Methods, therapies and uses for treating cancer

Abstract

Dosing regimens and methods of treatment with an anti-BCMA / anti-CD3 bispecific antibody are provided.

Description

[0001] PC073210A

[0002] METHODS, THERAPIES AND USES FOR TREATING CANCER

[0003] REFERENCE TO SEQUENCE LISTING

[0004] This application contains a Sequence Listing submitted as an electronic .xml file named PC73210_sequence_listing.xml", having a size of 43 KB, and created on October 15, 2025. The information contained in this .xml file is hereby incorporated by reference in its entirety.

[0005] BACKGROUND

[0006] Multiple myeloma (MM) is a hematological B-cell malignancy characterized by dysregulated proliferation of bone marrow (BM) plasma cells. Globally, there are approximately 176,000 new cases and 117,000 deaths per year attributed to MM (Sung H, et al., CA Cancer J Clin. 2021 ; 71(3): 209-49). The American Cancer Society estimates that for the US in 2021 , approximately 34,920 new MM cases will be diagnosed and approximately 12,410 MM related deaths will occur.

[0007] Despite recent advances in treatment, MM remains an incurable disease and almost all patients, even those who initially respond to treatment, are expected to relapse. Even for patients who receive autologous stem cell transplant (ASCT), the median time to relapse is only 17.2 months (Jimenez-Zepeda et al., Bone Marrow Transplant. 2015; 50(2): 204-8). Similarly, for patients who are treated with novel proteasome inhibitor (Pl)-based or immunomodulatory drug (IMiD)-based combination regimens as frontline treatment, the median time to relapse is 16.4 months (Lopez A et al, Leuk Res Rep. 2015; 4(2): 64-9).

[0008] MM patients typically receive many lines of treatment as their disease progresses and becomes refractory to various therapeutic approaches. Common standard regimens include either a PI or an ImiD in combination with dexamethasone with or without a monoclonal antibody such as daratumumab (a CD38-targeting monoclonal antibody). With each successive relapse, the depth and duration of response typically decreases.

[0009] The approval of anti-CD38 antibodies-based regimens as first-line therapy for myeloma patients makes the treatment with second and subsequent lines of therapy very challenging with no established standard of care. Panel / committee recommendations for second line therapy after an approved front line anti-CD38 antibody based regimen do not include rechallenge with daratumumab and use of sequential anti-CD38 antibodies is considered unlikely to be an appropriate option; instead, recommended treatment options focus primarily on anti-CD38 antibody free regimens. PVd, Kd and EPd are regimens that are approved for first and / or subsequent relapses are CD38 antibody free. There is an unmet medical need in this patient population and new treatment approaches are required. BCMA is a transmembrane glycoprotein belonging to the TNFr superfamily. BCMA is normally expressed exclusively in lymphocytes of the B-cell lineage, including plasma blasts and differentiated plasma cells, where it is involved in the regulation of B-cell maturation. BCMA is widely expressed on malignant plasma cells collected from patients with MM whereas BCMA is detected in a very small proportion of normal BM mononuclear cells from healthy volunteers (Sanchez et al, 2012). In MM, BCMA expression was identified at each disease stage, and in patients with differing cytogenetic risks (Carpenter et al, Clin Cancer Res.2013;19(8):2048-60.). Furthermore, BCMA expression persists following treatment with ASCT or chemotherapy (Lee et al, Br J Haematol.2016;174(6):911-22).

[0010] T-cells are potent immune cells capable of mediating adaptive immunity through the expression of TCRs, which are comprised of an alpha beta heterodimer responsible for antigen recognition and a transmembrane CD3 protein complex that mediates receptor signaling and triggering of T-cell activation (Smith-Garvin et al, Annu Rev Immunol.2009;27:591-619). TCRs recognize specific protein fragments (i.e. , peptides) presented by MHC proteins on APCs, virally infected cells, and tumor cells. Triggering of CD3 signaling in a CD8+ T-cell synapsed with another cell presenting a target antigen can cause the T-cell to release perforin and granzyme B, resulting in cancer cell lysis and death. Cancer cells can avoid T-cell recognition and destruction by down modulating peptide / MHC presentation. One way to remove dependence on peptide / MHC presentation is through direct bridging of a cell-surface antigen on a target cell with the extracellular CD3 on T-cells, leading to T-cell signaling equivalent to that generated by MHC / TCR based engagement.

[0011] Anti-BCMA I anti-CD3 bispecific antibody approaches show great promise for various types of cancer, including MM. Elranatamab is an anti-BCMA I anti-CD3 bispecific antibody that is being studied in adult participants with relapsed / refractory MM (RRMM), as well as in adult participants with newly diagnosed MM (NDMM).

[0012] SUMMARY

[0013] Provided herein are therapies for the treatment of cancer with an anti-BCMA I anti-CD3 bispecific antibody, and related methods and compositions. In some embodiments, the anti-BCMA I anti-CD3 bispecific antibody is elranatamab.

[0014] In some embodiments, provided herein is a method of treating a cancer in a patient, the method comprising administering an anti-BCMA I anti-CD3 bispecific antibody to the patient, wherein the anti-BCMA I anti-CD3 bispecific antibody is elranatamab.

[0015] In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is advanced multiple myeloma. In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the cancer is triple class refractory multiple myeloma. In some embodiments, the multiple myeloma of the subject is refractory to all three types of the following multiple myeloma therapies (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody.

[0016] In some embodiments, the cancer is double class refractory multiple myeloma. In some embodiments, the multiple myeloma of the subject is refractory to at least two of the following three types of multiple myeloma therapies (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody.

[0017] In some embodiments, the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma, and the subject has received stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant or allogeneic stem cell transplant. In some embodiments, the subject is minimum residual disease positive post stem cell transplant.

[0018] In some embodiments, the cancer is multiple myeloma, wherein in some embodiments the subject has progressed or is intolerant of an established multiple myeloma therapy. In some embodiments, the established multiple myeloma therapy comprises at least one drug selected from the group consisting of a proteasome inhibitor, an I M id drug and an anti-CD38 antibody.

[0019] In some embodiments, the cancer is multiple myeloma wherein the subject has received at least four prior therapies and the subject’s multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma therapy that comprises an proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 monoclonal antibody, and wherein the subject has demonstrated disease progression on the last therapy. In one aspect of these embodiments, the subject has received a prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T. In another aspect of these embodiments, the subject has not received any prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T.

[0020] In some embodiments, the cancer is multiple myeloma, the subject has received at least one, at least two, at least three or at least four prior multiple myeloma therapies, and the subject’s multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody, and the subject has demonstrated disease progression on the last multiple myeloma therapy. In one aspect of this embodiment, the subject has received at least three prior multiple myeloma therapies. In another aspect of this embodiment, the subject has received at least four prior multiple myeloma therapies.

[0021] In some embodiments, the previous multiple myeloma therapies the subject received comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received comprise a BCMA directed therapy.

[0022] In some embodiments, the previous multiple myeloma therapies the subject received do not comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received do not comprise a BCMA directed therapy.

[0023] In some embodiments, the cancer is multiple myeloma, and the subject has received at least one or at least two prior multiple myeloma therapies, the subject’s multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor and (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent. In some embodiments, the subject has demonstrated disease progression on the last multiple myeloma therapy.

[0024] In some embodiments, the cancer is multiple myeloma, and the subject has not received any prior multiple myeloma therapies. In some embodiments, the subject has not received any prior multiple myeloma therapies after the diagnosis of multiple myeloma. In some embodiments, the subject is stem cell transplant ineligible. In some embodiments, the cancer is multiple myeloma, and the subject is stem cell transplant ineligible. In some embodiments, the subject is autologous stem cell transplant ineligible. In some embodiments, the subject is allogeneic stem cell transplant ineligible. In some embodiments, the subject is ineligible for autologous stem cell transplant and is also ineligible for allogeneic stem cell transplant.

[0025] In some embodiments, the multiple myeloma is smoldering myeloma, indolent myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of the bone, light chain myeloma, or non-secretory myeloma. In some embodiments, provided herein are methods for the treatment or management of smoldering myeloma, indolent myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of the bone, light chain myeloma, or non-secretory myeloma.

[0026] BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 depicts the schema for the study described in Example 1

[0027] FIG. 2 depicts the schema for the study described in Example 2

[0028] DETAILED DESCRIPTION The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0029] Exemplary embodiments (E) of the invention provided herein include:

[0030] E1. A method of treating a cancer in a patient, the method comprising administering an anti-BCMA I anti-CD3 bispecific antibody to the patient, wherein the antibody is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises: (a) 14 days, and wherein the antibody is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle; or (b) 28 days, and wherein the antibody is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 and 15, and optionally 22, of the first cycle;

[0031] and wherein following the first cycle (a) or (b) the antibody is administered for at least two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W) or less frequently; and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W) or less frequently.

[0032] E2. A method of E1 , wherein the antibody is administered at a dose of about 76 mg Q2W in the at least two 28-day treatment cycles.

[0033] E3. A method of E2, wherein the antibody is administered on days 1 and 15 of the at least two 28-day treatment cycles.

[0034] E4. A method of E2 or E3, wherein the antibody is administered at a dose of about 76 mg Q2W for two, three, four, five or six 28-day treatment cycles.

[0035] E5. A method of E2 or E3, wherein the antibody is administered at a dose of about 76 mg Q2W for two, three or six 28-day treatment cycles.

[0036] E6. A method of E1 , wherein the antibody is administered at a dose of about 76 mg Q4W in the at least two 28-day treatment cycles.

[0037] E7. A method of E6, wherein the antibody is administered on day 1 of each treatment cycle.

[0038] E8. A method of any one of E1 to E7, wherein the antibody is administered at a dose of about 76 mg Q4W in the subsequent treatment cycles.

[0039] E9. A method of E8, wherein the antibody is administered on day 1 of the subsequent treatment cycles. E10. A method of any one of E1 to E7, wherein the antibody is administered at a dose of about 76 mg once every eight weeks (Q8W) or once every sixteen weeks (Q16W) in the subsequent treatment cycles.

[0040] E11. A method of any one of E1 to E10, wherein if a patient has received treatment for at least six months and / or disease response shows at least a partial response (PR) or better with responses persisting for at least two months, the dose interval may be changed to less frequent dosing than the last dose.

[0041] E12. A method of E11 , wherein the dose is changed from about 76 mg Q4W to 76 mg Q8Wor 76 mg Q16W.

[0042] E13. A method of any one of E1 to E10, wherein if a patient shows evidence of persistent disease, the dose frequency is not changed to less frequent dosing in the next 28-day treatment cycle.

[0043] E14. A method of any one of E1 to E13, wherein the antibody is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg once a week (QW) on day 8, 15 and 22 of the first cycle.

[0044] E15. The method of any one of E1 to E14, wherein the method further comprising administering to the patient at least one dose of a premedication prior to each of the first and second priming doses and / or the first treatment dose.

[0045] E16. The method of E15, wherein the premedication may be acetaminophen (or equivalent such as paracetamol), diphenhydramine (or equivalent) and / or dexamethasone (or equivalent).

[0046] E17. The method of E15 or E16, wherein dexamethasone is administered at a dosing of about 10 mg to about 40 mg daily oral or intravenous, such as 20 mg.

[0047] E18. The method of any one of E15 to E17, wherein acetaminophen is administered at a dose of 650 mg or paracetamol is administered at a dose of 500 mg.

[0048] E19. The method of any of E15 to E18, wherein diphenhydramine is administered at a dose of 25 mg, oral or intravenous.

[0049] E20. The method of any one of E1 to E19, wherein the anti-BCMA I anti-CD3 bispecific antibody comprises a first antigen binding domain that binds to BCMA and a second antigen binding domain that binds to CD3, wherein the first antigen binding domain comprises a VH and a VL, wherein the second antigen binding domain comprises a VH and a VL, and wherein one or both of:

[0050] a) the first antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 1, 2, and 3, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 4 and 5, a VH CDR3 comprising the sequence shown in SEQ ID NO: 6, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 7, a VL CDR2 comprising the sequence shown in SEQ ID NO: 8, a VL CDR3 comprising the sequence shown in SEQ ID NO: 9; and

[0051] b) the second antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 12, 13, and 14, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 15 and 16, a VH CDR3 comprising the sequence shown in SEQ ID NO: 17, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 18, a VL CDR2 comprising the sequence shown in SEQ ID NO: 19, a VL CDR3 comprising the sequence shown in SEQ ID NO: 20. E21. The method of E20, wherein

[0052] a) the first antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 1, a VH CDR2 comprising the sequence shown in SEQ ID NO: 4, a VH CDR3 comprising the sequence shown in SEQ ID NO: 6, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 7, a VL CDR2 comprising the sequence shown in SEQ ID NO: 8, a VL CDR3 comprising the sequence shown in SEQ ID NO: 9; and

[0053] b) the second antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 12, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 15, a VH CDR3 comprising the sequence shown in SEQ ID NO: 17, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 18, a VL CDR2 comprising the sequence shown in SEQ ID NO: 19, a VL CDR3 comprising the sequence shown in SEQ ID NO: 20.

[0054] E22 The method of E20 or E21 , wherein

[0055] a) the first antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 2, a VH CDR2 comprising the sequence shown in SEQ ID NO: 5, a VH CDR3 comprising the sequence shown in SEQ ID NO: 6, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 7, a VL CDR2 comprising the sequence shown in SEQ ID NO: 8, a VL CDR3 comprising the sequence shown in SEQ ID NO: 9; and

[0056] b) the second antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 13, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 16, a VH CDR3 comprising the sequence shown in SEQ ID NO: 17, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 18, a VL CDR2 comprising the sequence shown in SEQ ID NO: 19, a VL CDR3 comprising the sequence shown in SEQ ID NO: 20.

[0057] E23. The method of any one of E20 to E22, wherein

[0058] a) the first antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 3, a VH CDR2 comprising the sequence shown in SEQ ID NO: 5, a VH CDR3 comprising the sequence shown in SEQ ID NO: 6, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 7, a VL CDR2 comprising the sequence shown in SEQ ID NO: 8, a VL CDR3 comprising the sequence shown in SEQ ID NO: 9; and

[0059] b) the second antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in SEQ ID NO: 14, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 16, a VH CDR3 comprising the sequence shown in SEQ ID NO: 17, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 18, a VL CDR2 comprising the sequence shown in SEQ ID NO: 19, a VL CDR3 comprising the sequence shown in SEQ ID NO: 20.

[0060] E24. The method of any one of E20 to E23, wherein the first antigen binding domain VH comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10, and the first antigen binding domain VL comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11; the second antigen binding domain VH comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21 , and the second antigen binding domain VL comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22.

[0061] E25. The method of any one of E1 to E24, wherein the antibody is elranatamab.

[0062] E26. A method of treating a cancer in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises: (a) 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle; or (b) 28 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 and 15 and optionally 22, of the first cycle;

[0063] and wherein following the first cycle (a) or (b) elranatamab is administered for two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W) or less frequently; and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W) or less frequently.

[0064] E27. A method of treating a cancer in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 28 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg once a week (QW) on day 8, 15 and 22 of the first cycle; and wherein following the first cycle elranatamab is administered for two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

[0065] E28. A method of treating a cancer in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle;

[0066] and wherein following the first cycle elranatamab is administered for three 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

[0067] E29. The method of any one of E1 to E28, wherein the anti-BCMA I anti-CD3 bispecific antibody such as elranatamab is administered subcutaneously.

[0068] E30. The method of any one of E1 to E29 wherein the cancer is multiple myeloma. E31. A method of treating multiple myeloma in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises: (a) 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle; or (b) 28 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 and 15 and optionally 22, of the first cycle;

[0069] and wherein following the first cycle (a) or (b) elranatamab is administered for two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W) or less frequently; and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W) or less frequently.

[0070] E32. A method of treating multiple myeloma in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 28 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg once a week (QW) on day 8, 15 and 22 of the first cycle;

[0071] and wherein following the first cycle elranatamab is administered for two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W). E33. A method of treating multiple myeloma in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle;

[0072] and wherein following the first cycle elranatamab is administered for three 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

[0073] E34. A method of treating multiple myeloma in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle;

[0074] and wherein following the first cycle elranatamab is administered for six 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

[0075] E35. The method of E34, wherein elranatamab is administered in combination with lenalidomide.

[0076] E36. The method of E35, wherein lenalidomide is administered at a dose of about 25 mg PO on days 1-21 of each treatment cycle

[0077] E37. The method of any one of E30 to E36, wherein the multiple myeloma is relapsed or refractory (R / R) or resistant multiple myeloma (MM).

[0078] E38. The method of any one of E30 to E37, wherein the patient has previously been treated with:

[0079] a. at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody;

[0080] b. at least three prior lines of therapy, which may include a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody;

[0081] c. at least two prior lines of therapy, which may include two of the following: a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; or

[0082] d. at least one prior line of therapy, which may include one of the following: a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

[0083] E39. The method of E38 when dependent on E31 or E32, wherein the patient has previously been treated with one prior line of therapy, which includes lenalidomide and a proteasome inhibitor. E40. The method of E39, wherein elranatamab is administered in combination with daratumumab.

[0084] E41. The method of E39 or E40, wherein the method comprises administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 28 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg once a week (QW) on day 8, followed by a dose of about 76 mg once every two weeks (Q2W) on day 15 of the first cycle;

[0085] and wherein following the first cycle elranatamab is administered for two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

[0086] E42. The method of E41, wherein daratumumab is administered ata dose of about 1800 mg on day 15 of the first cycle, QW through day 8 of the second treatment cycle, Q2W from day 15 of the second treatment cycle through the sixth treatment cycle; and Q4W from day 1 of the seventh treatment cycle through day 1 of the eleventh cycle.

[0087] E43. The method of any one of E30 to E36, wherein the cancer is newly diagnosed multiple myeloma.

[0088] E44. The method of E43, wherein the patient has received stem cell transplant, optionally autologous stem cell transplant or allogeneic stem cell transplant.

[0089] E45. The method of any of E30 to E34, wherein the patient has not received any prior multiple myeloma therapies.

[0090] E46. The method of E34 to E36, wherein the patient is ineligible for stem cell transplant, optionally stem cell transplant, further optionally autologous stem cell transplant.

[0091] E47. The method of any one of E30 to E33, wherein the multiple myeloma is smoldering multiple myeloma.

[0092] E48. The method of E47, wherein the multiple myeloma is low risk, medium risk or high-risk smoldering multiple myeloma.

[0093] E49. The method of E48, wherein the multiple myeloma is high-risk smoldering multiple myeloma.

[0094] E50. The method of any one of E30 to E33, wherein the multiple myeloma is monoclonal gammopathy of undetermined significance (MGLIS).

[0095] E51. The method of any one of E1 to E50, wherein if the subject experiences CRS, the subject is administered supportive therapy for CRS.

[0096] E52. The method of E51, wherein the subject is administered an effective amount of tocilizumab. E53. The method of any one of E1 to E52, wherein the method further comprises administered immunoglobulin replacement therapy.

[0097] E54. The method of E53, wherein immunoglobulin replacement therapy is administered if IgG level < 400 mg / dL.

[0098] E55. The method of E53 or E54, wherein the immunoglobulin replacement therapy is administered if immunoparesis / hypogammaglobulinemia is determined.

[0099] E56. The method of any one of E53 to E55, wherein the immunoglobulin replacement therapy is administered every 4 weeks.

[0100] E57. The method of E56, wherein the immunoglobulin replacement therapy is administered during the first six 28-day treatment cycles.

[0101] E58. The method of any one of E53 to E57, wherein the immunoglobulin replacement therapy is administered to patients at high risk of infection if IgG level < 400 mg / dL.

[0102] E59. The method of E58, wherein the immunoglobulin replacement therapy is administered during a seventh to twelfth 28-day treatment cycles.

[0103] E60. The method of E58 or E59, wherein the patients is at high risk of developing Grade 3-4 infection during the method of treatment.

[0104] E61. The method of any of E53 to E60, wherein the immunoglobulin replacement therapy is administered intravenously or subcutaneously.

[0105] E62. The method of any of E53 to E61 , wherein the immunoglobulin replacement therapy results in decreased infection rates.

[0106] E63. The method of any of E53 to E62, wherein the immunoglobulin replacement therapy is administered until IgG level > 400 mg / dL and / or resolution of immunoparesis / hypogammaglobulinemia.

[0107] E64. The method of any one of E1 to E63, wherein the anti-BCMA I anti-CD3 bispecific antibody is administered until disease progression.

[0108] E65. A method of any one of E1 to E64, wherein the treatment improves one or more of PFS, OS, PFS by Investigator, PFS2 by Investigator, ORR, DOR, VGPRR, CRR, DOOR, TTR, MRD negativity rate, sustained MRD negativity rate, and duration of MRD negativity.

[0109] E66. A method of E65, wherein the treatment improves PFS and / or OS.

[0110] E67. A method of E65, wherein the treatment improves PFS, OS and / or MRD negativity rate of the subject relative to PFS, OS and / or MRD negativity rate of a reference subject or a reference population of subjects.

[0111] E68. A method of E65, wherein the objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100%.

[0112] E69. The method of any one of E65 to E68, wherein the subject exhibits progression-free survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, or at least about 120 months.

[0113] E70. The method of any one of E65 to E69, wherein the subject exhibits overall survival of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, at least about 126 months, at least about 132 months, at least about 138 months, at least about 144 months, at least about 150 months, at least about 156 months, or at least about 162 months.

[0114] E71. The method of any one of E65 to E70, wherein the duration of response is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, at least about 126 months, at least about 132 months, at least about 138 months, at least about 144 months, at least about 150 months, at least about 156 months, or at least about 162 months. E72. The method of any one of E65 to E70, wherein the method of treatment results in a MRD negativity rate of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%. In some embodiments, the MRD negativity rate is at least about 55%.

[0115] E73. The method of any one of E65 to E71 , wherein the method of treatment results in a MRD negativity rate at 12 months of at least about 20%, at least about 25%, at least about 30%, at least about 35%. In some embodiments, the MRD negativity rate at 12 months is at least 30%.

[0116] E74. An anti-BCMA I anti-CD3 bispecific antibody for use to treat a patient according to the method of any one of E1 to E73.

[0117] E75. An anti-BCMA I anti-CD3 bispecific antibody for use of E74, wherein the antibody is elranatamab.

[0118] E76. Use of an anti-BCMA I anti-CD3 bispecific antibody in the manufacture of a medicament for use to treat a patient according to the method of any one of E1 to E73.

[0119] E77. Use of E76, wherein the antibody is elranatamab.

[0120] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0121] All references cited herein, including patent applications, patent publications, UniProtKB accession numbers are herein incorporated by reference, as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety.

[0122] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al, Molecular Cloning: A Laboratory Manual 3rd. edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. CURRENT PROTOCOLS IN MOLECULAR BIOLOGY (F. M. Ausubel, etal. eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.): PCR 2: A PRACTICAL APPROACH (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) ANTIBODIES, A LABORATORY MANUAL, and ANIMAL CELL CULTURE (R. I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al, eds., 1994); Current Protocols in Immunology (J. E. Coligan et al, eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999)); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and updated versions thereof.

[0123] Definitions

[0124] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention have the meanings that are commonly understood by those of ordinary skill in the art.

[0125] As used herein, the singular form "a", "an", and "the" include plural references unless indicated otherwise. For example, "an" antibody includes one or more antibodies.

[0126] Where aspects or embodiments of the invention are described in terms of a Markush group or other grouping of alternatives, the present invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present invention also envisages the explicit exclusion of one or more of any of the group members in the claimed invention.

[0127] Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

[0128] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of an anti-BCMA I anti-CD3 bispecific antibody such as elranatamab) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 76 mg means 5% ± 10%, i.e. it may vary between 72 mg and 80 mg.

[0129] The term “identity” or “identical to” refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g., DNA molecules or RNA molecules) or between polypeptide molecules. “Identity” measures the percent of identical matches between two or more sequences with gap alignments addressed by a particular mathematical model of computer programs (e.g. algorithms), which are well known in the art.

[0130] Calculation of the percent identity of two nucleic acid or polypeptide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second sequence for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of a reference sequence. The nucleotides at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.

[0131] To determine percent identity, sequences can be aligned using the methods and computer programs, including BLAST, available over the world wide web at ncbi.nlm.nih.gov / BLAST / . Other alignment programs include MegAlign® program in the Lasergene® suite of bioinformatics software (DNASTAR®, Inc., Madison, Wl). Another alignment algorithm is FASTA, available in the Genetics Computing Group (GCG) package, from Madison, Wis., USA. Other techniques for alignment are described in Methods in Enzymology, vol. 266: Computer Methods for Macromolecular Sequence Analysis (1996), ed. Doolittle, Academic Press, Inc. Of particular interest are alignment programs that permit gaps in the sequence. Smith-Waterman is one type of algorithm that permits gaps in sequence alignments. See Meth. Mai. Biol. 70: 173-187 (1997). Also, the GAP program using the Needleman and Wunsch alignment method can be utilized to align sequences. See J. Mai. Biol.

[0132] 48: 443-453 (1970).

[0133] Also, of interest is the BestFit program using the local homology algorithm of Smith and Waterman (1981, Advances in Applied Mathematics 2: 482-489) to determine sequence identity. The gap generation penalty will generally range from 1 to 5, usually 2 to 4 and in some embodiments will be 3. The gap extension penalty will generally range from about 0.01 to 0.20 and in some instances will be 0.10. The program has default parameters determined by the sequences inputted to be compared. Preferably, the sequence identity is determined using the default parameters determined by the program. This program is available also from Genetics Computing Group (GCG) package, from Madison, Wl, USA.

[0134] Another program of interest is the FastDB algorithm. FastDB is described in Current Methods in Sequence Comparison and Analysis, Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149, 1988, Alan R. Liss, Inc. Percent sequence identity is calculated by FastDB based upon the following parameters: Mismatch Penalty: 1.00; Gap Penalty: 1.00; Gap Size Penalty: 0.33; and Joining Penalty: 30.0. The terms "treating", "treat" or "treatment" refer to an approach for obtaining clinical benefit or desired clinical results, e.g. such as to partially or completely relieve, alleviate, ameliorate, inhibit, delay the onset of, reduce the severity of, reduce the frequency of, reduce the incidence of, slow the progression of, or any combination thereof, of one or more symptoms of the patient’s disease, disorder or condition or any tissue damage associated with the disease. Treatment may also include improved survival rate, decreased duration of the disease, reduction in the number, extent or duration of symptoms of the disease, disorder or condition. Treatment may be prophylactic (to delay the onset of the disease, or to prevent the manifestation of at least one clinical symptom thereof) or therapeutic suppression of or alleviation of a symptom after manifestation of the disease. In some embodiments, the disease, disorder or condition is a cancer, in some embodiments, multiple myeloma.

[0135] The terms “subject, “individual” or “patient,” (used interchangeably herein), refer to any animal, including mammals. Mammals according to the invention include canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, humans and the like, and encompass mammals in utero. In an embodiment, humans are suitable subjects. Human subjects may be of any gender and at any stage of development. In some embodiments, a subject is a patient with cancer, in some embodiments, multiple myeloma.

[0136] The term “therapeutically effective amount” refers to the amount of active ingredient that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e. , arresting or slowing further development of the pathology or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology or symptomatology).

[0137] The terms “prevent” or “prevention” refer to preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease. In some embodiments, prevention is assessed on a population basis such that an agent is considered to “prevent” a particular disease, disorder or condition if a statistically significant decrease in the development, frequency or intensity of the disease, disorder or condition is observed in a population susceptible to the disease, disorder or condition. Prevention may be considered complete when onset of disease, disorder or condition has been delayed for a predefined period of time.

[0138] As used herein “dosing” refers to both the “dose amount”, for example 76 mg, and the “dose frequency”, for example, once a day (QD), once a week (Q1 W or QW), once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every eight weeks (Q8W), and once every sixteen weeks (Q16W). Dosing may also include the administration route of a drug, such as for example, subcutaneously (SC), intravenously (IV), oral (PO), if so specified. Similarly, a “priming dosing”, a “first treatment dosing”, a “second treatment dosing” and so on, each refers to both the dose amount and dose frequency of such dosing and optionally also includes the administration route if so specified. In some embodiments, there is one dose amount and one dose frequency in a dosing. In some embodiments, there are more than one dose amounts, and / or more than one dose frequencies in a dosing.

[0139] The terms “dose delay” and “dose interruption” are used interchangeably to refer to therapy being withheld to manage toxicity or other adverse event, or reaction related to the therapy. For example, in some embodiments, a dose delay can result if a subject experiences cytokine release syndrome (CRS), neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS), infections, neutropenia, hepatoxicity, or other toxicity or adverse event or reaction. After resolution of the toxicity or other adverse event, administration of the anti-BCMA I anti-CD3 bispecific antibody is restarted according to the defined re-starting dosing schedule.

[0140] The terms “increase,” improve,” “decrease” or “reduce” refer to values that are relative to a baseline measurement, such as a measurement in the same individual prior to initiation of treatment described herein, or a measurement in a control individual or subject (or multiple control individuals or subjects) in the absence of the treatment described herein. In some embodiments, a “control individual” is an individual afflicted with the same form of disease or injury as an individual being treated. In some embodiments, a “control individual” is an individual that is not afflicted with the same form of disease or injury as an individual being treated.

[0141] As used herein the “subject’s response”, “patient’s response” (used interchangeably herein), refers to the clinical response of the subject being treated with the pharmaceutical product that comprises elranatamab. The ‘subject’s response” includes one or more aspects with regard to clinical efficacy, such as complete response, partial response and duration of the response. “Subject’s response” may also include additional aspects such as toxicity and adverse events.

[0142] As used herein, “IMWG response” and / or “IMWG criteria” refers to a patient’s (subject’s) clinical response to a pharmaceutical product to treat multiple myeloma, wherein the response, such as a complete response, or partial response, is defined according to the most up to date definition from the International Myeloma Working Group (see Kumar et al., Lancet Oncol.

[0143] 2016;17(8):e328-e46).

[0144] As used herein, “cycle”, and “week” when used in the context of describing a method of treating cancer including uses thereof, a dosing, or a dosing schedule, refer to a duration of time. A first cycle (used interchangeably with “priming cycle”) can be 7, 14, 21 or 28 days and a treatment cycle can be 7, 14, 21 or 28 days, unless otherwise specified, when a subject is treated with a therapeutic agent, a pharmaceutical product thereof, such as an anti-BCMA I anti-CD3 bispecific antibody (for example, elranatamab), or a pharmaceutical product thereof. Week 1 refers to the first week when the subject is treated under the method, or any of the dosing or dosing schedules therein unless otherwise specified. Week 2 starts immediately after week 1 ends, week 3 starts immediately after week 2 ends, and so on. Cycle 1 starts on the first day of week 1 , the first day of week 2, or the first day of week three, unless otherwise specified. Unless stated otherwise, cycle 2 starts immediately after cycle 1 ends, cycle 3 starts immediately after cycle 2 ends, and so on.

[0145] An “antibody” refers to an immunoglobulin molecule capable of specific binding to a target, such as a polypeptide, carbohydrate, polynucleotide, lipid, etc., through at least one antigen binding domain, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” can encompass any type of antibody (e.g. monospecific, bispecific) and includes portions of intact antibodies that retain the ability to bind to a given antigen (e.g. an “antigen-binding fragment”), and any other modified configuration of an immunoglobulin molecule that comprises an antigen binding domain. An exemplary antibody comprises i) a variable region of the light chain, heavy chain or both and ii) a constant region of the heavy chain comprising three sequential immunoglobulin domains (CH1 , CH2, and CH3) and of the light chain comprising a single immunoglobulin domain (CL).

[0146] An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains (HC), immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGi, lgG2, IgGs, lgG4, IgAi and lgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0147] Examples of antibody antigen-binding fragments and modified configurations include (i) a Fab fragment (a monovalent fragment consisting of the VL, VH, CL and CH1 domains); (ii) a F(ab')2 fragment (a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region); and (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody. Furthermore, although the two domains of an Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)); see e.g., Bird et al., Science 1988; 242:423-426 and Huston et al., Proc. Natl. Acad. Sci. 1988 USA 85:5879-5883. Other forms of single chain antibodies, such as diabodies are also encompassed.

[0148] In addition, further encompassed are antibodies that are missing a C-terminal lysine (K) amino acid residue on a heavy chain polypeptide (e.g. human lgG1 heavy chain comprises a terminal lysine). As is known in the art, the C-terminal lysine is sometimes clipped during antibody production, resulting in an antibody with a heavy chain lacking the C-terminal lysine. Alternatively, an antibody heavy chain may be produced using a nucleic acid that does not include a C-terminal lysine.

[0149] Further encompassed are antibodies that have post-translational modifications at one or more amino acids in one or both of the heavy chain and light chain.

[0150] A “bispecific antibody” refers to a molecule that has binding specificity for at least two different epitopes. In some embodiments, bispecific antibodies can bind simultaneously two different antigens. In other embodiments, the two different epitopes may reside on the same antigen. In certain embodiments, the bispecific antibody is capable of simultaneously binding two antigens expressed on two distinct cells.

[0151] A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FRs) connected by three complementarity determining regions (CDRs) also known as hypervariable regions and contribute to the formation of the antigen binding domain of antibodies. If variants of a subject variable region are desired, particularly with substitution in amino acid residues outside of a CDR region (i.e., in the framework region), appropriate amino acid substitution, preferably, conservative amino acid substitution, can be identified by comparing the subject variable region to the variable regions of other antibodies which contain CDR1 and CDR2 sequences in the same canonical class as the subject variable region (Chothia and Lesk, J Mol Biol 196(4): 901-917, 1987).

[0152] In certain embodiments, definitive delineation of a CDR and identification of residues comprising the binding domain of an antibody is accomplished by solving the structure of the antibody or solving the structure of the antibody-ligand complex. In certain embodiments, that can be accomplished by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. In certain embodiments, various methods of analysis can be employed to identify or approximate the CDR regions. Examples of such methods include, but are not limited to, the Kabat definition, the Chothia definition, the AbM definition, the contact definition, the extended definition, and the conformational definition.

[0153] The Kabat definition is a standard for numbering the residues in an antibody and is typically used to identify CDR regions. See, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28: 214-8. The Chothia definition is similar to the Kabat definition, but the Chothia definition takes into account positions of certain structural loop regions. See, e.g., Chothia et al., 1986, J. Mol. Biol., 196: 901-17; Chothia et al., 1989, Nature, 342: 877-83. The extended definition is the combination of the Kabat and Chothia definitions. The AbM definition uses an integrated suite of computer programs produced by Oxford Molecular Group that model antibody structure. See, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; “AbM™, A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK; Oxford Molecular, Ltd. The AbM definition models the tertiary structure of an antibody from primary sequence using a combination of knowledge databases and ab initio methods, such as those described by Samudrala et al., 1999, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach,” in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198. The contact definition is based on an analysis of the available complex crystal structures. See, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45. In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166. Still other CDR boundary definitions may not strictly follow one of the above approaches but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs may be defined in accordance with any one or more of Kabat, Chothia, extended, AbM, contact, or conformational definitions.

[0154] Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This particularly may be the case where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to Kabat EU index). Therefore, the C-terminal lysine, or the C-terminal glycine and lysine, of an antibody provided herein may or may not be present. Elranatamab is an anti-BCMA I anti-CD3 bispecific antibody. Elranatamab is described, for example in US Patent No. 9,969,809, incorporated by reference in its entirety. The selected sequences of Elranatamab are shown in Table 1 herein. Elranatamab is also known as PF- 06863135 and these terms are used interchangeably herein. Elranatamab comprises the sequences shown in Table 1 herein. SEQ ID NOs 1-11, 23 and 24 are sequences of the anti- BCMA binding domain. The heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3, are provided in SEQ ID Nos 1, 4 and 6, respectively, using Chothia numbering; SEQ ID Nos 2, 5 and 6, respectively using Kabat numbering; and SEQ ID Nos 3, 5, 6, respectively, in extended numbering format. The light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 are provided in SEQ ID Nos 7, 8 and 9 respectively. The heavy chain variable region (VH) is provided in SEQ ID NO: 10. The light chain variable region (VL) is provided in SEQ ID No: 11. The heavy chain is provided in SEQ ID No: 23. The light chain is provided in SEQ ID No: 24. SEQ ID NOs 12-22, 25, and 26 are sequences of the anti- CD3 binding domain of elranatamab. The heavy chain complementarity determining region 1 (HCDR1), HCDR2 and HCDR3, are provided in SEQ ID Nos 12, 15 and 17, respectively using Chothia numbering; SEQ ID Nos 13, 16 and 17, respectively, using Kabat numbering; and SEQ ID Nos 14, 16 and, 17, respectively, in extended numbering format. The light chain complementarity determining region 1 (LCDR1), LCDR2 and LCDR3 are provided in SEQ ID Nos 18, 19 and 20, respectively. The heavy chain variable region (VH) is provided in SEQ ID NO: 21. The light chain variable region (VL) is provided in SEQ ID No: 22. The heavy chain is provided in SEQ ID No: 25. The light chain is provided in SEQ ID No: 26. In some instances, the heavy chain sequence for the anti-BCMA binding domain of elranatamab may lack the C- terminal lysine residue that is present in SEQ ID NO: 23. In some instances, the heavy chain sequence for the anti-CD3 binding domain of elranatamab may lack the C-terminal lysine residue that is present in SEQ ID NO: 25. In some instances, the heavy chain sequence for the anti- BCMA binding domain of elranatamab may lack the C-terminal lysine residue that is present in SEQ ID NO: 23 and the heavy chain sequence for the anti-CD3 binding domain of elranatamab may lack the C-terminal lysine residue that is present in SEQ ID NO: 25.

[0155] Lenalidomide is a thalidomide analogue that has immunomodulatory, tumoricidal, and antiangiogenic properties. It synergizes with dexamethasone to augment anti-myeloma activity. Lenalidomide, in combination with dexamethasone, is indicated for the treatment of multiple myeloma in adult participants who have received at least 1 prior therapy and also for the treatment of adult participants with previously untreated multiple myeloma who are not eligible for transplant. In both settings, the recommended dose is 25 mg PO QD on Days 1-21 of repeated 28-day cycles.

[0156] An “IMiD drug”, “imid drug”, or an “immunomodulatory agent”, as used herein, interchangeably, refers to a drug that is understood by a practicing physician treating multiple myeloma as an IMiD drug or immunomodulatory agent in the context of the treatment of multiple myeloma. Examples of an I M id drug or an immunomodulating agent includes, without limitation, thalidomide, lenalidomide and pomalidomide.

[0157] Daratumumab refers to an antibody that specifically binds CD38 comprising a heavy chain complementarity determining region 1 (HCDR1) of SEQ ID NO: 27, a HCDR2 of SEQ ID NO: 28, a HCDR3 of SEQ ID NO: 29, a light chain complementarity determining region 1 (LCDR1) of SEQ ID NO: 30, a LCDR2 of SEQ ID NO: 31, a LCDR3 of SEQ ID NO: 32, a heavy chain variable region (VH) of SEQ ID NO: 33, a light chain variable region (VL) of SEQ ID NO: 34, a heavy chain (HC) of SEQ ID NO: 35 and a light chain (LC) of SEQ ID NO: 36. . Daratumumab is marketed under the trade names DARZALEX®, DARZALEX® SC, and DARZALEX FASPRO®.

[0158] Hyaluronidase refers to an enzyme that degrades hyaluronic acid (EC 3.2.1.35) and lowers the viscosity of hyaluronan in the extracellular matrix, thereby increasing tissue permeability. An exemplary hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20). rHuPH20 comprises an amino acid sequence of SEQ ID NO: 39-43 - see Table 2. Enzymatic activity of hyaluronidase, including rHuPH20 can be defined by units per mL (U / rnL) or by total enzyme activity in a particular formulation (II). The standard definition for one unit (II) of enzyme activity is the amount of enzyme that catalyzes the reaction of 1 nmol of substrate per minute.

[0159] Immunoglobulin replacement therapy (also referred to as IVIG) refers to administration of a composition of IgG immunoglobulins to a subject. The composition can be administered intravenously or subcutaneously.

[0160] “BCMA directed ADC therapy”, refers to a multiple myeloma therapy that comprises an antibody drug conjugate, wherein the antibody binds to B-cell maturation antigen (BCMA). Examples of a BCMA directed ADC includes, without limitation, belantamab mafodotin -blmf, which was approved by LISFDA and marketed under the brand name BLENREP.

[0161] “BCMA directed CAR-T cell therapy”, or “anti-BCMA CAR-T cell” as used herein, interchangeably, refers to a multiple myeloma therapy that comprises a chimeric antigen receptor T cell wherein the chimeric antigen receptor recognizes B-cell maturation antigen (BCMA). Examples of a “BCMA targeted CAR-T therapy”, or “anti-BCMA CAR T cell therapy” includes, without limitation, idecabtgene vicleucel (ide-cel; or bb2121 ) and JNJ-4528, also known as LCAR-B38M.

[0162] “BCMA directed therapy”, refers to a multiple myeloma therapy which active ingredient comprises a component that binds to the B-Cell maturation antigen. BCMA directed therapy includes BCMA directed ADC Therapy, BCMA directed CAR-T therapy, and multiple myeloma therapies that comprises BCMA bispecific antibodies.

[0163] As used herein “multiple myeloma” refers to hematological conditions characterized by malignant plasma cells and includes at least the following disorders: monoclonal gammopathy of undetermined significance (MGLIS); relapsed, refractory or resistant multiple myeloma; low risk, intermediate risk, and high risk multiple myeloma; newly diagnosed multiple myeloma (including low risk, intermediate risk, and high risk newly diagnosed multiple myeloma); transplant eligible and transplant ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including low risk, intermediate risk, and high risk smouldering multiple myeloma); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; non-secretory myeloma; Immunoglobulin D myeloma; and Immunoglobulin E myeloma; and multiple myeloma characterized by genetic abnormalities, such as Cyclin D translocations (for example, t(11 ;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20);); MMSET translocations (for example, t(4;14)(p16;q32)); MAF translocations (for example, t(14;16)(q32;q32); t(20;22); t(16; 22)(q11;q13); or t(14;20)(q32;q11)); or other chromosome factors (for example, deletion of 17p13, or chromosome 13; del(17 / 17p), nonhyperdiploidy, and gain(1q)).

[0164] Smoldering multiple myeloma (SMM) is an intermediate stage between MGLIS and multiple myeloma and can be defined by the IMWG diagnostic criteria (Rajkumar et al. Lancet Oncol.

[0165] 2014;15(12):e538).

[0166] “Newly diagnosed multiple myeloma” refers to multiple myeloma wherein the patient (subject) has not yet received any treatment for the diagnosis of multiple myeloma. As used herein, “transplant ineligible” refers to patient diagnosed with multiple myeloma being not eligible for stem cell transplant, such as stem cell transplant as a treatment for the multiple myeloma.

[0167] A ’’reference subject” or “reference population of subjects” refers to a subject or population of subjects having multiple myeloma who are substantially the same as the subject or population of subjects that are treated in the defined methods of treatment. In some embodiments there are a plurality reference subjects or a plurality of subjects within the reference population of subjects.

[0168] As used herein, “stem cell transplant ineligible” refers patient diagnosed with multiple myeloma being not eligible for stem cell transplant as a treatment for the multiple myeloma.

[0169] Anti-BCMA / Anti-CD3 Bispecific Antibody

[0170] Dosing regimens and methods provided herein include an anti-BCMA I anti-CD3 bispecific antibody. As used herein, an anti-BCMA I anti-CD3 bispecific antibody can be any molecule that can simultaneously bind to both BCMA (e.g. on B cells) and CD3 (e.g. on T cells). Anti-BCMA I anti-CD3 bispecific antibodies are also referred to herein as “BCMA x CD3” or “BCMA” bispecific antibodies.

[0171] B-cell maturation antigen (BCMA, also known as TNFRSF17 and CD269) is a candidate for bispecific antibody-based immunotherapy. BCMA expression is upregulated during B-cell maturation into plasma blasts and plasma cells, but it is not expressed on naive B cells, hematopoietic stem cells or normal tissues such as the heart, lung, kidney, or tonsil. In multiple myeloma, BCMA expression was identified at each disease stage, and on patients with differing cytogenetic risks. Furthermore, BCM A expression was not influenced by treatment with autologous stem cell transplant (ASCT) or chemotherapy. In vivo, bispecific antibodies against BCMA have been shown to induce T-cell activation, reduce tumor burden and prolong survival.

[0172] Examples of anti-BCMA I anti-CD3 bispecific antibodies that may be useful in the combination therapies of the present invention include, but are not limited to, AMG 420 (BCMAxCD3 bispecific T-cell engager, BiTE®, Amgen), AMG 701 (BCMAxCD3 BiTE®, Amgen), CC-93269 (BCMAxCD3 bispecific antibody, Celgene), teclistamab (JNJ-64007957 - Jansen), elranatamab (BCMAxCD3 bispecific antibody, Pfizer Inc.), TNB-383B (TeneoBio / AbbVie), linvoseltamab (REGN5458 - BCMAxCD3 bispecific antibody, Regeneron), alnuctamab (CC-93269 - BMS), AFM26 (BCMAxCD16 tetravalent bispecific antibody, Affimed GmbH), HPN217 (BCMAxALBxCD3 trispecific, Harpoon Therapeutics).

[0173] In some aspects, the anti-BCMA I anti-CD3 bispecific antibody comprises a first antigen binding domain and a second antigen binding domain, wherein the first antigen binding domain specifically binds to BCMA, and wherein the second antigen binding domain specifically binds to CD3.

[0174] In some aspects, an anti-BCMA I anti-CD3 bispecific antibody may have any of the features or characteristics of any of the BCMA bispecific antibodies provided in WO2016 / 166629, which is hereby incorporated by reference for all purposes.

[0175] In some aspects, the first antigen binding domain specifically binds to BCMA. Information about BCMA is provided, for example, via UniProtKB ID # Q02223. In some aspects, the antigen binding domain comprises three CDRs of a heavy chain variable region (VH) comprising the amino acid sequence shown in SEQ ID NO: 10, and / or three CDRs of a light chain variable region (VL) comprising the amino acid sequence shown in SEQ ID NO: 11. In some aspects, the VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 1 , 2, and 3, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 4 and 5 , a VH CDR3 comprising the sequence shown in SEQ ID NO: 6, and / or the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 7, a VL CDR2 comprising the sequence shown in SEQ ID NO: 8, a VL CDR3 comprising the sequence shown in SEQ ID NO: 9. In some aspects, the VH comprises the sequence shown in SEQ ID NO: 10, and / or the VL comprises the sequence shown in SEQ ID NO: 11. In some aspects, the bispecific antibody comprises a first heavy chain and a first light chain comprising the first antigen binding domain, wherein the first heavy chain comprises the amino acid sequence shown in SEQ ID NO: 23, and / or the first light chain comprises the amino acid sequence shown in SEQ ID NO: 24.

[0176] In some aspects, the second antigen binding domain specifically binds to CD3. Information about CD3 is provided, for example, via UniProtKB #P07766. In some aspects, the second antigen binding domain comprises three CDRs of a heavy chain variable region (VH) comprising the amino acid sequence shown in SEQ ID NO: 21, and / or three CDRs of a light chain variable region (VL) comprising the amino acid sequence shown in SEQ ID NO: 22. In some aspects, the VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 12, 13, and 14, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 15 and 16, a VH CDR3 comprising the sequence shown in SEQ ID NO: 17, and / or the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 18, a VL CDR2 comprising the sequence shown in SEQ ID NO: 19, a VL CDR3 comprising the sequence shown in SEQ ID NO: 20. In some aspects, the VH comprises the sequence shown in SEQ ID NO: 21, and / or the VL comprises the sequence shown in SEQ ID NO: 22. In some aspects, the bispecific antibody comprises a second heavy chain and a second light chain comprising the second antigen binding domain, wherein the second heavy chain comprises the amino acid sequence shown in SEQ ID NO: 25, and / or the second light chain comprises the amino acid sequence shown in SEQ ID NO: 26.

[0177] In some embodiments, the first antigen binding domain VH comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10, and the first antigen binding domain VL comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11 ; and the second antigen binding domain VH comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 21, the second antigen binding domain VL comprises a sequence that is at least about 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 22.

[0178] In some embodiments, the first heavy chain may lack the C-terminal lysine residue that is present in SEQ ID NO:23. In some embodiments, the second heavy chain may lack the C-terminal lysine residue that is present in SEQ ID NO:25. In some embodiments, the first heavy chain may lack the C-terminal lysine residue that is present in SEQ ID NO:23 and the second heavy chain may lack the C-terminal lysine residue that is present in SEQ ID NO:25.

[0179] In some aspects, the anti-BCMA I anti-CD3 bispecific antibody is elranatamab. Elranatamab is a heterodimeric humanized full-length bispecific antibody comprised of one B-cell maturation antigen (BCMA) binding domain and one cluster of differentiation (CD3) binding domain paired through hinge mutation technology. It utilizes a modified human lgG2Da fragment crystallizable (Fc) region. Elranatamab is described, for example in US Patent No. 9,969,809, which is hereby incorporated for all purposes. The sequences of elranatamab are shown in Table 1. SEQ ID NOs 1-11, 23 and 24 are the sequences of the BCMA arm and SEQ ID NOs 12-22, 25, and 26 are the sequences of the CD3 arm of elranatamab.

[0180] Methods of Treatment and composition for use in such methods Provided herein are therapies for the treatment of cancer with an anti-BCMA I anti-CD3 bispecific antibody, and related methods and compositions. In some embodiments, the anti-BCMA I anti-CD3 bispecific antibody is elranatamab.

[0181] In some embodiments, the methods provided herein involving an anti-BCMA I anti-CD3 bispecific antibody include one, two, or more priming doses as part of a priming cycle. Priming doses can be utilised to initially sensitize the immune system at lower doses therefore reducing the rate, duration and grade of cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). In some embodiments, a first priming dose may be 12 mg and a second priming dose may be 32 mg. Exemplary priming doses for elranatamab are a first priming dose of 12 mg and a second priming dose of 32 mg. An exemplary priming dose schedule is to administer the first priming dose (e.g. 12 mg) on day 1, the second priming dose (e.g. 32 mg) on day 4, followed by a first treatment dose. In some embodiments the first treatment dose (e.g. 76 mg) is on day 8 (i.e. 1 week after the first priming dose). In some embodiments, the treatment dose is 76 mg. In some embodiments, the first priming dose is 12 mg, the second priming dose is 32 mg and the treatment dose is 76 mg.

[0182] In some embodiments, an anti-BCMA I anti-CD3 bispecific antibody may be administered in methods and regimens provided herein once a week (Q1W or QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W), or less frequently, for example once every eight weeks (Q8W) or once every sixteen weeks (Q16W). In some embodiments, the antibody is administered QW, Q2W or Q4W. In some embodiments, if a patient has received treatment for at least six months and / or disease response shows at least a partial response (PR) or better with responses persisting for at least two months, the dose interval may be changed to less frequent dosing at the same dose level / dosage (for example, 76 mg QW to 76 mg Q2W or 76 mg Q2W to 76 mg Q4W). These dosing frequencies may be part of treatment cycles, such as 14-day, 21-day, or 28-day cycles. In some embodiments, the treatment cycles are 28-day cycles.

[0183] In some embodiments, the method further comprising administering to the patient at least one dose of a premedication prior to each of the single priming dose, the first priming dose, the second priming dose and / or the first treatment dose of the anti-BCMA I anti-CD3 bispecific antibody is administered to the patient. In some embodiments, the premedication is administered prior to the first and second priming doses and the first treatment dose. The premeditation may be acetaminophen (or equivalent such as paracetamol), diphenhydramine (or equivalent) and / or dexamethasone (or equivalent). In some embodiments, dexamethasone is administered at a dexamethasone dosing of about 10 mg to about 40 mg daily oral or intravenous, such as 20 mg. In some embodiments, acetaminophen is administered at a dose of 650 mg or paracetamol is administered at a dose of 500 mg. In some embodiments, diphenhydramine is administered at a dose of 25 mg, oral or intravenous. In some embodiments, the premedication dosing can be the same or different while the subject is on the priming dosing, the first treatment and subsequent dosing of the bispecific antibody.

[0184] Dosing regimens and methods provided herein may be is useful to treat a variety of cancer cells. These include liquid (hematological) and solid tumours. Solid tumours can be treated with the dosing regimens and methods provided herein, to reduce the size, number or growth rate thereof and to control growth of cancer stem cells. Such solid tumours include tumours in bladder, brain, breast, lung, colon, ovary, prostate, liver and other tissues as well. In one embodiment, dosing regimens and methods provided herein can used to inhibit the growth or proliferation of hematological cancers. As used herein, “hematological cancer” refers to a cancer of the blood, and includes leukemia, lymphoma and myeloma among others.

[0185] “Leukemia” refers to a cancer of the blood, in which too many white blood cells that are ineffective in fighting infection are made, thus crowding out the other parts that make up the blood, such as platelets and red blood cells. It is understood that cases of leukemia are classified as acute or chronic. Certain forms of leukemia may be, by way of example, acute lymphocytic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); myeloproliferative disorder / neoplasm (MPDS); and myelodysplastic syndrome. “Lymphoma” may refer to a Hodgkin’s lymphoma, both indolent and aggressive non-Hodgkin’s lymphoma, Burkitt's lymphoma, and follicular lymphoma (small cell and large cell), among others. Myeloma may refer to multiple myeloma (MM), giant cell myeloma, heavy-chain myeloma, and light chain or Bence-Jones myeloma. In particular embodiments, dosing regimens and methods provided herein are useful to treat T cell lymphomas that are a very heterogeneous group of lymphoid malignancies divided into cutaneous and peripheral TCL, which themselves are divided into nodal or extranodal types. CTCL derive from skin-homing T cells and consist of mycosis fungoides, Sezary syndrome, primary cutaneous T cell lymphoproliferative disorders, and anaplastic large cell lymphoma. The common features of TCL are aggressive course and poor response to therapy, with the exception of ALK and ALCL.

[0186] In some other embodiments, the hematological cancer treated with dosing regimens and methods is a leukemia, preferably selected from acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome, preferably, human acute myeloid leukemia.

[0187] In other embodiments, the hematological cancer treated with a dosing regimen or method provided herein is a lymphoma or myeloma selected from Hodgkin’s lymphoma, both indolent and aggressive non-Hodgkin’s lymphoma, Burkitt's lymphoma, follicular lymphoma (small cell and large cell), multiple myeloma (MM), giant cell myeloma, heavy-chain myeloma, and light chain or Bence-Jones myeloma as well as leimyosarcoma. In some embodiments, a cancer treated with a dosing regimen or method provided herein is relapsed and / or refractory (R / R). In some embodiments, a subject treated with a dosing regimen or method provided herein has been previously treated with 1-3 lines of therapy for the cancer.

[0188] In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is advanced multiple myeloma. In some embodiments, the cancer is relapsed or refractory multiple myeloma.

[0189] In some embodiments, the cancer is triple class refractory multiple myeloma. In some embodiments, the multiple myeloma of the subject is refractory to all three types of the following multiple myeloma therapies (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody.

[0190] In some embodiments, the cancer is double class refractory multiple myeloma. In some embodiments, the multiple myeloma of the subject is refractory to at least two of the following three types of multiple myeloma therapies (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody.

[0191] In some embodiments, the cancer is newly diagnosed multiple myeloma. In some embodiments, the cancer is multiple myeloma, and the subject has received stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant. In some embodiments, the subject has received autologous stem cell transplant or allogeneic stem cell transplant. In some embodiments, the subject is minimum residual disease positive post stem cell transplant. In some embodiments the treatment is of newly diagnosed multiple myeloma in a patient who is transplant ineligible. In some embodiments, the subject has not received any prior multiple myeloma therapies after the diagnosis of multiple myeloma. In some embodiments, the subject is stem cell transplant ineligible, such as autologous stem cell transplant ineligible.

[0192] In some embodiments, the cancer is multiple myeloma, wherein in some embodiments the subject has progressed or is intolerant of an established multiple myeloma therapy. In some embodiments, the established multiple myeloma therapy comprises at least one drug selected from the group consisting of a proteasome inhibitor, an I M id drug and an anti-CD38 antibody.

[0193] In some embodiments, the cancer is multiple myeloma wherein the subject has received at least four prior therapies and the subject’s multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma therapy that comprises an proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody, and wherein the subject has demonstrated disease progression on the last therapy. In one aspect of these embodiments, the subject has received a prior therapy of a BCMA targeted ADC or a BCM A targeted CAR-T. In another aspect of these embodiments, the subject has not received any prior therapy of a BCMA targeted ADC or a BCMA targeted CAR-T.

[0194] In some embodiments, the cancer is multiple myeloma, the subject has received at least one, at least two, at least three or at least four prior multiple myeloma therapies, and the subject’s multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor, (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent and (3) a prior multiple myeloma therapy that comprises an anti-CD38 antibody, and the subject has demonstrated disease progression on the last multiple myeloma therapy. In one aspect of this embodiment, the subject has received at least three prior multiple myeloma therapies. In another aspect of this embodiment, the subject has received at least four prior multiple myeloma therapies.

[0195] In some embodiments, the previous multiple myeloma therapies the subject received comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received comprise a BCMA directed therapy.

[0196] In some embodiments, the previous multiple myeloma therapies the subject received do not comprise a BCMA directed ADC therapy or a BCMA directed CAR-T cell therapy. In some embodiments, the previous multiple myeloma therapies the subject received do not comprise a BCMA directed therapy.

[0197] In some embodiments, the cancer is multiple myeloma, and the subject has received at least one or at least two prior multiple myeloma therapies, the subject’s multiple myeloma is refractory or relapsed to (1) a prior multiple myeloma therapy that comprises a proteasome inhibitor and (2) a prior multiple myeloma therapy that comprises an immunomodulatory agent. In some embodiments, the subject has demonstrated disease progression on the last multiple myeloma therapy. In some embodiments, the subject has received at least one prior multiple myeloma therapy including lenalidomide and a proteasome inhibitor.

[0198] In some embodiments, the cancer is multiple myeloma, and the subject has not received any prior multiple myeloma therapies. In some embodiments, the subject has not received any prior multiple myeloma therapies after the diagnosis of multiple myeloma. In some embodiments, the subject is stem cell transplant ineligible. In some embodiments, the cancer is multiple myeloma and the subject is stem cell transplant ineligible. In some embodiments, the subject is autologous stem cell transplant ineligible. In some embodiments, the subject is allogeneic stem cell transplant ineligible. In some embodiments, the subject is ineligible for autologous stem cell transplant and is also ineligible for allogeneic stem cell transplant.

[0199] In some embodiments, the multiple myeloma is smoldering myeloma, indolent myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of the bone, light chain myeloma, or non-secretory myeloma. In some embodiments, provided herein are methods for the treatment or management of smoldering myeloma, indolent myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of the bone, light chain myeloma, or non-secretory myeloma.

[0200] An anti-BCMA I anti-CD3 bispecific antibody provided herein can be administered to the subject through any of the routes established for protein delivery, in particular, intravenous, intradermal and subcutaneous injection or infusion, or by oral or nasal administration. In some embodiments, the anti-BCMA I anti-CD3 bispecific antibody (e.g. elranatamab) is administered subcutaneously.

[0201] In some embodiments, the methods provided herein are useful for achieving one or more clinical trial endpoints in a patient. In certain embodiments, the methods provided herein are useful for improving one or more of these clinical trial endpoints in a patient. In some embodiments the clinical endpoints include one or more of PFS, OS, PFS by Investigator, PFS2 by Investigator, ORR, DOR, VGPRR, CRR, DOOR, TTR, MRD negativity rate, sustained MRD negativity rate, and duration of MRD negativity. In some embodiments the clinical endpoint is PFS. In some embodiments the clinical endpoint is OS.

[0202] In some embodiments, the response may be assessed using the International Multiple Myeloma Working Group (IMWG) consensus criteria for response and minimal residual disease assessment (Rajkumaref a / ., Blood, 2011, 117(18):4691 -5; Kumar etal., Lancet Oncol., 2016,17(8):e328-e346).

[0203] In some embodiments, Progression Free Survival (PFS) is defined as the time from the date of randomization to date of confirmed PD per IMWG criteria or death due to any cause, whichever occurs first. PFS is calculated in months as follows:

[0204] PFS (months) = (date of event or censoring- randomization date +1) 130.4375

[0205] In some embodiments, Overall Survival (OS) is defined as the time from the date of randomization to date of death due to any cause. If a participant is loss of follow-up or withdrawal of consent but not known to have died at the time of the cutoff for analysis, then OS is censored at the date of last contact. OS is calculated in months as follows:

[0206] OS (months) = [date of death or censoring - date of randomization +1] / 30.4375 In some embodiments, PFS by investigator has the same definition as the PFS by BICR above, except the timepoint disease assessments and determination of the date of confirmed PD will be based on investigator assessments.

[0207] In some embodiments, PFS2 is defined as the time from the date of randomization to the date of second objective disease progression per IMWG, or death due to any cause, whichever occurs first. Second objective disease progression is PD after the start of subsequent anticancer therapy

[0208] In some embodiments, Best Overall Response (BOR) is assessed based on reported overall responses recorded at evaluation time points from the date of randomization until the first documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first.

[0209] • Objective Response encompasses confirmed sCR, CR, VGPR and PR.

[0210] • Clinical Benefit encompasses confirmed sCR, CR, VGPR, PR, and MR.

[0211] In some embodiments, Objective Response Rate (ORR) is defined as the proportion of participants with an objective response per IMWG criteria. Point estimates of ORR is calculated along with the 2-sided exact 95% Cis using the Clopper-Pearson method.

[0212] In some embodiments, VGPRR (> VGPR) is defined as the proportion of participants in the analysis population with a sCR / CR / VGPR per IMWG criteria. Point estimates of VGPRR is calculated along with the 2-sided exact 95% Cis using the Clopper-Pearson method.

[0213] In some embodiments, Complete Response Rate (CRR) is defined as the proportion of participants a sCR / CR per IMWG criteria. Point estimates of CRR is calculated along with the 2-sided exact 95% Cis using the Clopper-Pearson method.

[0214] In some embodiments, Duration of Response (DOR) is defined, for participants with an objective response per IMWG criteria, as the time from the first documentation of response that is subsequently confirmed, until confirmed PD per IMWG criteria, or death due to any cause, whichever occurs first. DOR is censored on the date of the last adequate disease assessment for participants who do not have an event (confirmed PD or death due to any cause), on the date of the last adequate disease assessment before the new anticancer therapy for participants who start a new anticancer therapy prior to an event, or on the date of the last adequate disease assessment before the 2 or more missing disease assessments for participants with an event after 2 or more missing disease assessments.

[0215] In some embodiments Duration of Complete Response (DOCR) is defined, for participants with a confirmed sCR or CR per IMWG criteria, as the time for the first documentation of sCR or CR that is subsequently confirmed, until confirmed PD per IMWG criteria, or death due to any cause, whichever occurs first. DOCR is censored on the date of the last adequate disease assessment for participants who do not have an event (confirmed PD or death due to any cause), on the date of the last adequate disease assessment before the new anticancer therapy for participants who start a new anticancer therapy prior to an event, or on the date of the last adequate disease assessment before the 2 or more missing disease assessments for participants with an event after 2 or more missing disease assessments.

[0216] In some embodiments Time to Response (TTR) is defined, for participants with an objective response per IMWG criteria, as the time from the date of randomization to the first documentation of response that is subsequently confirmed. TTR is summarized using mean, standard deviation, minimum, median, and maximum.

[0217] In some embodiments, MRD negativity rate is the proportion of participants in the analysis population with MRD negative status (CR or better by BICR per IMWG criteria and negative MRD by NGS) by BMA from the date of randomization until documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first. Point estimates of MRD negativity rate is calculated along with the 2-sided 95% Cis using the Clopper-Pearson method.

[0218] In some embodiments, Sustained MRD negativity rate for at least 12 months is the proportion of participants in the analysis population with MRD-negative status (CR or better by BICR per IMWG criteria and negative MRD by NGS) confirmed at least 12 months apart without positive MRD in between per IMWG criteria by BMA from the date of randomization until documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first. Point estimates of Sustained MRD negativity rate is calculated along with the 2-sided 95% Cis using the Clopper-Pearson method.

[0219] In some embodiments, Duration of MRD negativity is defined, for participants with an MRD-negative status (CR or better by BICR per IMWG criteria and negative MRD by NGS), as the time from the first documentation of MRD-negative status to the first documentation of relapse or death due to any cause. Relapse is defined as any one or more of the following criteria:

[0220] • Loss of MRD-negative status (evidence of clonal plasma cells on NGS or positive imaging study for recurrence of myeloma);

[0221] • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;

[0222] • Development of >5% clonal plasma cells in the bone marrow;

[0223] • Appearance of any other sign of progression.

[0224] Duration of MRD negativity is censored on the date of the last adequate disease assessment for participants who do not have an event (relapse or death), on the date of the last adequate disease assessment before the new anticancer therapy for participants who start a new anticancer therapy prior to an event, or on the date of the last adequate disease assessment before the 2 or more missing disease assessments for participants with an event after 2 or more missing disease assessments. Duration of MRD negativity is estimated using the Kaplan-Meier method and displayed graphically by treatment arm.

[0225] In some embodiments, the method of the treatment improves PFS, OS and / or MRD negativity rate of the subject relative to PFS, OS and / or MRD of a reference subject or a reference population of subjects.

[0226] In some embodiments, the method of the treatment results in an objective response rate of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100%.

[0227] In some embodiments, the method of the treatment results in progression-free survival of the subject of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, or at least about 120 months.

[0228] In some embodiments, the method of the treatment results in overall survival of the subject of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, at least about 48 months, at least about 54 months, at least about 60 months, at least about 66 months, at least about 72 months, at least about 78 months, at least about 84 months, at least about 90 months, at least about 96 months, at least about 102 months, at least about 108 months, at least about 114 months, at least about 120 months, at least about 126 months, at least about 132 months, at least about 138 months, at least about 144 months, at least about 150 months, at least about 156 months, or at least about 162 months.

[0229] In some embodiments, the method of the treatment results in duration of response of the subject of at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about eighteen months, at least about two years, at least about three years, at least about four years, or at least about five years.

[0230] In some embodiments, the method of treatment results in a MRD negativity rate of at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%. In some embodiments, the MRD negativity rate is at least about 55%. In some embodiments, the method of treatment results in a MRD negativity rate at 12 months of at least about 20%, at least about 25%, at least about 30%, at least about 35%. In some embodiments, the MRD negativity rate at 12 months is at least 30%.

[0231] In embodiments that refer to a method of treatment as described herein, such embodiments are also further embodiments of an anti-BCMA I anti-CD3 bispecific antibody for use in that treatment, or alternatively embodiments of the use of an anti-BCMA I anti-CD3 bispecific antibody in the manufacture of a medicament for use in that treatment.

[0232] The following examples of specific aspects for carrying out the present invention are offered for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0233] The foregoing description and following Examples detail certain specific embodiments of the disclosure and describes the best mode contemplated by the inventors. It will be appreciated, however, that no matter how detailed the foregoing may appear in text, the disclosure may be practiced in many ways and the disclosure should be construed in accordance with the appended claims and any equivalents thereof.

[0234] Although the disclosed teachings have been described with reference to various applications, methods, kits, and compositions, it will be appreciated that various changes and modifications can be made without departing from the teachings herein and the claimed disclosure below. The following examples are provided to better illustrate the disclosed teachings and are not intended to limit the scope of the teachings presented herein. While the present teachings have been described in terms of these exemplary embodiments, the skilled artisan will readily understand that numerous variations and modifications of these exemplary embodiments are possible without undue experimentation. All such variations and modifications are within the scope of the current teachings.

[0235] Sequences

[0236] Sequences for an anti-BCMA I anti-CD3 bispecific antibody provided herein are summarized in Table 1 below.

[0237] Table 1 :

[0238]

[0239]

[0240]

[0241] Sequences for daratumumab provided herein are summarized in Table 2 below.

[0242] Table 2:

[0243]

[0244]

[0245]

[0246]

[0247] EXAMPLES

[0248] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0249] Example 1 :

[0250] This study is a Phase 3, open-label, multi-center, randomized study to evaluate the efficacy and safety of elranatamab monotherapy versus the investigator’s choice of elotuzumab in combination with pomalidomide and dexamethasone (EPd) or pomalidomide in combination with bortezomib and dexamethasone (PVd) or carfilzomib in combination with dexamethasone (Kd) in participants with RRMM who have received at least 1 but no more than 4 prior lines of therapy including an anti-CD38 antibody and lenalidomide. Participants will have RRMM and be relapsed or refractory to the last anti-myeloma treatment regimen and will not have received previous treatment with a BCMA-directed therapy.

[0251] Considering that participants who will be enrolled in this study will have been previously treated with lenalidomide and an anti-CD38-antibody, pomalidomide in combination with bortezomib and dexamethasone (PVd) or carfilzomib in combination with dexamethasone (Kd) or elotuzumab in combination with pomalidomide and dexamethasone (EPd) were the standard regimens selected as the control arm for this study. These anti-CD38 antibody free regimens are consistent with panel / committee treatment recommendations which do not include rechallenge with daratumumab after front-line use and the use of sequential anti-CD38 antibodies is considered unlikely to be an appropriate option. The choice of the regimen for participants who will be randomized in Arm B is left at the investigator’s discretion depending on the previous lines of therapies and the participants’ comorbidities.

[0252] Arm A (elranatamab)

[0253] The elranatamab dosing regimen includes the 2 step-up priming doses of 12 mg on C1D1 and 32 mg on C1D4 followed by 76 mg QW through C1 (C1D8, C1D15, and C1D22), then 76 mg Q2W through Cycles 2 and 3, and then changing the dosing interval from Q2Wto Q4W starting C4D1.

[0254] Based on the totality of PK, PD, efficacy, and safety results of the C1071003 study, the recommended elranatamab dosing regimen is 76 mg QW for the first 6 cycles administered as a SC injection following the 2 step-up priming doses of 12 mg on C1D1 and 32 mg on C1D4. The 2 step-up priming doses are to mitigate the incidence and severity of CRS. Sufficient stimulation of cytokines with the first dose of 12 mg and a predictable timing and manageable CRS profile is achieved with the 2 step-up regimen.

[0255] The data from study C 1071003 indicated continued clinical benefit after switching to Q2W starting C7. Further reduction of the dosing interval to Q4W has been implemented in several elranatamab studies including C1071003 and C1071005. Simulations from a mechanistic model for > 6 months also indicated maintenance of responses following switch of the dosing regimen to Q2W similar to that observed under continuous QW dosing, and that further reduction to Q4W schedule will continue to maintain the clinical benefit.

[0256] Considering the rapid and durable responses achieved with elranatamab treatment with reduced dosing frequency, this study (C 1071032) will implement a regimen of 76 mg QW for C1, 76 mg Q2WforC2 and C3, followed by elranatamab 76 mg Q4WC4 onward. Simulations using an updated mechanistic model indicated generally similar efficacy (biochemical response rate) for this regimen with reduced dosing vs a regimen of 76 mg QWforC1-C6, 76 mg Q2W for C7-C12 for participants who achieved a PR or better response, followed by elranatamab 76 mg Q4W C13 onward. The reduced dosing aims at achieving and maintaining clinical benefit while potentially improving safety and patient convenience.

[0257] Elranatamab dosing schedule:

[0258]

[0259]

[0260] * At least 2 weekly (QW) consecutive doses must be completed prior to starting Q2W dosing. ** Elranatamab administration may continue on Q2W dosing schedule beyond Cycle 3 if there is evidence of persistent disease burden.

[0261] Premedication forCRS prophylaxis is required approximately 60 minutes (±15 minutes) prior to both priming doses (on C1 D1 and C1 D4) and the first full dose of elranatamab (on C1D8):

[0262] □ Acetaminophen 650 mg (or paracetamol 500 mg)*, oral or IV

[0263] □ Diphenhydramine 25 mg (or equivalent)*, oral or IV

[0264] □ Dexamethasone 20 mg (or equivalent)*, oral or IV

[0265] * Different but comparable doses due to local strength variations per local prescribing information are permissible.

[0266] Similar premedications for doses at other time points may be given at the discretion of the investigator.

[0267] Participants are required to be hospitalized and monitored for CRS / ICANS for at least 2 days for C1D1 dose for safety surveillance. For C1D4, 1 day hospitalization is optional and based on CRS / ICANS occurrence after first dose (C1 D1) per investigator’s discretion. If not hospitalized for C1 D4, participants should be instructed to remain within proximity of a healthcare facility for 24 hours.

[0268] Participants should be instructed to not drive for 48 hours after the administration of the Elranatamab priming doses. Participants should be counselled to seek urgent medical attention should signs or symptoms of CRS or neurological toxicity occur.

[0269] Elranatamab dosing at 32 mg and 76 mg on C1D4 and C1D8, respectively, should proceed only if the participant meets re-treatment criteria (Section 6.6.1.1). A minimum of 2 days should be maintained between the 2 step-up doses (C1D1 and C1D4), and a minimum of 3 days between the C1D4 dose and the first full dose (C1D8); a minimum of 6 days should be maintained between doses thereafter. Participants will receive study interventions until confirmed disease progression, unacceptable toxicity, withdrawal of consent, lost to follow-up or study termination.

[0270] Arm B

[0271] Arm B regimens will be administered in accordance with approved dosing regimens.

[0272] The below table summarises the study arms and duration.

[0273] >

[0274] >

[0275]

[0276] >

[0277]

[0278] Arm A, Elranatamab

[0279] Re-treatment Criteria

[0280] During a cycle: Re-treatment following interruption for treatment-related toxicity and for peripheral neuropathy (any causality) within a cycle should follow the dose modification guidance in the below Table.

[0281] At the start of a cycle: Re-treatment at the start of any new cycle should not occur until all of the following parameters have been met:

[0282] > ANC >1,000 / mm3

[0283] > Platelet count >25, 000 / mm3

[0284] > Recovery of treatment-related non-hematologic toxicities to baseline or Grade <1 severity > For any dosing day (at start of a cycle or during a cycle),

[0285] o no ongoing CRS or ICANS of any grade

[0286] o at least 2 weeks have lapsed from the time of complete resolution of signs and symptoms of serious infection o see Section 10.11.3 for participants with confirmed or presumed SARS-CoV-2 infection □ Recovery of treatment-emergent peripheral neuropathy to Grade <1 or baseline severity. □ During the initial 6 months of treatment, IgG >400 mg / dL (excluding the M-spike in participants with IgG myeloma), based on most recent available results, unless immunoglobulin replacement has been administered in the past 28 days.

[0287] Dose Interruptions / Delays

[0288] Doses may be held as needed until toxicity resolution. Appropriate follow-up assessments should be done until adequate recovery occurs as assessed by the investigator.

[0289] Missed doses will not be made up and cycles will not be extended to allow for missed doses. A minimum of 2 days should be maintained between the 2 step-up doses (C1D1 and C1 D4) and a minimum of 3 days between the C1 D4 dose and the first full dose (01 D8); a minimum of 6 days is required between doses thereafter.

[0290] 01 D1 will be based on Day 1 of elranatamab dosing. After 01 D4, for each cycle, if elranatamab cannot be administered on the planned day, it should be skipped until the next planned dose (e.g., if Day 15 cannot be administered within -1 / +3 days of planned dose, the dose should be skipped until Day 22).

[0291] Participants must receive both elranatamab priming doses before receiving the full elranatamab dose of 76 mg. If 01 D4 cannot be administered within the protocol defined window, elranatamab treatment may restart at the planned 01 D4 dose upon meeting the retreatment criteria. Upon re-treatment, if the 01 D4 dose was tolerable, the elranatamab dose should be increased to the full dose (76 mg) 4 days later, after which QW dosing with the full dose (76 mg) should continue until Q2Wis permitted (see Section 6.1.1).

[0292] If elranatamab treatment is interrupted for >2 weeks within the first cycle between the 32 mg priming dose and the first full dose (76 mg), the participant should be retreated with 32 mg elranatamab. If tolerable, the elranatamab dose can be escalated to 76 mg about 1 week later.

[0293] If re-treatment criteria are not met within 4 weeks (or within 8 weeks for Q4W regimen) of treatment interruption / delay, elranatamab should be permanently discontinued, unless the benefit / risk assessment per the investigator suggests otherwise, in agreement with the sponsor. In the event of a treatment interruption / delay lasting >4 weeks (or >8 weeks for Q4W regimen) for reasons other than treatment-related toxicity (e.g., elective surgery), treatment resumption will be decided in agreement with the sponsor.

[0294] Treatment interruption for >4 weeks due to serious infection (e.g., pneumonia) is permitted to allow for complete resolution prior to resuming study treatment. In participants who develop serious infections (regardless of causality), study treatment should resume no earlier than at least 2 weeks from the time of complete resolution of signs and symptoms of infection (as assessed by the investigator). Study treatment may be resumed earlier if there is evidence of increase in disease burden only in agreement with the Sponsor.

[0295] Dose Modifications for Elranatamab-Related Toxicity, and for Peripheral Neuropathy (all causality)

[0296] The dose modifications for elranatamab-related toxicities and peripheral neuropathy (all causality) are presented in Table 9. All dose modifications should be based on the worst preceding toxicity and must be recorded on the CRF.

[0297] Dose Modifications for Elranatamab-Related Toxicity and for Peripheral Sensory or Motor Neuropathy

[0298] <

[0299] <

[0300] < <

[0301]

[0302] < <

[0303]

[0304] a. Both elranatamab priming doses must be administered before the full elranatamab dose. If C1 D4 dosing is interrupted / delayed, elranatamab treatment may restart at the planned 32 mg C1 D4 dose upon meeting the retreatment criteria. If the 32 mg dose is tolerable, elranatamab should be increased to the full 76 mg dose 4 days later.

[0305] If after the C1 D4 priming dose a participant experiences a treatment-related AE that leads to dose interruption / delay (e.g., dose held on Cycle 1 Day 8), elranatamab treatment may restart at the same dose (32 mg) upon meeting the re-treatment criteria. If the 32 mg dose was tolerable, the elranatamab dose should be increased to 76 mg about 1 week later.

[0306] If elranatamab treatment is interrupted for >2 weeks within the first cycle between the 32 mg priming dose and the first full dose (76 mg), the participant should be retreated with 32 mg elranatamab. If tolerable, the elranatamab dose can be escalated to 76 mg about 1 week later. In case of ongoing CRS or ICANS of any grade on any dosing day, dosing will be held until CRS or ICANS resolution. Participants with recurrent, confirmed Grade 3 CRS or ICANS are to be permanently discontinued following consultation and confirmation with the Sponsor Severity of CRS and ICANS assessed according to ASTCT criteria (Lee et al, Biol Blood Marrow Transplant. 2019;25(4):625-38).

[0307] b. Grade 3 or 4 nausea, vomiting or diarrhea that does not improve to Grade < 2 despite maximal medical management has been initiated to require dose modification or permanent discontinuation.

[0308] c. Excludes lymphopenia which is expected based on the elranatamab mechanism of action. d. For thrombocytopenia: dosing can continue if platelet re-treatment criteria are met.

[0309] e. AEs graded per NCI CTCAE v5.0, except CRS and ICANS per ASTCT criteria (Lee et al, 2019).

[0310] f. Consider additional diagnostic work-up.

[0311] g. Excludes laboratory abnormalities that are not considered clinically relevant.

[0312] Dose Reductions

[0313] Dose reduction of elranatamab is not permitted; dose interruption is the primary method for managing elranatamab-related toxicities. Appropriate follow-up assessments should be done until adequate recovery occurs as assessed by the investigator.

[0314] Study Population

[0315] Key Inclusion Criteria:

[0316] □ Participants aged 18 years or older (or the minimum age of consent in accordance with local regulations if >18) at screening.

[0317] □ Prior diagnosis of MM (multiple myeloma) per IMWG criteria and previously received at least 1 but not more than 4 prior lines of therapy for MM including:

[0318] □ At least 2 consecutive cycles of an anti-CD38 antibody-containing regimen in any prior line AND

[0319] □ At least 2 consecutive cycles of a lenalidomide-containing regimen in any prior line □ Documented evidence of progressive disease or failure to achieve a response to last line of MM therapy based on investigator's determination of response by IMWG criteria.

[0320] □ Measurable disease based on IMWG criteria as defined by at least 1 of the following (assessed by central laboratory):

[0321] □ Serum M-protein (myeloma protein) >0.5 g / dL;

[0322] □ Urinary M-protein excretion >200 mg / 24 hours;

[0323] □ Serum involved immunoglobulin FLC (free light chain) >10 mg / dL (>100 mg / L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or

[0324] >1.65).

[0325] □ Corrected serum calcium <14 mg / dL (<3.5 mmol / L), or free ionized calcium <6.5 mg / dL (<1.6 mmol / L)

[0326] □ Adequate bone marrow function (ANC, platelets, hemoglobin)

[0327] □ ECOG (Eastern Cooperative Oncology Group) performance status <2.

[0328] Key Exclusion Criteria:

[0329] □ Plasma cell leukemia, Smoldering MM, Waldenstrom’s macroglobulinemia, Amyloidosis, POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin abnormalities) Syndrome, known CNS (central nervous system) involvement or clinical signs of myelomatous meningeal involvement, stem cell transplant within 12 weeks prior to enrollment, active GVHD (graft versus host disease) (other than Grade 1 skin involvement) or GVHD requiring treatment.

[0330] □ Active HBV (Hepatitis B virus), HCV (Hepatitis C virus), SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), HIV [human immunodeficiency virus], or any active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 21 days prior to enrollment. Treatment with systemic anti-infective agents must have completed at least 28 days prior to enrollment. Prophylactic use of systemic anti-infective agents is permitted. □ Ongoing Grade >3 peripheral sensory or motor neuropathy; history of GBS (Guillain- Barre syndrome) or GBS variants; history of any Grade >3 peripheral motor polyneuropathy.

[0331] □ Impaired cardiovascular function or clinically significant cardiovascular diseases within 6 months prior to enrollment, including LVEF (left ventricular ejection fraction) <40% as determined by ECHO (echocardiography) at screening.

[0332] □ Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ or Stage 0 / 1 malignancy with minimal risk of recurrence per investigator.

[0333] □ Known or suspected hypersensitivity to the study interventions or any of their excipients. □ Unresolved acute effects (excluding alopecia) of any prior therapy (not resolved to baseline severity or CTCAE Grade < 1).

[0334] □ Previous treatment with a BCMA-directed orCD3 (cluster of differentiation 3) redirecting therapy.

[0335] □ Individuals who have never achieved a response (partial response [PR] or better) with any treatment during the disease course.

[0336] □ Unable to receive a control therapy (must be able and willing to adhere to any applicable requirements per Single Reference Safety Document [SRSD] for at least one choice of control therapy, including contraceptive requirements, and must not meet the exclusions listed below for the choice of control therapy):

[0337] □ unable to receive PVd if any of the following are present:

[0338] □ Received prior pomalidomide therapy

[0339] □ Does not meet criteria for bortezomib retreatment, (i.e. , must not have progressive disease during treatment or within 60 days of the last dose of a bortezomib containing regimen)

[0340] □ Grade 1 peripheral neuropathy with pain or Grade >2 peripheral neuropathy as defined by NCI-CTCAE v5.0

[0341] □ Received a strong cytochrome P (CYP) 3A4 inducer within 5 half-lives prior to enrollment □ Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery (gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed, assuming no drug interaction potential).

[0342] □ unable to receive Kd if any of the following are present:

[0343] □ Received prior carfilzomib therapy

[0344] □ Uncontrolled hypertension

[0345] □ unable to receive EPd if any of the following are present:

[0346] □ Received prior pomalidomide therapy

[0347] □ Received prior elotuzumab therapy

[0348] □ Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery (gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed, assuming no drug interaction potential).

[0349] □ Live attenuated vaccines within 4 weeks of the first dose of study intervention;

[0350] □ Cumulative dose of corticosteroids equivalent to >140 mg of prednisone within the 14-day period before the first dose of study intervention;

[0351] □ Anti-myeloma drug therapy, within 14 days of the initiation of study intervention (includes dexamethasone). Bisphosphonate use permitted.

[0352] □ Impaired hepatic or renal function.

[0353] Previous administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Participation in studies of other investigational products (drug or vaccine) at any time during their participation in this study.

[0354] Objectives, Endpoints and Estimands

[0355]

[0356] >

[0357]

[0358]

[0359]

[0360]

[0361] Primary Estimand (PFS): treatment effect of the experimental arm (elranatamab, Arm A) on PFS based on BICR assessment per the IMWG response criteria compared to the control arm (EPd or PVd or Kd, Arm B) from randomization to the earliest of confirmed PD or death due to any cause.

[0362] The estimand has the following attributes:

[0363] > Population: Patients with RRMM, as defined by the inclusion and exclusion criteria to reflect the targeted population of the treatment.

[0364] > Variable: PFS defined as the time from randomization until confirmed PD based on BICR assessment per the IMWG criteria or death due to any cause, whichever occurs first.

[0365] > Intercurrent events: Adherence to randomized treatment assignment is not considered as an intercurrent event for this analysis. PFS data will be censored on the date of last adequate disease assessment for participants who do not have any event (confirmed PD based on BICR assessment per IMWG criteria or death due to any cause), for participants who start a new anticancer therapy prior to an event or for participants with an event after 2 or more missing disease assessments. Participants who do not have an adequate post-baseline disease assessment will be censored on the date disease assessment (i.e., <70 days after the date of randomization) in which case the death will be considered an event. > Population-level summary measure: HR for PFS and corresponding 2-sided 95% Cl based on Cox Proportional Hazards model stratified by the randomization strata and including data from all randomized participants.

[0366] Key Secondary Estimand (OS): treatment effect of the experimental arm (elranatamab, Arm A) on OS compared to the control arm (EPd or PVd or Kd, Arm B) from randomization to death due to any cause or the last known alive date.

[0367] The estimand has the following attributes:

[0368] > Population: Patients with RRMM, as defined by the inclusion and exclusion criteria to reflect the targeted population of the treatment.

[0369] > Variable: OS defined as the time from randomization until death due to any cause.

[0370] > Intercurrent event(s): Adherence to randomized treatment assignment is not considered as an intercurrent event for this analysis. Participants who have lost to follow-up or withdrew consent for survival follow-up but not known to have died are censored on the last known alive date. □ Population-level summary measure: HR for OS and corresponding 2-sided Cl for the HR calculated based on Cox’s Proportional Hazard model stratified by the randomization strata and including data from all randomized participants.

[0371] PFS is defined as the time from the date of randomization to date of confirmed PD per IMWG criteria or death due to any cause, whichever occurs first. PFS will be calculated in months as follows:

[0372] PFS (months) = (date of event or censoring- randomization date +1) 130.4375 Overall Survival (OS) is defined as the time from the date of randomization to date of death due to any cause. If a participant is loss of follow-up or withdrawal of consent but not known to have died at the time of the cutoff for analysis, then OS will be censored at the date of last contact. OS will be calculated in months as follows:

[0373] OS (months) = [date of death or censoring - date of randomization +1] / 30.4375 PFS by investigator has the same definition as the PFS by BICR above, except the timepoint disease assessments and determination of the date of confirmed PD will be based on investigator assessments.

[0374] PFS by investigator will be summarized similarly to PFS by BICR.

[0375] PFS2 is defined as the time from the date of randomization to the date of second objective disease progression by investigator assessment per IMWG, or death due to any cause, whichever occurs first. Second objective disease progression is PD after the start of subsequent anticancer therapy

[0376] BOR will be assessed based on reported overall responses recorded at evaluation time points from the date of randomization until the first documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first.

[0377] • Objective Response will encompass confirmed sCR, CR, VGPR and PR.

[0378] • Clinical Benefit will encompass confirmed sCR, CR, VGPR, PR, and MR.

[0379] ORR is defined as the proportion of participants with an objective response per IMWG criteria. Point estimates of ORR will be calculated along with the 2-sided exact 95% Cis using the Clopper-Pearson method. A Pearson test (un-stratified) and Cochran-Mantel-Haenszel test stratified by randomization strata will be used to compare ORR of Arm A versus Arm B.

[0380] VGPRR (> VGPR) is defined as the proportion of participants in the analysis population with a sCR / CRA / GPR per IMWG criteria. Point estimates of VGPRR will be calculated along with the 2-sided exact 95% Cis using the Clopper-Pearson method. A Pearson test (un-stratified) and Cochran-Mantel-Haenszel test stratified by randomization strata will be used to compare VGPRR of Arm A versus Arm B.

[0381] VGPRR by BICR and VGPRR by investigator will be summarized.

[0382] CRR is the proportion of participants in the analysis population with a sCR / CR per IMWG criteria. Point estimates of CRR will be calculated along with the 2-sided exact 95% Cis using the Clopper-Pearson method. A Pearson test (un-stratified) and Cochran-Mantel-Haenszel test stratified by randomization strata will be used to compare CRR of Arm A versus Arm B.

[0383] CRR by BICR and CRR by investigator will be summarized.

[0384] DOR is defined, for participants with an objective response per IMWG criteria, as the time from the first documentation of response that is subsequently confirmed, until confirmed PD per IMWG criteria, or death due to any cause, whichever occurs first. DOR will be censored on the date of the last adequate disease assessment for participants who do not have an event (confirmed PD or death due to any cause), on the date of the last adequate disease assessment before the new anticancer therapy for participants who start a new anticancer therapy prior to an event, or on the date of the last adequate disease assessment before the 2 or more missing disease assessments for participants with an event after 2 or more missing disease assessments.

[0385] DOR will be estimated using the Kaplan-Meier method and displayed graphically by treatment arm. The median DOR and associated 95% Cis will be presented by treatment arm.

[0386] DOR rates at different time points will be estimated with corresponding 2-sided 95% Cis. DOR by BICR and DOR by investigator will be summarized.

[0387] DOCR is defined, for participants with a confirmed sCR or CR per IMWG criteria, as the time for the first documentation of sCR or CR that is subsequently confirmed, until confirmed PD per IMWG criteria, or death due to any cause, whichever occurs first. DOCR will be censored on the date of the last adequate disease assessment for participants who do not have an event (confirmed PD or death due to any cause), on the date of the last adequate disease assessment before the new anticancer therapy for participants who start a new anticancer therapy prior to an event, or on the date of the last adequate disease assessment before the 2 or more missing disease assessments for participants with an event after 2 or more missing disease assessments.

[0388] DOCR by BICR and DOCR by investigator is summarized the same as DOR except for the subset of participants with sCR / CR.

[0389] TTR is defined, for participants with an objective response per IMWG criteria, as the time from the date of randomization to the first documentation of response that is subsequently confirmed. TTR will be summarized using mean, standard deviation, minimum, median, and maximum.

[0390] TTR by BICR and TTR by investigator will be summarized.

[0391] MRD negativity rate is the proportion of participants in the analysis population with MRD negative status (CR or better by BICR per IMWG criteria and negative MRD by NGS) by BMA from the date of randomization until documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first. Point estimates of MRD negativity rate will be calculated along with the 2-sided 95% Cis using the Clopper-Pearson method. A Pearson test (un-stratified) and Cochran-Mantel-Haenszel test stratified by randomization strata will be used to compare MRD negativity rate of Arm A versus Arm B.

[0392] Sustained MRD negativity rate for at least 12 months is the proportion of participants in the analysis population with MRD-negative status (CR or better by BICR per IMWG criteria and negative MRD by NGS) confirmed at least 12 months apart without positive MRD in between per IMWG criteria by BMA from the date of randomization until documentation of confirmed PD, death or start of new anticancer therapy, whichever occurs first. Point estimates of Sustained MRD negativity rate will be calculated along with the 2-sided 95% Cis using the Clopper-Pearson method. A Pearson test (un-stratified) and Cochran-Mantel-Haenszel test stratified by randomization strata will be used to compare Sustained MRD negativity rate of Arm A versus Arm B.

[0393] Duration of MRD negativity is defined, for participants with an MRD-negative status (CR or better by BICR per IMWG criteria and negative MRD by NGS), as the time from the first documentation of MRD-negative status to the first documentation of relapse or death due to any cause. Relapse is defined as any one or more of the following criteria:

[0394] • Loss of MRD-negative status (evidence of clonal plasma cells on NGS or positive imaging study for recurrence of myeloma);

[0395] • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;

[0396] • Development of >5% clonal plasma cells in the bone marrow;

[0397] • Appearance of any other sign of progression.

[0398] Duration of MRD negativity will be censored on the date of the last adequate disease assessment for participants who do not have an event (relapse or death), on the date of the last adequate disease assessment before the new anticancer therapy for participants who start a new anticancer therapy prior to an event, or on the date of the last adequate disease assessment before the 2 or more missing disease assessments for participants with an event after 2 or more missing disease assessments.

[0399] Duration of MRD negativity will be estimated using the Kaplan-Meier method and displayed graphically by treatment arm. The median duration of MRD negativity and associated 95% Cis will be presented by treatment arm. Duration of MRD negativity rates at different time points will be estimated with corresponding 2-sided 95% Cis.

[0400] The below tables provide IMWG MRD criteria and modified IMWG response criteria (adapted from Kumar et al, Lancet Oncol. 2016;17(8):e328-e46).

[0401] IMWG MRD Criteria:

[0402]

[0403] Modified IMWG Response Criteria:

[0404] < >

[0405]

[0406] < >

[0407] > <

[0408] >

[0409] > >

[0410] > <

[0411] >

[0412] > >

[0413] > > <

[0414] >

[0415] > >

[0416] > < > >

[0417]

[0418] >

[0419] >

[0420] > >

[0421] >

[0422] >

[0423] >

[0424] > > > >

[0425] >

[0426]

[0427] a All response categories require 2 consecutive assessments made any time before starting new therapy. Each category (except stable disease) will be considered unconfirmed until confirmatory test is performed. All categories (stable disease or better) require no known evidence of PD, new bone lesions or EM plasmacytomas if imaging studies were performed; imaging studies are not required to satisfy these response requirements except for requirement of FDG PET to confirm imaging plus MRD-negative.

[0428] b Bone marrow assessments do not need to be confirmed. Careful attention should be given to new positive immunofixation results appearing in participants who have achieved a CR, when the isotype is different. This often represents oligoclonal immune reconstitution and should not be confused with relapse; these bands typically disappear over time.

[0429] c Presence / absence of clonal cells on IHC / IF in the bone marrow is based upon the K / A ratio. An abnormal K / ratio by IHC / IF requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is K / A of >4:1 or <1 :2.

[0430] d Plasmacytoma measurements should be taken from the CT portion of the PET / CT, MRI scans or CT scans where applicable. Measurement of tumor size will be determined by the SPD.

[0431] e PD confirmation requires two consecutive assessments made at any time prior to the institution of any new anticancer therapy. If alternate therapy is started before confirming PD, any additional testing during subsequent therapy can be used to confirm PD. Participants will be considered to have PD if they meet the criteria for progression by a variable that was not considered measurable at baseline; however, for participants who had a measurable serum or urine M-spike at baseline, PD cannot be defined by increases in serum FLC alone.

[0432] f For PD, serum M-component increases of >1 g / dL are sufficient to define relapse if starting M-component is >5 g / dL.

[0433] Additional Notes:

[0434] □ If participants do not have measurable disease at baseline they can only be assessed for SD or PD.

[0435] □ Except for sCR, serum FLC levels should only be used for response assessment when both the serum and urine M-component levels are deemed not measurable at baseline (including at suspected CR).

[0436] □ In cases where SPEP is found to be unreliable (e.g., IgA, IgD myelomas) for M-protein assessment, quantitative immunoglobulin measurements are preferred for disease assessment; the same percentage changes apply as for serum M-protein. If used, quantitative immunoglobulin assessment must be used exclusively for a participant (i.e., quantitative immunoglobulin and SPEP cannot be used interchangeably for disease assessment of the same participant).

[0437] Risk Assessment

[0438] Elranatamab

[0439]

[0440] >

[0441]

[0442] >

[0443]

[0444] > >

[0445]

[0446] <

[0447]

[0448] Example 2

[0449] This study is an open-label, randomized study to evaluate the efficacy and safety of elranatamab in combination with lenalidomide (ER) in transplant-ineligible participants with newly diagnosed multiple myeloma (NDMM).

[0450] Elranatamab (E) and lenalidomide (R) are administered in the below schedule:

[0451] Step-up Dose period (D1-D14): E (SC): 12 mg D1, 32 mg D4, 76 mg D8.

[0452] C1+ (28-day cycle): E 76 mg SC Q2W for 6 cycles, 76 mg SC Q4W after at least 6 Q2W cycles (for participants who have achieved a PR or better persisting for >2 months) + R 25 mg PO D1-21.

[0453] The end of the study is defined as the date of the last study visit which is triggered by the total number of OS events required for the final OS analysis (unless there is mutual agreement with health authorities to end earlier).

[0454] Premedication forCRS prophylaxis is required approximately 60 minutes (±15 minutes) prior to the first 3 doses of elranatamab (both priming doses 12 mg and 32 mg) and the first full dose (76 mg) of elranatamab:

[0455] • Acetaminophen 650 mg (or paracetamol 500 mg)*

[0456] • Diphenhydramine 25 mg (or equivalent)*, oral or IV • Dexamethasone 20 mg (or equivalent)*, oral or IV

[0457] • Different but comparable doses due to local strength variations per local prescribing information are permissible.

[0458] Participants are required to be hospitalized and monitored forCRS / ICANS for 2 days for the first Priming Dose (12 mg) and 1 day for the second Priming Dose (32 mg). Hospitalization for the duration of the Priming Dose Period (5 days) may be considered. Outpatient medical observation can be considered part of hospitalization time.

[0459] Participants will receive SC administration of elranatamab. The initial priming doses of elranatamab will be 12 mg and 32 mg and will serve as the 2 step-up priming regimen. The dose of elranatamab should be increased to the full dose (76 mg) as long as the participant meets the criteria. If a participant does not meet these criteria, initiation of dosing with 76 mg will be deferred until the criteria are met.

[0460] A minimum of 2 days should be maintained between the first Priming Dose (12 mg) and the second Priming Dose (32 mg), and a minimum of 3 days between the second Priming Dose and the first full dose 76 mg; a minimum of 6 days will be maintained between doses thereafter.

[0461] Lenalidomide will be prepared and administered according to instructions in the current Revlimid Prescribing Information.

[0462] When lenalidomide is administered on the same day as other study interventions, the order of lenalidomide administration will follow local practice.

[0463] Participants should take their oral doses of lenalidomide without regard to food.

[0464] Inclusion Criteria

[0465] Participants must meet the following inclusion criteria to be eligible for enrollment into the study. Criteria are for both Part 1 and Part 2 unless otherwise specified:

[0466] Age and Sex:

[0467] • Participant’s age >18 years (or the minimum country specific age of consent if >18) at Visit 1 (Screening).

[0468] Type of Participant and Disease Characteristics:

[0469] • Diagnosis of multiple myeloma (MM) as defined according to IMWG criteria.

[0470] • Measurable disease based on IMWG criteria as defined by at least 1 of the following (as assessed by the central laboratory for Part 2):

[0471] • Serum M-protein >0.5 g / dL;

[0472] • Urinary M-protein excretion >200 mg / 24 hours;

[0473] • Involved free light chain (FLC) >10 mg / dL (>100 mg / L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).

[0474] • Part 1 only: Participant with NDMM or RRMM. NDMM participant must be transplant- ineligible as defined by age >65 years or transplant-ineligible as defined by age <65 years with comorbidities impacting the possibility of transplant. Participants with RRMM must have received 1-2 prior lines of MM therapy including at least one immunomodulatory drug (I MiD) and one proteasome inhibitor (PI).

[0475] • Eastern Cooperative Oncology Group (ECOG) performance status <2.

[0476] • Adequate hepatic, renal, and bone marrow (BM) function (absolute neutrophil count [ANC], platelet count, hemoglobin).

[0477] • Corrected serum calcium <14 mg / dL (<3.5 mmol / L), or free ionized calcium <6.5 mg / dL (<1.6 mmol / L).

[0478] • Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade <1 (Part 1 only).

[0479] Exclusion Criteria

[0480] Medical Conditions:

[0481] • Smoldering MM.

[0482] • Monoclonal gammopathy of undetermined significance (MGLIS).

[0483] • Plasma cell leukemia.

[0484] • Waldenstrom’s Macroglobulinemia.

[0485] • Systemic light chain amyloidosis.

[0486] • Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin abnormalities (POEMS) Syndrome.

[0487] • Impaired cardiovascular function or clinically significant cardiovascular diseases within 6 months prior to enrollment.

[0488] • Ongoing Grade 3 or higher peripheral sensory or motor neuropathy, history of Guillain-Barre syndrome (GBS) or GBS variants, or history of any Grade >3 peripheral motor polyneuropathy.

[0489] • Active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) coronavirus disease 2019 (COVID- 19) / severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis B virus (HBV), hepatitis C virus (HCV), and known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness. Active infections must be resolved at least 21 days prior to enrollment. Participants treated with systemic therapeutic anti-infective agents within 28 days prior to enrollment are not eligible. Prophylactic use of systemic antimicrobial agents is permitted.

[0490] • Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ, or Stage 0 / 1 with minimal risk of recurrence per investigator. • Participants with known or suspected hypersensitivity to the study interventions or any of their excipients.

[0491] • Participants with known or suspected central nervous system (CNS) or clinical signs of myelomatous meningeal involvement.

[0492] • Other surgical (including major surgery within 14 days prior to enrollment), medical or psychiatric conditions including recent (within the past year) or active suicidal ideation / behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.

[0493] • Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery that may significantly alter the absorption of oral drugs. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed (assuming no drug interaction potential).

[0494] Prior / Concomitant Therapy:

[0495] • Part 1 only:

[0496] • Previous treatment with a BCMA-directed therapy, anti-CD38-directed therapy within 6 months preceding the first dose of study intervention in this study, or refractory to prior anti-CD38-directed therapy (disease progression while on therapy or within 60 days of the last dose of therapy or participants who have not achieved at least a minimal response (MR) on prior anti-CD38-directed therapy).

[0497] • Primary refractory MM, defined as participants who have never achieved at least a MR with any prior anti-MM therapy based on investigator assessment using IMWG criteria.

[0498] • Stem cell transplant <3 months prior to first dose of study intervention or active graft versus host disease (GVHD).

[0499] • Participants who are unable to tolerate lenalidomide, or discontinued prior lenalidomide due to treatment-related toxicity (Part 1 only).

[0500] • Previous systemic treatment for MM except for a short course of corticosteroids (i.e. , total of 160 mg dexamethasone or equivalent before the first dose of study intervention). A cumulative dose of systemic corticosteroids equivalent to >20 mg of dexamethasone during screening.

[0501] • Live attenuated vaccine administered within 4 weeks of the first dose of study intervention. Prior / Concurrent Clinical Study Experience:

[0502] • Administration of investigational product (e.g., drug or vaccine) concurrent with study intervention or within 30 days (or as determined by the local requirement) preceding the first dose of study intervention used in this study. Elranatamab

[0503] Treatment Criteria

[0504] During a cycle: Re-treatment following interruption for treatment-related toxicity and for peripheral neuropathy (any causality) within a cycle should follow the dose modification guidance.

[0505] At the start of a cycle: Treatment at the start of any new cycle should not occur until all of the following parameters have been met:

[0506] • ANC >1 x 109 / L

[0507] • Platelet count >25 x 109 / L

[0508] • Recovery of treatment-related non-hematologic toxicities to baseline or Grade <1 severity

[0509] • For any dosing day (at start of a cycle or during a cycle), no ongoing CRS or ICANS of any grade

[0510] • Recovery of treatment-emergent peripheral neuropathy to Grade <1 severity

[0511] • Pneumonia / lung infection or other serious infection should be completely resolved to baseline for at least 2 weeks before dosing

[0512] • From first dose of study intervention up to and including the start of C6, functional* IgG >400 mg / dL (*excluding the M-spike in participants with IgG myeloma) on the most recent assessment unless immunoglobulin replacement has been administered in the past 28 days.

[0513] Dose Interruptions / Delays

[0514] A minimum of 2 days should be maintained between the first Priming Dose (12 mg) and the second Priming Dose (32 mg) and a minimum of 3 days between the second Priming Dose and the first full dose (76 mg); a minimum of 6 days is required between doses thereafter.

[0515] C1 D1 will be based on the 4thplanned dose of elranatamab (i.e., 14 days after the first Priming Dose [12 mg]) and should be the start of elranatamab dosing in combination with other study interventions. Missed doses will not be made up and cycles will not be extended to allow for missed doses.

[0516] Elranatamab administration schedule

[0517] > > >

[0518]

[0519] Participants must receive both elranatamab step-up priming doses before receiving the full (76 mg) elranatamab dose. If the second Priming Dose (32 mg) cannot be administered within the protocol defined window, elranatamab treatment may restart at the planned 32 mg dose upon meeting the re-treatment criteria. Upon re-treatment, if the 32 mg dose was tolerable, the elranatamab dose should be increased to 76 mg 4 days later. The first full dose (76 mg) of elranatamab must be given before administering elranatamab with other combination study therapy.

[0520] If elranatamab treatment is interrupted for >2 weeks within the Priming Period between the 32 mg priming dose and the first full dose, the participant should be retreated with 32 mg elranatamab. If tolerable, the elranatamab dose can be escalated to 76 mg about one week later.

[0521] If re-treatment criteria are not met within 8 weeks (12 weeks if on Q4W) of treatment interruption / delay due to treatment related toxicity or any other reason (e.g., elective surgery), treatment resumption will be decided in consultation with the Sponsor. For participants meeting re-treatment criteria, the decision to resume therapy will be based on a benefit-risk assessment.

[0522] Treatment interruption for >8 weeks due to severe or serious infections (e.g., pneumonia / lung infection) is permitted to allow for complete resolution prior to resuming study treatment. In participants who develop infections (regardless of causality), treatment with elranatamab should resume no earlier than at least 2 weeks from the time of complete resolution of signs and symptoms of infection (as assessed by the investigator). Study treatment may be resumed earlier if there is evidence of increase in disease burden.

[0523] Dose Modifications for Elranatamab-Related Toxicity

[0524] The dose modifications for elranatamab-related toxicities are presented below. All dose modifications should be based on the worst preceding toxicity and must be recorded on the CRF.

[0525] Switching to a less frequent dosing schedule can be considered for the management of elranatamab-related toxicity. Dose Modifications for Elranatamab-Related Toxicity and for Peripheral Sensory or Motor Neuropathy

[0526] <

[0527] <

[0528] < <

[0529] < <

[0530]

[0531] Dose Modifications for Elranatamab-Related Toxicity and for Peripheral Sensory or Motor Neuropathy

[0532]

[0533] a. Both elranatamab priming doses must be administered before the full elranatamab dose. If the second Priming Dose (32 mg) is interrupted / delayed, elranatamab treatment may restart at the planned 32 mg dose upon meeting the re-treatment criteria. If the 32 mg dose is tolerable, elranatamab should be increased to the full 76 mg dose 4 days later. If after the second Priming Dose (32 mg), a participant experiences a treatment-related AE that leads to dose interruption / delay (i.e., dose held on the day of the planned first full dose), elranatamab treatment may restart at the same dose (i.e., 32 mg) upon meeting the re-treatment criteria. If elranatamab treatment is interrupted for >2 weeks within the Priming Period between the 32 mg priming dose and the first full dose (76 mg), the participant should be retreated with 32 mg elranatamab. If tolerable, the elranatamab dose can be escalated to the first full dose (76 mg) about one week later.

[0534] In case of ongoing CRS or ICANS of any grade on any dosing day, dosing will be held until CRS or ICANS resolution. Severity of CRS and ICANS assessed according to ASTCT criteria. Participants with recurrent, confirmed Grade 3 CRS or ICANS are to be permanently discontinued following consultation with the Sponsor.

[0535] b. Grade 3 or 4 nausea, vomiting or diarrhea that does not improve to Grade 2 despite maximal medical management must occur to require dose modification or permanent discontinuation.

[0536] c. Excludes lymphopenia which is expected based on the elranatamab mechanism of action. d. For thrombocytopenia: dosing can continue if platelet re-treatment criteria, depending on treatment regimen, are met.

[0537] e. AEs graded per NCI CTCAE v5.0.

[0538] f. Consider additional diagnostic work-up

[0539] g. Excludes laboratory abnormalities that are not considered clinically relevant.

[0540] Lenalidomide

[0541] Treatment Criteria

[0542] During a cycle: Re-treatment following interruption for treatment-related toxicity and for peripheral neuropathy (any causality) within a cycle should follow the dose modification tables and guidance below.

[0543] At the start of a cycle: Treatment at the start of any new cycle should not occur until all of the following parameters have been met:

[0544] • ANC >1 x 109 / L • Platelet count >30 x 109 / L

[0545] • Recovery of treatment-related non-hematologic toxicities to baseline or Grade <1 severity

[0546] • For any dosing day (at start of a cycle or during a cycle), no ongoing CRS or ICANS of any grade

[0547] • For Part 1 and Part 2 Arm A, pneumonia / lung infection or other serious infection should be completely resolved to baseline for at least 2 weeks before dosing

[0548] • For Part 1 and Part 2 Arm A, from first dose of study intervention up to and including the start of 06, functional* IgG levels >400 mg / dL (*excluding the M-spike in participants with IgG myeloma) on the most recent assessment unless immunoglobulin replacement has been administered in the past 28 days.

[0549] Dose Modifications for Lenalidomide-Related Hematological Toxicity

[0550] Dose modifications for lenalidomide (i.e. , for Grade 3 or 4 neutropenia, thrombocytopenia, other Grade 3 or 4 toxicities judged to be related to lenalidomide) are permitted per manufacturer’s guidelines. Dose modifications in case of thrombocytopenia are outlined below for NDMM and for RRMM. Dose modification in case of neutropenia are outlined below for NDMM and for RRMM.

[0551] Lenalidomide Dose Adjustment for Thrombocytopenia for NDMM

[0552] < >

[0553]

[0554] a. If DLT occurs on >day 15 of a cycle, lenalidomide dosing will be interrupted for at least the remainder of the current 28-day cycle.

[0555] Lenalidomide Dose Adjustment for Thrombocytopenia for RRMM

[0556] < >

[0557] <

[0558]

[0559] Lenalidomide Dose Adjustment for Thrombocytopenia for RRMM

[0560] >

[0561]

[0562] Lenalidomide Dose Adjustment for Neutropenia for NDMM

[0563] <

[0564] >

[0565] >

[0566]

[0567] a. At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide.

[0568] Lenalidomide Dose Adjustment for Neutropenia for RRMM

[0569] <

[0570] >

[0571] >

[0572]

[0573] Lenalidomide Dose Adjustment for Neutropenia for RRMM

[0574]

[0575] a. At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of lenalidomide.

[0576] Dose Modifications for Lenalidomide-Related Non-Hematological Toxicity

[0577] 1) For non-hematological Grade 3 or 4 toxicities judged to be related to lenalidomide, hold treatment and restart at the investigator’s discretion at next lower dose level when toxicity has resolved to Grade 2 or below.

[0578] 2) Grade 2 or 3 skin rash. Lenalidomide interruption or discontinuation should be considered.

[0579] Lenalidomide must be discontinued for angioedema, anaphylactic reaction, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation from these reactions.

[0580] 3) Renal impairment. Lenalidomide dose adjustment should be instituted for participants with a creatinine clearance <60 mL / min. If creatinine clearance is between 30 and 60 mL / min, the dose of lenalidomide will be 10 mg QD. Once the creatinine clearance is >60 mL / min during the course of the treatment, lenalidomide can be increased to 25 mg.

[0581] 4) Peripheral neuropathy. For Grade >2 peripheral neuropathy, at the investigator’s discretion, consider reducing the dose of lenalidomide to the next lower dose level.

[0582] Treatment interruption for >8 weeks due to severe or serious infections (e.g., pneumonia / lung infection) is permitted to allow for complete resolution prior to resuming study treatment. In participants who develop infections (regardless of causality), treatment with lenalidomide should resume no earlier than at least 2 weeks from the time of complete resolution of signs and symptoms of infection (as assessed by the investigator). Treatment may be resumed earlier if there is evidence of increase in disease burden only in agreement with the Sponsor.

[0583] Dose Modifications and Dose Reductions for Lenalidomide

[0584] All dose modifications should be based on the worst preceding toxicity.

[0585] If lenalidomide cannot be administered on the planned day, it should be held until treatment criteria are met. If the 21 days of lenalidomide are not administered due to interruptions, lenalidomide should restart as planned with Day 1 of the next cycle. Missed lenalidomide doses will not be made up and cycles will not be extended to allow for missed doses.

[0586] Permitted dose reductions for lenalidomide are outlined below. Once a dose has been reduced for a given participant, all subsequent doses should be administered at that dose level unless: 1) further dose reduction is required; or 2) dose reescalation is agreed. Dose Levels for Lenalidomide

[0587]

[0588] Information.

[0589] Objectives, Endpoints and Estimands

[0590]

[0591]

[0592]

[0593] *DLTs will not be evaluated in a Dose Level that represent a lower dose level than an already cleared DL, or where the initial DLT period is the same as an already cleared DL.

[0594] The below tables provide IMWG MRD criteria and modified IMWG response criteria (adapted from Kumar et al, Lancet Oncol. 2016;17(8):e328-e46).

[0595] IMWG MRD Criteria

[0596]

[0597] Modified IMWG Response Criteria

[0598] <

[0599] > <

[0600] >

[0601] >

[0602] > > <

[0603] > > > < >

[0604]

[0605] Modified IMWG Response Criteria

[0606] >

[0607] > > >

[0608] > >

[0609] >

[0610] > > > >

[0611] >

[0612]

[0613] a All response categories require 2 consecutive assessments made any time before starting new therapy. Each category (except stable disease) will be considered unconfirmed until confirmatory test is performed. All categories (stable disease or better) require no known evidence of PD, new bone lesions or EMD plasmacytomas if imaging studies were performed; imaging studies are not required to satisfy these response requirements except for requirement of FDG PET to confirm imaging plus MRD-negative.

[0614] b Bone marrow assessments do not need to be confirmed. Careful attention should be given to new positive immunofixation results appearing in participants who have achieved a CR, when the isotype is different. This often represents oligoclonal immune reconstitution and should not be confused with relapse; these bands typically disappear overtime. Modified IMWG Response Criteria

[0615]

[0616] c Presence / absence of clonal cells is based upon the K / A ratio. An abnormal K / A ratio by IHC or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is K / A of >4:1 or <1 :2.

[0617] d Plasmacytoma measurements should be taken from the CT portion of the PET / CT, or dedicated CT scans where applicable. Measurement of tumor size will be determined by the SPD.

[0618] e PD confirmation requires two consecutive assessments with the initial PD prior to the initiation of any new anticancer therapy. Participants will be considered to have PD if they meet the criteria for progression by a variable that was not considered measurable at baseline; however, for participants who had a measurable serum or urine M-spike at baseline, PD cannot be defined by increases in serum FLC alone.

[0619] f For PD, serum M-component increases of >1 g / dL are sufficient to define relapse if starting M-component is >5 g / dL.

[0620] Additional notes:

[0621] • If participants do not have measurable disease at baseline they can only be assessed for CR or PD.

[0622] • Except for sCR, serum FLC levels should only be used for response assessments when both the serum and urine M-component levels are deemed not measurable or uninterpretable.

[0623] • In cases where SPEP is found to be unreliable (e.g., IgA, IgD myelomas) for M- protein assessment, quantitative immunoglobulin measurements are preferred for disease assessment; the same percentage changes apply as for serum M-protein. If used, quantitative immunoglobulin assessment must be used exclusively for a participant (i.e. , quantitative immunoglobulin and SPEP cannot be used interchangeably for disease assessment of the same participant).

[0624] Risk Assessment

[0625]

[0626]

[0627] >

[0628]

[0629] >

[0630]

[0631]

[0632]

[0633]

[0634] Example 3

[0635] This study is a Phase 3, open-label, 3-arm, multicenter, randomized study to evaluate the efficacy and safety of elranatamab monotherapy and elranatamab + daratumumab versus control (daratumumab + pomalidomide + dexamethasone) in participants with RRMM who have received at least 1 prior line of therapy, but not more than 3, including lenalidomide and a PI. Participants will not have received previous treatment with a B-cell maturation antigen (BCMA)-directed therapy, cluster of differentiation 3 (CD3)-redirecting therapy or pomalidomide.

[0636] Participants who have received anti-cluster of differentiation 38 (CD38)-directed therapy within 6 months preceding first dose of study treatment or who have disease determined to be refractory to anti-CD38-directed therapy at any time will be excluded. Part 1 will precede the randomized component of the study and will be conducted in a minimum of 20 participants to assess the safety of an elranatamab priming regimen that includes premedication and 2 step-up priming doses to be administered within the first week of elranatamab treatment (on days 1 and 4). In addition, Part 1 will evaluate the safety, tolerability, PK, pharmacodynamic (PD), and preliminary efficacy of the RP3D of elranatamab + daratumumab in up to 20 participants. Part 1 of the study includes 2 elranatamab dose levels to be evaluated sequentially. Part 1 will enroll participants who have received at least 3 prior lines of therapy including lenalidomide and a PI. Part 1 participants will not have received anti-CD38-directed therapy within 6 months preceding this study or previous treatment with a BCMA-directed or CD3-redirecting therapy. The RP3D for elranatamab + daratumumab will be selected for Arm B of Part 2 based on an assessment of the totality of the available data including safety, tolerability, PK, PD, and preliminary anti-myeloma activity data.

[0637] In Part 2, approximately 730 participants will be enrolled using a 1:1:1 randomization ratio, stratified by prior lines of therapy (1 vs 2-3) and prior treatment with anti-CD38-directed therapy (yes vs no). In Part 2 the enrollment of participants who have previously received any anti-CD38-directed therapy will be restricted to a maximum of 25%. Part 2 of this study is designed to test the hypothesis for Arm A versus Arm C with a 1 -sided alpha of 0.025. The Arm B versus Arm C analyses will be exploratory and descriptive. The primary objective is to compare PFS of elranatamab monotherapy versus control, as assessed by BICR using IMWG criteria. After close of enrollment for Part 2 Arm B per E-DMC recommendation, enrollment will complete using 1:1 randomization for Arms A and C.

[0638] In response to an External Data Monitoring Committee (E-DMC) recommendation for this study and prior to completion of Part 2 enrollment, enrollment in the elranatamab plus daratumumab treatment arm (Arm B) was closed and daratumumab treatment in Arm B in ongoing participants with less than 4 months of combination study treatment (participants with a next scheduled dose of daratumumab in Cycles 1 to 3) was discontinued (participants could continue elranatamab monotherapy). Arm B participants who completed at least 3 months of study treatment (participants with a next scheduled dose of daratumumab in Cycle 4 or greater) could continue to receive combination treatment (elranatamab + daratumumab) as planned. Enrollment and ongoing treatment in Arms A and C and continue as planned. All Part 1 participants had completed at least three months of study treatment and continue to receive combination treatment (elranatamab + daratumumab) as planned. The changes to study conduct recommended by the E-DMC were based on data in which Arm B showed evidence of increased early (Cycles 1 to 3) mortality relative to Arm C. Most of the deaths in Arm B were due to serious infections, including pneumonia, with a majority of the events being due to COVID-19 infection. Additional risk minimization measures for serious infections, including COVID-19 monitoring, have been incorporated into the protocol since enrollment of Part 2 Arm B.

[0639] In Part 3, the effect of enhanced risk minimization measures, including required infection prophylaxis from the initiation of study treatment, will be assessed in 2 arms: elranatamab monotherapy (Arm D) and elranatamab + daratumumab (Arm E). Arms D and E will enroll approximately 50 and 100 participants, respectively. Participants in both arms previously received 1 to 3 prior lines of therapy including lenalidomide. Arm D participants previously also received a prior anti-CD38-directed therapy, while Arm E participants may have previously received a prior anti-CD38-directed therapy if not refractory to it.

[0640] A sponsor safety review team will review cumulative safety data throughout the study. This study will use an E-DMC for Parts 2 and 3. The E-DMC is independent of the study team and includes only external members.

[0641] BICR will evaluate disease response for Part 2.

[0642] This study will also use a Steering Committee (consisting of both sponsor representatives and at least 2 participating investigators).

[0643] Number of Participants

[0644] The planned sample size of the study is approximately 914 enrolled participants including 34 participants in Part 1, approximately 730 participants in Part 2 and approximately 150 participants in Part 3.

[0645] Study Population

[0646] Key inclusion and exclusion criteria are listed below.

[0647] Key Inclusion Criteria:

[0648] • Participants age > 18 years (or the minimum country-specific age of consent if >18).

[0649] • Prior diagnosis of MM as defined according to IMWG criteria.

[0650] • Measurable disease based on IMWG criteria as defined by at least 1 of the following:

[0651] - Serum M-protein >0.5 g / dL;

[0652] - Urinary M-protein excretion >200 mg / 24 hours;

[0653] - Serum immunoglobulin FLC >10 mg / dL (>100 mg / L) AND abnormal serum immunoglobulin kappa to lambda FLC ratio (<0.26 or >1.65).

[0654] • Prior anti-MM therapy:

[0655] - Part 1 : At least 3 prior lines of anti-MM therapy including treatment with lenalidomide and a PI.

[0656] - Part 2: At least 1 , but not more than 3, prior lines of anti-MM therapy including treatment with lenalidomide and a PI. A response of MR or better must have been achieved with any prior anti-MM therapy based on investigator assessment using IMWG criteria.

[0657] - Part 3 Arm D: At least 1 , but not more than 3, prior lines of anti-MM therapy including treatment with lenalidomide and an anti-CD38-directed therapy:

[0658] o At least 2 consecutive cycles of a lenalidomide-containing regimen in any prior line. o At least 2 consecutive cycles of an anti-CD38-directed therapy-containing regimen in any prior line.

[0659] A response of PR or better must have been achieved with any prior anti-MM therapy based on investigator assessment using IMWG criteria.

[0660] Documented evidence of progressive disease or failure to achieve a response to last line of MM therapy based on investigator's determination of response per IMWG criteria. - Part 3 Arm E: At least 1 , but not more than 3, prior lines of anti-MM therapy including treatment with lenalidomide:

[0661] o At least 2 consecutive cycles of a lenalidomide-containing regimen in any prior line A response of PR or better must have been achieved with any prior anti-MM therapy based on investigator assessment using IMWG criteria.

[0662] Documented evidence of progressive disease or failure to achieve a response to last line of MM therapy based on investigator's determination of response per IMWG criteria.

[0663] • ECOG performance status s2.

[0664] • LVEF >40% as determined by a MLIGA scan or ECHO.

[0665] • Adequate hepatic, renal and bone marrow function.

[0666] • Corrected serum calcium <14 mg / dL (<3.5 mmol / L), or free ionized calcium <6.5 mg / dL (<1.6 mmol / L).

[0667] • Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade <1.

[0668] Key Exclusion Criteria:

[0669] • Smoldering MM.

[0670] • Plasma cell leukemia.

[0671] • Amyloidosis, Waldenstrom’s macroglobulinemia, or POEMS Syndrome.

[0672] • Known active CNS involvement or clinical signs of myelomatous meningeal involvement. • Stem cell transplant within 12 weeks prior to enrollment, active GVHD (other than Grade 1 skin involvement), or GVHD requiring treatment.

[0673] • Impaired cardiovascular function or clinically significant cardiovascular diseases within 6 months prior to enrolment.

[0674] • Ongoing Grade 3 or higher peripheral sensory or motor neuropathy. • History of GBS or GBS variants, or history of any Grade >3 peripheral motor polyneuropathy.

[0675] • Active HBV, HCV, SARS-CoV-2, HIV, or any active, uncontrolled bacterial, fungal, or viral infection. Active infections must be resolved at least 21 days prior to enrollment. Treatment with systemic anti-infective agents must have completed at least 28 days prior to enrollment. Prophylactic use of systemic agents is permitted.

[0676] • Lung imaging is required within 7 days prior to enrollment. Participants with evidence of active respiratory infection are excluded.

[0677] • Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ, or Stage 0 / 1 malignancy with minimal risk of recurrence per investigator.

[0678] • Participants with known or suspected hypersensitivity to the study interventions or any of their excipients.

[0679] • Other surgical (including major surgery within 14 days prior to enrollment), medical (including gastrointestinal disease that may significantly alter the absorption of pomalidomide) or psychiatric conditions including recent (within the past year) or active suicidal ideation / behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the • Previous treatment with a BCMA-directed therapy or a CD3-redirecting therapy.

[0680] • Parts 1 and 2: Anti-CD38-directed therapy within 6 months preceding the first dose of treatment in this study.

[0681] • Part 2: Refractory to prior anti-CD38-directed therapy (disease progression while on or within 60 days of the last dose of any anti-CD38-directed therapy or failure to achieve at least MR).

[0682] Part 3 Arm E: Refractory to prior anti-CD38-directed therapy (disease progression while on or within 60 days of the last dose of any anti-CD38-directed therapy). Participants treated with an induction regimen containing an anti-CD38-directed therapy may be eligible if nonrefractory.

[0683] • Part 2: Previous pomalidomide therapy.

[0684] • Part 2: Concurrent or anticipated use of a non-topical medication known to be a strong CYP1A2 inhibitor, or use of >10 mg QD prednisone (or equivalent) within 14 days or 5 halflives (whichever is longer) of the first dose of study intervention.

[0685] Part 3: Cumulative dose of corticosteroids equivalent to >140 mg of prednisone within the 14-day period before the first dose of study intervention.

[0686] Part 3: Anti-myeloma drug therapy within 14 days of the first dose of study intervention (includes dexamethasone). Bisphosphonate use permitted. • Live attenuated vaccine must not be administered within 4 weeks of the first dose of study intervention.

[0687] • Concomitant Therapy.

[0688] • Administration of an investigational product (e.g., drug or vaccine) concurrent with study intervention or within 30 days preceding the first dose of study intervention used in this study. A participant may be eligible if they are in the follow-up phase of an investigational study if they meet the criterion for time elapsed from previous administration of investigational product. Cases must be discussed with sponsor’s medical monitor to judge eligibility.

[0689] • For women of childbearing potential: Pregnancy test positive at screening.

[0690] • Part 2: Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery. Gastroesophageal reflux disease under treatment with proton pump inhibitors is allowed (assuming no drug interaction potential).

[0691] Study Arms and Duration

[0692] All participants are expected to receive study intervention until confirmed disease progression, withdrawal of consent, lost to follow-up, or unacceptable toxicity.

[0693] The final analysis of OS for Part 2 will occur once the required number of events have been observed supporting the key secondary objective. This is expected to occur approximately 51 months after the first participant is randomized in Part 2.

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[0700] Objectives and Endpoints

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[0707]

Claims

CLAIMSIt is claimed:

1. A method of treating a cancer in a patient, the method comprising administering an anti-BCMA I anti-CD3 bispecific antibody to the patient, wherein the antibody is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises: (a) 14 days, and wherein the antibody is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle; or (b) 28 days, and wherein the antibody is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 and 15, and optionally 22, of the first cycle;and wherein following the first cycle (a) or (b) the antibody is administered for at least two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W) or less frequently; and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W) or less frequently.

2. The method of claim 1, wherein the antibody is administered at a dose of about 76 mg Q2W in the at least two 28-day treatment cycles, optionally wherein the antibody is administered on days 1 and 15 of the at least two 28-day treatment cycles.

3. The method of claim 2, wherein the antibody is administered at a dose of about 76 mg Q2W for two, three, four, five or six 28-day treatment cycles.

4. The method of claim 1 , wherein the antibody is administered at a dose of about 76 mg Q4W in the at least two 28-day treatment cycles, optionally wherein the antibody is administered on day 1 of each treatment cycle.

5. The method of any one of claims 1 to 4, wherein the antibody is administered at a dose of about 76 mg Q4W in the subsequent treatment cycles, optionally wherein the antibody is administered on day 1 of the subsequent treatment cycles.

6. The method of any one of claims 1 to 5, wherein the antibody is administered at a dose of about 76 mg once every eight weeks (Q8W) or once every sixteen weeks (Q16W) in the subsequent treatment cycles.

7. The method of any one of claim 1 to 6, wherein if a patient has received treatment for at least six months and / or disease response shows at least a partial response (PR) or better with responses persisting for at least two months, the dose interval may be changed to less frequent dosing than the last dose, optionally wherein the dose is changed from about 76 mg Q4W to 76 mg Q8W or 76 mg Q16W.

8. The method of any one of claims 1 to 6, wherein if a patient shows evidence of persistent disease, the dose frequency is not changed to less frequent dosing in the next 28-day treatment cycle.

9. The method of any one of claims 1 to 8, wherein the method further comprising administering to the patient at least one dose of a premedication prior to each of the first and second priming doses and / or the first treatment dose, optionally wherein the premedication may be acetaminophen (or equivalent such as paracetamol), diphenhydramine (or equivalent) and / or dexamethasone (or equivalent).

10. The method of any one of claims 1 to 9, wherein the anti-BCMA / anti-CD3 bispecific antibody comprises a first antigen binding domain and a second antigen binding domain, wherein the first antigen binding domain specifically binds to BCMA, and wherein the second antigen binding domain specifically binding to a CD3, and wherein the first antigen binding domain comprises a VH and a VL, wherein the second antigen binding domain comprises a VH and a VL, and wherein one or both of:a) the first antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 1, 2, and 3, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 4 and 5 , a VH CDR3 comprising the sequence shown in SEQ ID NO: 6, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 7, a VL CDR2 comprising the sequence shown in SEQ ID NO: 8, a VL CDR3 comprising the sequence shown in SEQ ID NO: 9; andb) the second antigen binding domain VH comprises a VH CDR1 comprising the sequence shown in one or more of SEQ ID NO: 12, 13, and 14, a VH CDR2 comprising the sequence shown in one or more of SEQ ID NO: 15 and 16, a VH CDR3 comprising the sequence shown in SEQ ID NO: 17, and the VL comprises a VL CDR1 comprising the sequence shown in SEQ ID NO: 18, a VL CDR2 comprising the sequence shown in SEQ ID NO: 19, a VL CDR3 comprising the sequence shown in SEQ ID NO: 20.

11. The method of any one of claims 1 to 10, wherein the antibody is elranatamab.

12. A method of treating a cancer in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle;and wherein following the first cycle elranatamab is administered for three 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

13. The method of any one of claims 1 to 12, wherein the anti-BCMA I anti-CD3 bispecific antibody such as elranatamab is administered subcutaneously.

14. The method of any one of claims 1 to 13 wherein the cancer is multiple myeloma.

15. A method of treating multiple myeloma in a patient, the method comprising administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 14 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg on day 8 of the first cycle;and wherein following the first cycle elranatamab is administered for six 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

16. The method of claim 15, wherein elranatamab is administered in combination with lenalidomide, optionally wherein lenalidomide is administered at a dose of about 25 mg PO on days 1-21 of each treatment cycle.

17. The method of any one of claims 14 to 16, wherein the multiple myeloma is relapsed or refractory (R / R) multiple myeloma (MM), optionally wherein the patient has previously been treated with:a. at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody;b. at least three prior lines of therapy, which may include a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody;c. at least two prior lines of therapy, which may include two of the following: a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody; ord. at least one prior line of therapy, which may include one of the following: a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody.

18. The method of claim 17, wherein the patient has previously been treated with one prior line of therapy, which includes lenalidomide and a proteasome inhibitor.

19. The method of claim 18, wherein elranatamab is administered in combination with daratumumab.

20. The method of claim 18 or 19, wherein the method comprises administering elranatamab to the patient, wherein elranatamab is administered to the patient for at least a first cycle and subsequent treatment cycles, wherein the first cycle comprises 28 days, and wherein elranatamab is administered as a first priming dose of about 12 mg on day 1 and a second priming dose of about 32 mg on day 4 followed by a first treatment dose of about 76 mg once a week (QW) on day 8, followed by a dose of about 76 mg once every two weeks (Q2W) on day 15 of the first cycle;and wherein following the first cycle elranatamab is administered for two 28-day treatment cycles at a dose of about 76 mg once every two weeks (Q2W); and in subsequent 28-day treatment cycles at a dose of about 76 mg once every four weeks (Q4W).

21. The method of claim 20, wherein daratumumab is administered at a dose of about 1800 mg on day 15 of the first cycle, QW through day 8 of the second treatment cycle, Q2W from day 15 of the second treatment cycle through the sixth treatment cycle; and Q4W from day 1 of the seventh treatment cycle through day 1 of the eleventh cycle.

22. The method of any one of claims 14 to 16, wherein the multiple myeloma is newly diagnosed multiple myeloma, optionally wherein a) the subject has received stem cell transplant, optionally autologous stem cell transplant or allogeneic stem cell transplant, or optionally the subject is transplant ineligible; or b) the subject has not received any prior multiple myeloma therapies.

23. The method of claim 14, wherein the multiple myeloma is a) smoldering myeloma, optionally low risk, medium risk or high-risk smoldering myeloma; or b) monoclonal gammopathy of undetermined significance (MGLIS).

24. The method of any one of claims 1 to 23, wherein the treatment improves one or more of PFS, OS, PFS by Investigator, PFS2 by Investigator, ORR, DOR, VGPRR, CRR, DOOR, TTR, MRD negativity rate, sustained MRD negativity rate, and duration of MRD negativity.

25. An anti-BCMA I anti-CD3 bispecific antibody for use to treat a patient according to the method of any one of claims 1 to 24.

26. Use of an anti-BCMA I anti-CD3 bispecific antibody in the manufacture of a medicament for use to treat a patient according to the method of any one of claims 1 to 24.

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