example demonstrates that administration of etentamig in combination with DARA-DEX results in reduced instances of CRS, ICANS, and other adverse events.

[0140] Patients with relapsed or refractory multiple myeloma (RRMM) who had received at least three prior lines of therapy including lenalidomide, a PI, and an anti-CD38 antibody, were enrolled into a treatment arm to characterize the safety and toxicity profile of etentamig when co- administered with DARA-DEX. Patient demographic and disease characteristics can be found in Table 7 below.

[0141] Briefly, 86 patients were enrolled and treated across three dose levels of etentamig plus DARA-DEX. Median age was 69 years (range 39–89) and 34 (40%) patients were female. The majority of patients were White (n=76, 88%); 6 (7%) were Asian and 4 (5%) were Black or African American. Revised-International Staging System (R-ISS) score at study entry was I in 22 (26%) patients, II in 28 (33%), and III in 20 (24%). Patients had received a median of 4 (range 3–9) prior lines of therapy. Forty-eight (56%) patients were refractory to prior anti-CD38 monoclonal antibody therapy and 72 (84%) were refractory to the most recent MM therapy. Table 7. Patient Demographics and Disease Characteristics 20 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose )43 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation44 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalationantibody.

[0142] Etentamig was administered on cycle 1 day 1 and once every four weeks (Q4W) thereafter. Treatment was initiated with an etentamig dose escalation phase, followed by a safety expansion phase. The dose escalation phase began with the lowest etentamig dose level (i.e., Dose Level 1, 20 mg Q4W), with at least three DLT-evaluable patients enrolled for each treatment arm. Following safety and tolerability assessments during cycle 1, the next dose level of etentamig was initiated, following the same enrollment precautions as the lowest dose level. The dosing levels of etentamig are described in Table 8, below. After a median follow-up of seven months (range 0–17), 51 (59%) patients remained on therapy; the majority of study drug discontinuations were due to progressive disease (n=19, 22%). Similar results were obtained after a longer follow-up (Table 9). Table 8. Etentamig Dose Levels 20 mg20 mg 40 mg 40 mg 60 mg Total Dose Safet Dose Safet Dose45 NAI-5002116038v120 mg20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion EscalationTable 9. Etentamig Dose Levels 20 mg20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dosed sease assessment to be cons dered eva uab e or e cacy ana ys s.

[0143] Dose escalation decisions were guided by application of a Bayesian optimal interval (BOIN) design and based on the cumulative number of subjects who experience a DLT at the current etentamig dose level. Dose escalation meetings occurred at the end of the DLT- 46 NAI-5002116038v1observation period for each dose level to assess safety, tolerability, and dosing decisions (escalation and de-escalation) according to the BOIN design. Based on the recommended dose of etentamig for the safety expansion phase, etentamig in combination with DARA-DEX was investigated in separate safety expansion arms (see Table 8). Dosage amounts and regimens for DARA-DEX can be found in Table 10, below. Table 10. Dosage of DARA, and DEX Study Drug Dosage s

[0144] A toxicity monitoring rule was implemented in the safety expansion phase after 6 subjects were enrolled. The rule monitored the occurrence of DLTs and paused enrollment to that arm if the posterior probability that the DLT rate exceeds 0.25 is > 80%. The prior distribution for the DLT rate was assumed to follow a beta (1.5, 4.5) distribution, reflecting a prior mean DLT rate of 0.25 and effective sample size of 6.

[0145] The median duration of follow-up was between 0.7 and 13 months, with longer duration of follow-up in the lowest dose escalation cohort, 20 mg Q4W dose escalation. With the exception of the subjects enrolled in the 20 mg safety expansion cohort and with limited follow- up, all subjects in other cohorts experienced an adverse event (AE) of any grade and the majority of subjects experienced Grade 3 or 4 AEs. Forty-nine (57%) subjects had an AE that led to interruption of etentamig (interruption of infusion or delay of cycle start). Twelve subjects overall had AEs that led to discontinuation of etentamig. An overview of the key safety data can be found in Table 11, below. Similar results were observed with longer duration of follow-up (Table 12). 47 NAI-5002116038v1Table 11: Key Safety Data in Etentamig DEX-DARA Study 20 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation ) ) ) ) ) ) ) ) ) ) ) )48 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation ) ) ) ) ) ) ) )20 mg 20 mg 40 mg 40 mg 60 mg Total D S f t D S f t D ) ) )49 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation ) ) ) ) ) ) ) ) ) ) ) )e mos common s oserve across a sujecs reae w eenamg pus DARA-DEX included CRS and cytopenias (including neutropenia, anemia, thrombocytopenia) and cytopenias made up the most common Grade 3 or 4 AEs. An overview of the AEs of any 50 NAI-5002116038v1grade and grade 3 or 4 is provided in Table 13 and Table 14, respectively. Table 13. Summary of Adverse Events (Any Grade) by Dosing Cohort 20 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose E l ti E i E l ti E i E l ti ) ) ) ) ) ) ) ) ) ) )20 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safet Dose Safet Dose ) 4) ) ) 1)51 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation ) 2) 4) 1) A-DEX results in low instances of serious adverse events (SAE). SAE in more than 5% of the total DARA-DEX treatment population are shown in Table 15 and percentage and grade of all CRS and ICANS are shown in Table 16. The most common serious AEs were CRS (20%), COVID- 19 pneumonia, and pneumonia (Table 15). To date, Grade 3 / 4 infections occurred in 26% (22 / 86) of patients, primarily consisting of pneumonia in 11 patients, and rhinovirus, influenza, and sepsis in 2 patients each. CRS occurred in 20 (27%) patients. The majority of CRS events were Grade 1 (n=8, 11%) or 2 (n=9, 12%); three (4%) patients had Grade 3 events. ICANS was reported in two (3%) patients total; one event was Grade 2 and one Grade 4 (Table 16). Other common treatment-emergent adverse events (TEAEs) in the treated population (n=74) included (any Grade / Grade 3–4) neutropenia (39% / 38%), anemia (24% / 18%), fatigue (22% / 0%), and thrombocytopenia (30% / 18%). In total eight subjects discontinued treatment due to AEs. The most common AE leading to treatment discontinuation was disease progression, which was captured by PT of “disease progression,” and “malignant neoplasm progression.” In addition, the event of “bone pain” was considered to be in the context of disease progression. Twelve deaths occurred during the study to date, mostly due to disease progression (n=6). Table 15. SAEs in 5% Total Population (Safety Analysis Population) 20 mg 40 mg 60 mg 20 mg 40 mg Total 0)52 NAI-5002116038v120 mg 40 mg 60 mg 20 mg 40 mg Total Dose Dose Dose Safety Safety Escalation Escalation Escalation Ex ansion Ex ansion. etentamig 20 / 40 / 60 mg + Dara (n=74) Total C1 DEX Dose 40 mgetentamig as a monotherapy indicates combination therapy results in lower overall instances of CRS. As shown in Table 17, DARA-DEX combination therapy resulted in 29% of patients experiencing CRS. In contrast, etentamig as a monotherapy resulted in an instance of CRS in 43% of patients. Table 17: Instances of CRS in Patients Receiving Etentamig + DEX by Treatment Category. Etentamig 60 mg Q4W Etentamig 60 mg + Dara (n=21) (n=14)

[0009] ab e 8 deta s or a subset o pat ents (n=6 ) t e percentage experenc ng C S or ICANS within the combination etentamig and DARA-DEX by etentamig dosage levels. Instances of CRS were most frequent in patients receiving 40 mg etentamig Q4W (34% of patients), followed by those receiving etentamig at 60 mg Q4W (28% of patients), and 20 mg 53 NAI-5002116038v1Q4W (24% of patients). Table 18 also illustrates instances of ICANS in the same subset of patients receiving combination etentamig and DARA-DEX across etentamig dosage levels. No patients in the 20 mg Q4W dosing cohort experienced ICANS. In contrast, 3% of patients in the 40 mg Q4W and 7 % of patients in the 60 mg Q4W dosing cohorts experienced Grade 2 or higher ICANS. Table 18. Percentages of Patients Exhibiting CRS or ICANS After Administration of Etentamig in Combination with DARA. Etentamig 20 mg Etentamig 40 mg Etentamig 60 mg Q4W + Dara (n=12) Q4W + Dara (n=35) Q4W + Dara (n=14). gg g , experienced DLTs across the dose escalation cohorts. The majority of these DLTs were non- hematologic in nature and those who occurred in 2 or more subjects included Grade 3 CRS (n=2 with one subject also experiencing ICANS), Grade 3 AST / ALT increased (n=2), and Grade 3 tumor lysis syndrome (n=2). DLTs for six of the subjects occurred after etentamig administration and prior to initiation of daratumumab in cycle 1.

[0151] The results also indicated that treatment with etentamig in combination with DARA- DEX is efficacious. The population enrolled into the treatment study is a heavily pretreated 54 NAI-5002116038v1population with 43% of subjects being triple-class refractory and more than half of all subjects (57%) being refractory to anti-CD38 monoclonal antibody therapy. The duration of follow-up varied across cohorts, with the longest follow-up in the 20 mg dose escalation cohort (median 13 months), as summarized in Table 19 and Table 20. Objective response rates increased with increasing dose of etentamig from 20 mg to 40 mg, and slightly decreased with increasing dose of etentamig from 40 mg to 60 mg (56% in 20 mg combined dose escalation and safety expansion cohort with median follow-up of 4 months, 83% in 40 mg combined dose escalation and safety expansion cohort with median follow-up of 8 months and 82% in 60 mg dose escalation with median follow-up of 8 months), as shown in FIG.4. Median time to best response ranged from 1 to 5 months.80 patients were evaluable for disease assessment. The aggregate objective response rate (ORR) (escalation plus expansion cohorts) for the total evaluable population was 71% (45 / 80). ORRs in the different dose cohorts were 56% (19 / 34) in the 20 mg Q4W etentamig cohort at a median follow-up of 4 months (range 0–17), 83% (29 / 35) in the 40 mg cohort at a median follow-up of 8 months (1–13), and 82% (9 / 11) in the 60 mg cohort at a median follow-up of 8 months (1–10). Table 19. Duration of Follow Up and Response Rates 20 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose – 1) 8) 3) 4) 4) 5) 9) 6) ) –55 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation – 5) 5) ) 2 5) 5) ) eesponse); C (Compete esponse). ata presented as n(%) were app cabe. Table 20. Duration of Follow Up and Response Rates 20 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose 4) 4) 7) ) 2) ) 0) 7) ) 4) 2)56 NAI-5002116038v120 mg 20 mg 40 mg 40 mg 60 mg Total Dose Safety Dose Safety Dose Escalation Ex ansion Escalation Ex ansion Escalation 8) 8) 4) e

[0152] Treatment with combination etentamig with DARA-DEX was effective regardless of the anti-CD38 refractory status of patients. Table 21 details the response rates of the anti-CD38 refractory patient population (n=36) and the anti-CD38 sensitive / naïve patient population (n=24) across etentamig Dosage cohorts. Anti-CD38 refractory patients were defined as those failing to achieve a minimal response to treatment on or within 60 days of the last dose. The total overall response percentages were similar in anti-CD38 refractory patients (69%) and sensitive / naïve patients (71%). Median time to response was 1.0 (range 0–6) months in the anti-CD38 refractory population and 1.0 (range 0–3) months in the anti-CD38 sensitive / naive population. Table 21. Response rates for anti-CD38 sensitive / naïve population and anti-CD38 refractory population Dose Level 20 mg 40 mg 60 Total ry);VGPR (Very Good Partial Response); sCR (Stringent Compete Response); CR (Complete Response).

[0153] Taken together, this Example demonstrates that administration of etentamig in combination with DARA-DEX supports the efficacy of the combined dosing regimen for 57 NAI-5002116038v1patients with RRMM. This preliminary data suggest etentamig in combination with DARA-DEX is tolerable. Overall rates of CRS were low and early response rates were promising in the investigated population of heavily pretreated patients with MM. * * * * * 58 NAI-5002116038v1

Claims

WHAT IS CLAIMED:

1. A method for safely and effectively treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 60 mg of etentamig once per a four- week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, thereby treating said R / R MM.

2. The method of claim 1, wherein the anti-CD38 monoclonal antibody is daratumumab.

3. The method of claim 1, wherein the etentamig is administered intravenously.

4. The method of claim 1, wherein the anti-CD38 monoclonal antibody is administered subcutaneously.

5. The method of claim 2, wherein the anti-CD38 monoclonal antibody dose is about 1800 mg.

6. The method of claim 1, wherein the anti-CD38 monoclonal antibody is administered weekly during cycles 1 and 2.

7. The method of claim 1, wherein the anti-CD38 monoclonal antibody is administered about every 2 weeks during cycle 3 to cycle 6.

8. The method of claim 1, wherein the anti-CD38 monoclonal antibody is administered every 4 weeks after cycle 6.

9. The method of claim 1, wherein the method comprises administering the etentamig on day 1 of cycle 1.

10. The method of claim 1, wherein the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the etentamig. 59 NAI-5002116038v111. The method of claim 1, wherein the method comprises administering the anti-CD38 monoclonal antibody on day 2 of cycle 1.

12. The method of claim 1, wherein the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the anti-CD38 monoclonal antibody in cycle 1.

13. The method of claim 1, wherein the method comprises administering the etentamig and the anti-CD38 monoclonal antibody on day 1 of each cycle after cycle 1.

14. The method of claim 1, wherein the method further comprises administering dexamethasone weekly.

15. The method of claim 1, wherein the R / R MM has progressed after treatment with at least one prior line of therapy.

16. The method of claim 1, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody results in a partial response (PR) in the subject.

17. The method of claim 1, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody results in a stringent complete response (sCR) in the subject.

18. The method of claim 1, wherein the administration of the bispecific antibody and the anti-CD38 monoclonal antibody results in a very good partial response (VGPR) in the subject.

19. The method of claim 1, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody provides an objective response rate that is greater than 50% or greater than 55%.

20. The method of claim 1, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody results in less than 50% incidence of any grade of CRS in the subject.

21. The method of claim 1, wherein the subject has received at least one prior line of therapy; 60 NAI-5002116038v1the etentamig is administered intravenously; the subject achieves a VGPR; and the subject does not experience a Grade 1, Grade 2 or Grade 3 CRS.

22. The method of claim 21, wherein administration of the etentamig and the anti-CD38 antibody results in a reduced incidence of at least one adverse event as compared to the administration of 60 mg of etentamig administered as a monotherapy in a four-week cycle.

23. The method of claim 22, wherein the adverse event is CRS.

24. A method for safely and effectively treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 60 mg of etentamig once per a four- week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, wherein the subject does not experience a Grade 1, Grade 2 or Grade 3 CRS; and wherein the subject experiences at least a partial response.

25. The method of claim 24, wherein the anti-CD38 monoclonal antibody is daratumumab.

26. The method of claim 25, wherein the etentamig is administered intravenously.

27. The method of claim 25, wherein the anti-CD38 monoclonal antibody is administered subcutaneously.

28. The method of claim 25, wherein the anti-CD38 monoclonal antibody dose is about 1800 mg.

29. The method of claim 25, wherein the anti-CD38 monoclonal antibody is administered weekly during cycles 1 and 2.

30. The method of claim 24, wherein the anti-CD38 monoclonal antibody is administered about every 2 weeks during cycle 3 to cycle 6. 61 NAI-5002116038v131. The method of claim 24, wherein the anti-CD38 monoclonal antibody is administered every 4 weeks after cycle 6.

32. The method of claim 24, wherein the method comprises administering the etentamig on day 1 of cycle 1.

33. The method of claim 24, wherein the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the etentamig.

34. The method of claim 24, wherein the method comprises administering the anti-CD38 monoclonal antibody on day 2 of cycle 1.

35. The method of claim 24, wherein the method further comprises administering to the subject one or more doses of dexamethasone prior to administering the anti-CD38 monoclonal antibody in cycle 1.

36. The method of claim 24, wherein the method comprises administering the etentamig and the anti-CD38 monoclonal antibody on day 1 of each cycle after cycle 1.

37. The method of claim 24, wherein the method further comprises administering dexamethasone weekly.

38. The method of claim 24, wherein the R / R MM has progressed after treatment with at least one prior line of therapy.

39. The method of claim 24, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody results in a stringent complete response (sCR) in the subject.

40. The method of claim 24, wherein the administration of the bispecific antibody and the anti-CD38 monoclonal antibody results in a very good partial response (VGPR) in the subject.

41. The method of claim 24, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody provides an objective response rate that is greater than 50% or greater than 55%. 62 NAI-5002116038v142. The method of claim 24, wherein the administration of the etentamig and the anti-CD38 monoclonal antibody results in less than 50% incidence of any grade of CRS in the subject.

43. The method of claim 24, wherein the subject has received at least one prior line of therapy; the etentamig is administered intravenously; and the subject achieves a VGPR.

44. The method of claim 43, wherein administration of the etentamig and the anti-CD38 antibody results in a reduced incidence of at least one adverse event as compared to the administration of 60 mg of etentamig administered as a monotherapy in a four-week cycle.

45. The method of claim 44, wherein the adverse event is CRS.

46. A method for treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises: (A) administering to the subject on day one of cycle 1: (i) about 40 mg dexamethasone, and (ii) a therapeutically effective amount of about 60 mg of etentamig; and (B) administering to the subject on day two of cycle 1: (i) about 20 mg dexamethasone, and (ii) about 1800 mg daratumumab; thereby treating said R / R MM.

47. The method of claim 46, wherein the method further comprises: (C) administering to the subject on day 1 of each subsequent cycle: (i) about 40 mg dexamethasone, (ii) a therapeutically effective amount of about 60 mg of etentamig, and (iii) about 1800 mg of the daratumumab. 63 NAI-5002116038v148. The method of claim 46, wherein each cycle comprises about four weeks.

49. The method of claim 46, wherein the etentamig is administered intravenously.

50. The method of claim 46, wherein the daratumumab is administered subcutaneously.

51. The method of claim 46, wherein the daratumumab is administered weekly during cycles 1 and 2.

52. The method of claim 46, wherein the daratumumab is administered every two weeks during cycles 3 and 6.

53. The method of claim 46, wherein the daratumumab is administered once per cycle after cycle 6.

54. The method of claim 46, wherein the dexamethasone is administered orally or intravenously.

55. The method of claim 46, wherein administration of about 40 mg dexamethasone is repeated once weekly per cycle.

56. The method of claim 46, wherein about 40 mg dexamethasone is administered on days 1, 8, 15, and 22 per cycle.

57. The method of claim 46, wherein the R / R MM has progressed after treatment with at least one prior line of therapy.

58. The method of claim 46, wherein the administration of the etentamig and the daratumumab results in a partial response (PR) in the subject.

59. The method of claim 46, wherein the administration of the etentamig and the daratumumab results in a stringent complete response (sCR) in the subject.

60. The method of claim 46, wherein the administration of the etentamig and the daratumumab results in a very good partial response (VGPR) in the subject.

61. The method of claim 46, wherein the administration of the etentamig and the 64 NAI-5002116038v1daratumumab provides an objective response rate that is greater than 50% or greater than 55%.

62. The method of claim 46, wherein the administration of the etentamig and the daratumumab results in less than 50% incidence of any grade of CRS in the subject.

63. The method of claim 46, wherein the subject has received at least one prior line of therapy; the etentamig is administered intravenously; the subject achieves a VGPR; and the subject does not experience Grade 1, Grade 2 or Grade 3 CRS.

64. The method of claim 46, wherein the subject experiences a reduced incidence of at least one adverse event as compared to the administration of 60 mg of administered as a monotherapy in a four-week cycle.

65. The method of claim 64, wherein the adverse event is CRS.

66. A method for safely and effectively treating relapsed or refractory multiple myeloma (R / R MM) in a human subject in need thereof, wherein the method comprises administering to the subject: (a) a therapeutically effective amount of about 60 mg of etentamig once per a four- week cycle, and (b) a therapeutically effective amount of an anti-CD38 monoclonal antibody, thereby treating said R / R MM, wherein when the method is used to treat a population of patients with R / R MM, a statistically significantly greater percentage of the patients achieve a reduced incidence of CRS and / or a greater objective response rate, compared to a control group of patients treated with about 60 mg etentamig monotherapy once per a four-week cycle.

67. The method of claim 66, wherein the anti-CD38 monoclonal antibody is daratumumab.

68. The method of claim 66, wherein the etentamig is administered intravenously.

69. The method of claim 66, wherein the anti-CD38 monoclonal antibody is administered subcutaneously. 65 NAI-5002116038v170. The method of claim 67, wherein the anti-CD38 monoclonal antibody dose is about 1800 mg. 66 NAI-5002116038v1

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