Combination treatment for multiple myeloma with Anti-BCMA antigen binding protein

Abstract

Provided herein are methods and compositions for treating multiple myeloma, such as relapsed and / or refractory multiple myeloma and newly-diagnosed multiple myeloma, including transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM). The methods involve administering to human patients diagnosed with multiple myeloma an anti-BCMA antigen binding protein (e.g., an anti-BCMA antibody or anti-BCMA antibody drug conjugate) in combination with lenalidomide, pomalidomide, bortezomib, carfilzomib and / or dexamethasone.

Description

[0001] Combination Treatment for Multiple Myeloma with Anti-BCMA Antigen Binding Protein

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 715,761 filed on 4 November 2024, which is herein incorporated by reference in its entirety.

[0003] BACKGROUND

[0004] Multiple myeloma (MM) is a clonal proliferation of abnormal plasma cells in the bone marrow and is the second most common hematological malignancy, accounting for approximately 10% of all cases. The treatment approach to newly-diagnosed multiple myeloma (NDMM) is guided mainly by risk factors based on certain chromosomal abnormalities and eligibility for autologous stem cell transplantation (ASCT), which is determined by factors such as age, general fitness, and presence of comorbidities. The current standard of care (SOC) for newly diagnosed younger, ‘fit’ patients (aged typically up to 70 years without significant frailty or comorbidities) is the sequential treatment of combination induction therapy, consolidation with high-dose melphalan and autologous stem cell transplantation, followed by maintenance therapy. However, the majority of patients are ineligible for transplant (TI-NDMM) at the time of diagnosis due to age (over 70), frailty and / or comorbidities (Dimopoulos et al. Ann Oncol. 2021; 32 (3): 309 22).

[0005] Despite the advancements in treatment options, transplant-ineligible (Tl) patients have worse clinical outcomes in terms of progression free survival (PFS), overall survival (OS), and depth of response, including lower achievement of minimal residual disease (MRD) negative status, when compared to patients who are eligible for ASCT (Attal et al. N Engl J Med. 1996;335:91-7; Child et al. N Engl J Med. 2003;348(19):1875-83; Barlogie et al. J Clin Oncol. 2006;24(6):92936; Attal et al. N Engl J Med.

[0006] 2017;376(14):1311-20; Dhakal et al. JAMA Oncol. 2018;4(3):343-50; Perrot A. et al. Blood. 2018;132(23):2456-64).

[0007] The recommended treatment for patients who are not eligible for ASCT involves triplet induction regimens aiming to achieve remission, followed by maintenance therapy until progressive disease (PD). Triplets have been shown to be more effective than doublet regimens in producing deeper and more durable responses with prolonged survival time. For example, the bortezomib, lenalidomide, and dexamethasone (VRd) regimen has been a widely accepted clinical SOC regimen in TI-NDMM (Mikhael et al. J Clin Oncol. 2019;37(14):1228-63. Erratum in: J Clin Oncol. 2020;38(21):2469;

[0008] Dimopoulos et al. Ann Oncol. 2021;32(3):309 22). VRd has been found to be highly active compared to lenalidomide and dexamethasone (Rd) doublet treatment, resulting in a significant increase in median PFS from 29 months to 41 months (Durie et al.

[0009] Lancet. 2017;389:519-27; Durie et al. Blood Cancer J. 2020;10:53). Furthermore, the SWOG S0777 Phase 3 clinical study demonstrated that VRd was superior to Rd, with a median OS reported as 69 months for Rd and not reached for VRd (Durie et al. Blood Cancer J. 2020; 10:53).

[0010] Recently, the combination of daratumumab, lenalidomide and dexamethasone (DRd) has become an alternative SOC for patients with TI-NDMM. This is based on the findings of the MAIA Phase 3 clinical study which evaluated DRd against Rd doublet treatment (Facon T et al. N Engl J Med. 2019;380(22):2104-15). After a median follow-up of 56.2 months (IQR: 52.7 to 59.9), median PFS was not reached (95% CI: 54.8, NR) in the DRd group vs. 34.4 months (29.6 to 39.2) in the control group (HR 0.53 [95% CI: 0.43, 0.66]; p<0.0001). At a median follow-up of 47.9 months (IQR: 44.2 to 51.3), MRD negativity rate was 31% in the DRd group vs. 10% in the control group (overall response: 3.91 [95% CI: 2.62, 5.84]; p<0.0001). Furthermore, median OS was not reached in either group (DRd group, [95% CI: NR, NR]; control group, [95% CI: 55.7, NR]; HR: 0.68 [95% CI: 0.53, 0.86]; p=0.0013). Due to the MAIA data, National Comprehensive Cancer Network (NCCN) Guidelines now includes DRd as a Category 1 recommended treatment regimen for patients with TI-NDMM and EHA / ESMO guidelines recommend DRd with Level 1A evidence.

[0011] Despite advances in treatment, multiple myeloma remains incurable. Standard first-line treatments — such as immunomodulatory drugs, proteasome inhibitors (Pls), and monoclonal antibodies — can induce remission, but most patients experience relapse even after successful initial therapy. As a result, patients often undergo multiple lines of therapy. Several triplet regimens comprising different combinations of PI, immunomodulatory drugs and anti-CD38 antibodies are also approved for 2nd and 3rd line patients. However, owing to exposure to these agents in first line, 2nd and 3rd line, patients are often refractory to them.

[0012] Belantamab mafodotin, a B-cell maturation antigen (BCMA)-directed therapy, has recently been approved for relapsed and / or refractory multiple myeloma (RRMM).

[0013] Belantamab mafodotin when administered in combination with standard backbone therapies to patients who have received at least one prior line of therapy, has demonstrated clinically meaningful and statistically significant improvements in progression-free survival (as observed with BVd [belantamab mafodotin + bortezomib + dexamethasone] and BPd [belantamab mafodotin + pomalidomide + dexamethasone] regimens) and overall survival (as observed with the BVd regimen) compared to standard-of-care treatments. The drug is well tolerated and offers convenient administration; however, ocular events are frequently observed and often result in dose delays.

[0014] SUMMARY OF THE INVENTION

[0015] Accordingly, there is an unmet medical need for novel combination therapies with manageable toxicity and non-cross-resistant mechanism of action that can: 1) improve clinical outcomes and overcome resistance to existing drugs for patients with multiple myeloma (MM) who have progressed on current standard of care (SoC) treatments, and / or 2) improve prognosis in earlier lines, including in patients with newly diagnosed multiple myeloma (NDMM) and patients who received prior treatment, such as one prior line of therapy (2L).

[0016] The invention satisfies this need by providing alternative triplet and quadruplet regimens for treatment of multiple myeloma, including NDMM, such as transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM), and relapsed and / or refractory (RRMM) that may provide additional therapeutic benefit over other standard of care triplet regimens, such as the combination of daratumumab, lenalidomide, and dexamethasone (DRd) and doublet regimens, such as daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) by improving outcomes of depth and durability of response, without compromising tolerability. In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone, wherein:

[0017] (a) the anti-BCMA antigen binding protein is administered:

[0018] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0019] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0020] (b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0021] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0022] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0023] In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone, wherein:

[0024] (a) the anti-BCMA antigen binding protein is administered:

[0025] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0026] (b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0027] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0028] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone, wherein:

[0029] (a) the anti-BCMA antigen binding protein is administered:

[0030] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0031] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0032] (b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and

[0033] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0034] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0035] In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone, wherein:

[0036] (a) the anti-BCMA antigen binding protein is administered:

[0037] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then

[0038] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0039] (b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and

[0040] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0041] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, and dexamethasone, wherein:

[0042] (a) the anti-BCMA antigen binding protein is administered:

[0043] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0044] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0045] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and

[0046] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0047] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0048] In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, and dexamethasone, wherein:

[0049] (a) the anti-BCMA antigen binding protein is administered:

[0050] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then

[0051] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0052] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and

[0053] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0054] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, carfilzomib, and dexamethasone, wherein:

[0055] (a) the anti-BCMA antigen binding protein is administered:

[0056] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0057] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0058] (b) the carfilzomib is administered on a 28-day treatment cycle (“carfilzomib treatment cycle”); and

[0059] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0060] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0061] In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, carfilzomib, and dexamethasone, wherein:

[0062] (a) the anti-BCMA antigen binding protein is administered:

[0063] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then

[0064] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0065] (b) the carfilzomib is administered on a 28-day treatment cycle (“carfilzomib treatment cycle”); and

[0066] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0067] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone, wherein:

[0068] (a) the anti-BCMA antigen binding protein is administered:

[0069] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles, and then

[0070] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0071] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);

[0072] (c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0073] (d) the dexamethasone is administered on a 28-day treatment cycle (“the dexamethasone treatment cycle”) thereafter,

[0074] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0075] In one aspect, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone, wherein:

[0076] (a) the anti-BCMA antigen binding protein is administered:

[0077] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles or until an adverse event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0078] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);

[0079] (c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and (d) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).

[0080] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0081] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0082] (a) the anti-BCMA antigen binding protein is administered:

[0083] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0084] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0085] (b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0086] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0087] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0088] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0089] (a) the anti-BCMA antigen binding protein is administered:

[0090] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0091] (b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0092] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0093] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0094] (a) the anti-BCMA antigen binding protein is administered:

[0095] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0096] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0097] (b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and

[0098] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0099] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0100] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone for use in the treatment of multiple myeloma, wherein:

[0101] (a) the anti-BCMA antigen binding protein is administered:

[0102] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then

[0103] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0104] (b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0105] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0106] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0107] (a) the anti-BCMA antigen binding protein is administered:

[0108] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0109] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0110] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and

[0111] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0112] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0113] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0114] (a) the anti-BCMA antigen binding protein is administered:

[0115] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then

[0116] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0117] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0118] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0119] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, carfilzomib, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0120] (a) the anti-BCMA antigen binding protein is administered:

[0121] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0122] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0123] (b) the carfilzomib is administered on a 28-day treatment cycle (“carfilzomib treatment cycle”); and

[0124] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0125] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0126] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, carfilzomib, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0127] (a) the anti-BCMA antigen binding protein is administered:

[0128] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then

[0129] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0130] (b) the carfilzomib is administered on a 28-day treatment cycle (“carfilzomib treatment cycle”); and (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);

[0131] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0132] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0133] (a) the anti-BCMA antigen binding protein is administered:

[0134] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles, and then

[0135] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0136] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);

[0137] (c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0138] (d) the dexamethasone is administered on a 28-day treatment cycle (“the dexamethasone treatment cycle”) thereafter,

[0139] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0140] In one aspect, provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0141] (a) the anti-BCMA antigen binding protein is administered:

[0142] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles or until an adverse event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter; (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);

[0143] (c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0144] (d) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).

[0145] wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0146] BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a schematic of the study design for a Phase III registrational clinical trial as described in Example 1.

[0147] FIG. 2 shows a schematic of the study design for a Phase II clinical trial as described in Example 2. In the schematic, AE = adverse event; BPd = belantamab mafodotin + pomalidomide + dexamethasone; BKd = belantamab mafodotin + carfilzomib + dexamethasone; BVd = belantamab mafodotin + bortezomib + dexamethasone; C = cycle; CRR = complete response rate; CTCAEs = common terminology criteria for adverse events; D = Day; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; HRQoL = health related quality of life; KVA = keratopathy and visual acuity; MRD = minimal residual response; ORR = objective response rate; OSDI = ocular surface disease index; PD = progressive disease; PFS = progressive-free survival; PLOT = prior line of therapy; PR = partial response; PRO CTCAE = Patient-reported outcomes version of the common terminology criteria for adverse events; PROSIM-Q = Patient-reported symptom and impact monitoring questionnaire; QXW = every X weeks; RRMM = relapsed / refractory multiple myeloma; SAE = serious adverse event; TTBR = time to best response; TTP = time to progression; TTR = time to response.

[0148] FIG. 3 shows a schematic of the study design for a Phase I clinical trial as described in Example 3. In the schematic, ADA, anti-drug antibodies; AE, adverse event; ASCT, autologous stem cell transplant; belamaf, belantamab mafodotin; CR, complete response; DLT, dose-limiting toxicities; ECOG, Eastern Cooperative Oncology Group; HDT, high-dose chemotherapy; IMWG, International Myeloma Working Group; MM, multiple myeloma; MRD, minimal residual disease; ORR, overall response rate; PK, pharmacokinetics; PR, partial response; QxW, every x weeks; RDI, relative dose intensity; SMM, smouldering MM; SOC, standard of care; VGPR, very good partial response; VRd, bortezomib, lenalidomide and dexamethasone.

[0149] FIG. 4 shows the time to, and resolution of best corrected visual acuity (BCVA) decreases across each of the cohorts treated with belantamab mafodotin in combination with standard of care agents in the clinical study described in Example 3 (QxW, every x weeks).

[0150] FIG. 5 shows the overall response rate (ORR) across each of the cohorts treated with belantamab mafodotin in combination with standard of care agents in the clinical study described in Example 3. In the figure, Cl, confidence interval; CR+, complete response or better; ORR, overall response rate; PR, partial response; QxW, every x weeks; sCR, stringent complete response; VGPR+, very good partial response or better.

[0151] FIGs. 6A-6B shows the MRD-negativity across each of the cohorts treated with belantamab mafodotin in combination with standard of care agents in the clinical study described in Example 3. MRD[-] was measured by next-generation sequencing [10-5] in patients achieving CR+. FIG. 6A: MRD[-] is shown as proportion of the ITT population. FIG. 6B: MRD[-] in higher dose cohorts and relative dose intensity (RDI). †Belamaf dose Interruptions, reductions, and delays for Grade 2+ KVA event occurred in 58% of patients; ‡Bortezomib and lenalidomide RDI data were analyzed at the previous data cut (March 27, 2023). Belamaf, belantamab mafodotin; CR,+ complete response or better; ITT, intention-to-treat; MRD[-], minimal residual disease negativity; QxW, every x weeks; Rd, lenalidomide and dexamethasone; VRd, bortezomib, lenalidomide, and dexamethasone.

[0152] FIGs. 7A-7B show the average belantamab mafodotin exposure at 21 days and 6 months, measured as described in Example 4. FIG. 7A: The top panel demonstrates that cycle 1 exposure increased with higher doses and that there was large interpatient variability within cohorts and large overlap among the dosing cohorts. The bottom panel shows that the average belantamab mafodotin concentration over the first 6 months, which considers individual dosing history, showed large variation (11 -fold over the 84 participants) with a trend for higher average exposure in patients with a starting dose of 1.9 mg / kg or a Q3 / 4W dosing schedule. FIG. 7B: Covariate abbreviations:

[0153] CAVGA_21D, ADC average concentration over 21 days; CAVGA_LND6M, ADC average concentration over 6 months; IDOSE, initial planned dose; IGGBL, baseline IgG; IGGFLG, IgG flag-M-protein is IgG type or not; LNCADC_21D, log-transformed ADC concentration at 21 days; MMIGTYCH, multiple-myeloma IG type; SCHCH2, planned schedule as a 3-category variable.

[0154] FIGs. 8A-8B show the probability of MRD negativity at sCR / CR and probability of sCR / CR based on belantamab mafodotin average concentration as described in Example 4. At the 6-month landmark analysis, 84 patients were evaluable for E-R. The independent variable was divided into quartiles. The summary statistics for each quartile are reported as median (minimum, maximum). Points and error bars represent the observed proportions and 95% Cis for each quartile (plotted at the median exposure within each quartile), respectively. The curves represent the prediction of the univariate logistic regression model, and the shaded regions represent the 95% Cl of the prediction. The displayed p-value is the p-value for the logistic regression slope.

[0155] Logistic regression plots demonstrating a positive correlation between belantamab mafodotin average concentration exposure metrics and probability of MRD negativity (FIG. 8A) as well as the probability of sCR / CR (FIG. 8B).

[0156] FIGs. 9A-9C show the progression free survival and overall survival in RRMM patients treated with BVd in the Phase 3 study described in Example 5. FIG. 9A shows the Kaplan-Meier analysis of independent review committee-assessed progression-free survival in the intention-to-treat population. FIG. 9B shows a post hoc supplementary analysis of progression-free survival in the intention-to-treat population in which any occurrence of disease progression or death after the start of a new antimyeloma therapy or after extended loss to follow-up was considered to be an event.

[0157] FIG. 9C shows overall survival. At the time of the data cutoff, data regarding overall survival were 29% mature.

[0158] FIGS. 10A-10C show the progression free survival and overall survival in RRMM patients treated with BPd in the Phase 3 study described in Example 6. FIG. 10A shows the Kaplan-Meier analysis of independent review committee-assessed progression-free survival in the intention-to-treat population. FIG. 10B shows a post hoc supplementary analysis of progression-free survival in the intention-to-treat population in which any disease progression or death after the start of new antimyeloma therapy or after extended loss to follow-up was included as an event. FIG. 10C shows overall survival. The 25th percentile of the overall survival duration was 19.0 months (95% Cl, 12.2 to 23.3) in the BPd group and 12.7 months (95% Cl, 8.0 to 18.5) in the PVd group, and overall survival at 12 months was 83% (95% Cl, 76 to 88) and 76% (95% Cl, 68 to 82), re- spectively. The efficacy boundary for overall survival was not crossed.

[0159] FIG. 11 shows overall response rate (ORR) in RRMM patients treated with BRd in the Ph 1 / 2 study described in Example 10. ORR was defined as a PR or better and CRR was defined as a confirmed CR or better; patients with unknown or missing responses were treated as non-responders. Deep responses are indicated as > VGPR. Cl, confidence interval; CR, complete response; CRR, complete response rate; ORR, overall response rate; PR, partial response; s, stringent; VGPR, very good partial response.

[0160] DETAILED DESCRIPTION OF THE INVENTION

[0161] Definitions

[0162] As used herein and in the claims, the term “comprising” encompasses “including” or “consisting,” e.g., a composition “comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.

[0163] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although any compositions and methods similar or equivalent to those described herein can be used in the practice or testing of the methods of the disclosure, exemplary compositions and methods are described herein. Any of the aspects and embodiments of the disclosure described herein may also be combined. For example, the subject matter of any dependent or independent claim disclosed herein may be multiply combined (e.g., one or more recitations from each dependent claim may be combined into a single claim based on the independent claim on which they depend).

[0164] Ranges provided herein include all values within a particular range described and values about an endpoint for a particular range. The figures and tables of the disclosure also describe ranges, and discrete values, which may constitute an element of any of the methods and uses disclosed herein.

[0165] Concentrations described herein are determined at ambient temperature and pressure. This may be, for example, the temperature and pressure at room temperature or within a particular portion of a process stream. Preferably, concentrations are determined at a standard state of 25 °C and 1 bar of pressure.

[0166] The term “QXW” as used herein with respect to a therapeutic agent, refers to the dosing frequency of the therapeutic agent and in particular indicates that the therapeutic agent is administered once every X number of weeks. For example, Q4W means administration once every four weeks; Q8W means administration once every eight weeks; Q12W means administration once every 12 weeks; and Q16W means administration once every 16 weeks.

[0167] Anti-BCMA Antigen Binding Proteins

[0168] The invention described herein provides triplet and quadruplet regimens comprising an anti-BCMA antigen binding protein in combination with standard of care (SoC) anti-myeloma therapies, including lenalidomide, pomalidomide, bortezomib, carflizomib and / or dexamethasone for treatment of BCMA-mediated diseases, including, for example, B-cell mediated cancers such as lymphomas and multiple myeloma. An anti-BCMA antigen binding protein described herein binds to human B-cell maturation antigen (BCMA), for example, human BCMA containing the amino acid sequence of GenBank Accession Number Q02223.2, or genes encoding human BCMA having at least 90 percent homology or at least 90 percent identity thereto.

[0169] The term “anti-BCMA antigen binding protein” as used herein refers to antibodies and other protein constructs, such as domains, which are capable of binding to BCMA. The terms “BCMA binding protein” and “BCMA antigen binding protein” and “anti-BCMA antigen binding protein” are used interchangeably herein.

[0170] Exemplary anti-BCMA antigen binding proteins and methods of making the same are disclosed in International Publication No. WO2012 / 163805 which is incorporated by reference herein in its entirety. Additional exemplary anti-BCMA antigen binding proteins include those described in WO2016 / 014789, WO2016 / 090320, WO2016 / 090327, WO2016 / 020332, WO2016 / 079177, WO2014 / 122143, WO2014 / 122144,

[0171] WO2017 / 021450, WO2016 / 014565, WO2014 / 068079, WO2015 / 166649,

[0172] WO2015 / 158671, WO2015 / 052536, WO2014 / 140248, WO2013 / 072415,

[0173] WO2013 / 072406, WO2014 / 089335, US2017 / 165373, WO2013 / 154760,

[0174] WO2018 / 201051 and WO2017 / 051068, each of which is incorporated by reference herein in its entirety.

[0175] In some embodiments, an anti-BCMA antigen binding protein disclosed herein may be derived from rat, mouse, primate (e.g., cynomolgus, Old World monkey or Great Ape) or human. The anti-BCMA antigen binding protein may be a human, humanized or chimeric antibody. The anti-BCMA antigen binding protein may comprise a constant region, which may be of any isotype or subclass. The constant region may be of the IgG isotype, for example lgG1, lgG2, lgG3, lgG4 or variants thereof. The anti-BCMA antigen binding protein constant region may be lgG1.

[0176] In one embodiment, an anti-BCMA antigen binding protein comprises an antibody (“anti-BCMA antibody”). In another embodiment, an anti-BCMA antigen binding protein comprises a monoclonal antibody. The term “antibody” is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanised, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., a domain antibody (DAB)), antigen binding antibody fragments, Fab, F(ab’)2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS, etc. and modified versions of any of the foregoing (for a summary of alternative “antibody” formats see Hol liger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9, 1126-1136). The term, full, whole or intact antibody, used interchangeably herein, refers to a heterotetrameric glycoprotein with an approximate molecular weight of 150,000 daltons. An intact antibody is composed of two identical heavy chains (HCs) and two identical light chains (LCs) linked by covalent disulphide bonds. This H2L2structure folds to form three functional domains comprising two antigen-binding fragments, known as ‘Fab’ fragments, and a ‘Fc’ crystallisable fragment. The Fab fragment is composed of the variable domain at the amino-terminus, variable heavy (VH) or variable light (VL), and the constant domain at the carboxyl terminus, CH1 (heavy) and CL (light). The Fc fragment is composed of two domains formed by dimerization of paired CH2 and CH3 regions. The Fc may elicit effector functions by binding to receptors on immune cells or by binding C1q, the first component of the classical complement pathway. The five classes of antibodies IgM, IgA, IgG, IgE and IgD are defined by distinct heavy chain amino acid sequences, which are called p, a, y, £ and 5 respectively, each heavy chain can pair with either a K or A light chain. The majority of antibodies in the serum belong to the IgG class, there are four isotypes of human IgG (lgG1, lgG2, lgG3 and lgG4), the sequences of which differ mainly in their hinge region.

[0177] Fully human antibodies can be obtained using a variety of methods, for example using yeast-based libraries or transgenic animals (e.g. mice) that are capable of producing repertoires of human antibodies. Yeast presenting human antibodies on their surface that bind to an antigen of interest can be selected using FACS (Fluorescence-Activated Cell Sorting) based methods or by capture on beads using labelled antigens. Transgenic animals that have been modified to express human immunoglobulin genes can be immunized with an antigen of interest and antigen-specific human antibodies isolated using B-cell sorting techniques. Human antibodies produced using these techniques can then be characterized for desired properties such as affinity, developability and selectivity.

[0178] Alternative antibody formats include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable nonimmunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U. S. Patent Application Publication Nos.

[0179] 2005 / 0053973, 2005 / 0089932, 2005 / 0164301) or an EGF domain. The mature variable regions of each light / heavy chain pair may form the antibody binding site (also referred to as the antigen binding site). The term “antigen binding site” refers to a site on an antigen binding protein that is capable of specifically binding to an antigen, this may be a single variable domain, or it may be paired VH / VL domains as can be found on a standard antibody. Thus, an intact antibody may have, for example, two binding sites. Single-chain Fv (ScFv) domains can also provide antigen-binding sites.

[0180] In some embodiments, an antigen binding protein, such as an antibody, can be defined by CDR sequences. “CDRs” are defined as the complementarity determining region amino acid sequences of an antigen binding protein, such as an antibody. These are the hypervariable regions of immunoglobulin heavy and light chains. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, "CDRs" as used herein refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

[0181] Throughout this specification, amino acid residues in variable domain sequences and variable domain regions within full-length antigen binding sequences, e.g. within an antibody heavy chain sequence or antibody light chain sequence, are numbered according to the Kabat numbering convention. Similarly, the terms “CDR”, “CDRL1”, “CDRL2”, “CDRL3”, “CDRH1”, “CDRH2”, “CDRH3” used herein follow the Kabat numbering convention. For further information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., U. S. Department of Health and Human Services, National Institutes of Health (1987).

[0182] It will be apparent to those skilled in the art that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. There are also alternative numbering conventions for CDR sequences, for example those set out in Chothia et al. (1989) Nature 342: 877-883. The structure and protein folding of the antigen binding protein may mean that other residues are considered part of the CDR sequence and would be understood to be so by a skilled person.

[0183] Other numbering conventions for CDR sequences available to a skilled person include “AbM” (University of Bath) and “contact” (University College London) methods. Table 1 below represents one definition using each numbering convention for each CDR or binding unit. The Kabat numbering scheme is used in Table 1 to number the variable domain amino acid sequence. It should be noted that some of the CDR definitions may vary depending on the individual publication used.

[0184] Table 1: CDR Naming Conventions

[0185]

[0186] The terms “variant”, “antibody variant”, “CDR variant” and “post-translational modification variant” refers to at least one amino acid change in an antibody sequence. Variants may be the result of a post translational modification, a chemical change or a sequence change via at least one deletion, substitution or addition. Some post-translational modifications result in a chemical change which does not change the sequence (e.g. Met and oxidized Met; or Asp and isomerized / iso-Asp; or aggregation) while others result in a sequence change such as the conversion of one amino acid residue into another (e.g. Asn conversion to Asp via deamidation; or lysine deletion). A variant antibody sequence which comprises a sequence change may be the result of a designed sequence change or a post-translational modification. An amino acid sequence change may be a deletion, substitution or addition.

[0187] In one such embodiment, substitutions are conservative substitutions. In an alternative embodiment, an antibody variant comprises at least one substitution while retaining the canonical of the antigen binding protein. In one embodiment, an antibody variant is an antibody that is at least about 90%, about 95%, or about 99% identical to (i.e. has sequence identity to) the antibody primary sequence. "Percent identity" between a query amino acid sequence and a subject amino acid sequence is the "Identities" value, expressed as a percentage, that is calculated by the BLASTP algorithm when a subject amino acid sequence has 100% query coverage with a query amino acid sequence after a pair-wise BLASTP alignment is performed. Such pairwise BLASTP alignments between a query amino acid sequence and a subject amino acid sequence are performed by using the default settings of the BLASTP algorithm available on the National Center for Biotechnology Institute's website with the filter for low complexity regions turned off. A query sequence may be described by an amino acid sequence identified in one or more claims herein.

[0188] CDRs may be modified by at least one amino acid substitution, deletion or addition, wherein the variant antigen binding protein substantially retains the biological characteristics of the unmodified protein, such as binding to the antigen. It will be appreciated that each of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3 may be modified alone or in combination with any other CDR, in any permutation or combination. In one embodiment, a CDR is modified by the substitution, deletion or addition of up to 3 amino acids, for example 1 or 2 amino acids, for example 1 amino acid. In one such embodiment, a substitution is a conservative substitution, for example as shown in Table 2 below. For example, in a variant CDR, the flanking residues that comprise the CDR as part of alternative definition(s) e.g. Kabat or Chothia, may be substituted with a conservative amino acid residue. Such antigen binding proteins comprising variant CDRs as described above may be referred to herein as “functional CDR variants”.

[0189] Table 2: Conservative Substitutions

[0190]

[0191] An antigen binding protein can comprise one or more modifications including, for example, a mutated constant domain such that, when the antigen binding protein is an antibody, the antibody has enhanced effector functions, such as enhanced antibody dependent cell mediated cytotoxic activity (ADCC) effector function and / or complement activation.

[0192] In one embodiment, an anti-BCMA antibody has enhanced antibody dependent cell mediated cytotoxic (ADCC) activity effector function. The term “effector function” as used herein refers to one or more of antibody-mediated effects including antibodydependent cell-mediated cytotoxicity (ADCC), antibody-mediated complement activation including complement-dependent cytotoxicity (CDC), complement-dependent cell-mediated phagocytosis (CDCP), antibody dependent complement-mediated cell lysis (ADCML), and Fc-mediated phagocytosis or antibody-dependent cellular phagocytosis (ADCP).

[0193] Fc engineering methods can be applied to modify the functional or pharmacokinetics properties of an antibody. Effector function may be altered by making mutations in the Fc region that increase or decrease binding to C1q or Fey receptors and modify CDC or ADCC activity respectively. Modifications to the glycosylation pattern of an antibody can also be made to change the effector function. The in vivo half-life of an antibody can be altered by making mutations that affect binding of the Fc region to the FcRn (Neonatal Fc Receptor).

[0194] The interaction between the Fc region of an antigen binding protein or antibody and various Fc receptors (FcR), including FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16), FcRn, C1q, and type II Fc receptors is believed to mediate the effector functions of the antigen binding protein or antibody. Significant biological effects can be a consequence of effector functionality. Usually, the ability to mediate effector function requires binding of the antigen binding protein or antibody to an antigen and not all antigen binding proteins or antibodies will mediate every effector function.

[0195] Effector function can be assessed in a number of ways including, for example, evaluating ADCC effector function of antibody coated to target cells mediated by Natural Killer (NK) cells via FcyRIII, or monocytes / macrophages via FcyRI, or evaluating CDC effector function of antibody coated to target cells mediated by complement cascade via C1q. For example, an antigen binding protein of the present invention can be assessed for ADCC effector function in a Natural Killer cell assay. Examples of such assays can be found in Shields et al, 2001, The Journal of Biological Chemistry, Vol. 276, p. 6591-6604; Chappel et al, 1993, The Journal of Biological Chemistry, Vol 268, p. 25124-25131; Lazaret al, 2006, PNAS, 103; 4005-4010. Examples of assays to determine CDC function include those described in J Imm Meth, 1995, 184: 29-38.

[0196] The effects of mutations on effector functions (e.g., FcRn binding, FcyRs and C1q binding, CDC, ADCML, ADCC, ADCP) can be assessed, e.g., as described in Grevys et al., J Immunol. 2015 Jun 1; 194(11): 5497–5508, or Tam et al., Antibodies 2017, 6(3); Monnet et al., 2014 mAbs, 6:2, 422-436.

[0197] In one embodiment, an anti-BCMA antibody comprises a heavy chain constant region with an altered glycosylation profile, such that the anti-BCMA antibody has an enhanced effector function, e.g. enhanced ADCC, enhanced CDC, or both enhanced ADCC and CDC. Examples of suitable methodologies to produce antigen binding proteins with an altered glycosylation profile are described in W02003011878, W02006014679 and EP1229125, all of which can be applied to the antigen binding proteins, such as anti-BCMA antibodies described herein.

[0198] In some embodiments, an anti-BCMA antibody comprises an afucosylated Fc region. In another embodiment, an anti-BCMA antibody is afucosylated at Asn297 (IgG1). In another embodiment, an anti-BCMA antibody is afucosylated at Asn297 (IgG1) according to EU index numbering.

[0199] The absence of the a1,6 innermost fucose residues on the Fc glycan moiety on N297 of IgG1 antibodies enhances affinity for FcyRIIIA. As such, afucosylated or low fucosylated monoclonal antibodies may have increased therapeutic efficacy (Shields et al., J Biol Chem. 2002, 277(30): 26733-40 and Monnet et al., 2014, mAbs, 6:2, 422-436). Such afucosylated or low fucosylated antibodies can be produced, for example, using the POTELLIGENT® technology system available from BioWa, Inc. (Princeton, NJ) in which CHOK1SV cells lacking a functional copy of the FUT8 gene produce monoclonal antibodies having enhanced ADCC activity that is increased relative to an identical monoclonal antibody produced in a cell with a functional FUT8 gene as described in US7214775, US6946292, W00061739 and W00231240, all of which are incorporated herein by reference. Those of ordinary skill in the art will also recognize other appropriate systems, including other cellular systems lacking a functional copy of the FUT8 gene.

[0200] Also provided is a method for the production of an antigen binding protein according to the invention comprising the steps of: a) culturing a recombinant host cell comprising an expression vector comprising the isolated nucleic acid as described herein, wherein the FUT8 gene encoding alpha-1, 6-fucosyltransferase has been inactivated in the recombinant host cell; and b) recovering the antigen binding protein. Such methods for the production of antigen binding proteins can be performed, for example, using the POTELLIGENT® technology system available from BioWa, Inc. (Princeton, NJ) as described above. In an embodiment of the invention, the antigen binding protein is produced in a host cell in which the FUT8 gene has been inactivated. In an embodiment of the invention, the antigen binding protein is produced in a - / - FUT8 host cell.

[0201] An antibody may be recovered and purified by conventional protein purification procedures. For example, the antibody may be harvested directly from the culture medium. Harvest of the cell culture medium may be via clarification, for example by centrifugation and / or depth filtration. Recovery of the antibody is followed by purification to ensure adequate purity. Therefore, in one aspect, there is provided a cell culture medium comprising an antibody described herein. In one embodiment, the cell culture medium comprises CHO cells.

[0202] The antibody may be subsequently purified from the cell culture medium. This may comprise harvesting the cell culture supernatant, placing the cell culture supernatant in contact with a purification medium (e.g. protein A resin or protein G resin to bind antibody molecules) and eluting the antibody molecules from the purification medium to produce an eluate. Therefore, in one aspect, there is provided an eluate comprising an antibody described herein.

[0203] One or more chromatography steps may be used in purification, for example one or more chromatography resins; and / or one or more filtration steps. For example, affinity chromatography using resins, such as protein A, G, or L may be used to purify the composition. Alternatively, or in addition to, an ion-exchange resin such as a cationexchange may be used to purify the composition. Alternatively, the purification steps comprise: an affinity chromatography resin step, followed by a cation-exchange resin step.

[0204] In one embodiment, an anti-BCMA binding protein comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6.

[0205] In one embodiment, an anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0206] In one embodiment, an anti-BCMA antigen binding protein comprises a heavy chain variable region (VH) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 8.

[0207] In one embodiment, an anti-BCMA antigen binding protein comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0208] In one embodiment, an anti-BCMA antigen binding protein is an antibody. In another embodiment, an anti-BCMA antigen binding protein is an IgG1 antibody. In another embodiment, an anti-BCMA antigen binding protein is an IgG1 antibody comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0209] In one embodiment, an anti-BCMA antigen binding protein comprises a heavy chain (HC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 10. In one embodiment, an anti-BCMA antigen binding protein comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10. In another embodiment, an anti-BCMA antigen binding protein is an anti-BCMA antibody comprising a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

[0210] In another embodiment, an anti-BCMA antigen binding protein is an antibody, wherein the antibody is afucosylated. In another embodiment, an anti-BCMA antigen binding protein is an anti-BCMA antibody comprising a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10, wherein the antibody is afucosyated.

[0211] In an embodiment, an anti-BCMA antigen binding protein is the anti-BCMA antibody belantamab.

[0212] Antibody Drug Conjugates

[0213] In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate. Antibody drug conjugates (ADCs) are potent anti-cancer agents, which have recently demonstrated remarkable clinical benefit. ADCs are comprised of a drug, such as cytotoxic agent, chemically bound to an antibody or antibody fragment via a linker. ADCs have been used for the local delivery of cytotoxic agents, i.e., drugs that kill or inhibit the growth or proliferation of cells, in the treatment of cancer (Lambert, J. (2005) Curr. Opinion in Pharmacology 5:543-549; Wu etal. (2005) Nature Biotechnology 23(9): 1137-1146; Syrigos and Epenetos (1999) Anticancer Research 19:605-614;

[0214] Niculescu-Duvaz and Springer (1997) Adv. Drug Deliv. Rev. 26:151-172; U. S. Pat. No.

[0215] 4,975,278). ADCs allow for the targeted delivery of a drug moiety or cytotoxic agent to a tumor, and intracellular accumulation therein, where systemic administration of unconjugated drugs or cytotoxic agents may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated (Baldwin et al., Lancet (Mar. 15, 1986) pp. 603-05; Thorpe (1985) "Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review," in Monoclonal Antibodies '84: Biological And Clinical Applications (A. Pinchera et al., eds) pp. 475-506. ADCs thus enable selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK) / pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy (Tsuchikama and An 2018); Beck A. et al (2017) Nature Rev. Drug Disc. 16: 315-337). Both polyclonal antibodies and monoclonal antibodies have been reported as useful in these strategies (Rowland et al., (1986) Cancer Immunol. Immunother. 21:183-87). Toxins used in antibody-toxin conjugates include bacterial toxins such as diphtheria toxin, plant toxins such as ricin, small molecule toxins such as geldanamycin (Mandler et al (2000) J. Nat. Cancer Inst. 92(19):1573-1581; Mandleret al (2000) Bioorganic & Med. Chem. Letters 10:1025-1028; Mandler et al (2002) Bioconjugate Chem. 13:786-791), maytansinoids (EP 1391213; Liu et al., (1996) Proc. Natl. Acad. Sci. USA 93:8618-8623), and calicheamicin (Lode et al (1998) Cancer Res.

[0216] 58:2928; Hinman et al (1993) Cancer Res. 53:3336-3342).

[0217] In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate (“anti-BCMA ADC”) comprising an antibody or antibody fragment conjugated to one or more cytotoxic agents. An “antibody drug conjugate” (interchangeably referred to as an “immunoconjugate,” “ADC,” or “antigen binding protein-drug conjugate”) comprises an anti-BCMA antigen binding protein as described herein conjugated to one or more drugs, such as a cytotoxic agent, a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g., a protein toxin, such as an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), an antiviral agent, or a radioactive isotope (i.e., a radioconjugate).

[0218] In some embodiments, an anti-BCMA ADC has the following general structure: ABP-((Linker)n-Ctx)m

[0219] wherein:

[0220] ABP is an anti-BCMA antigen binding protein;

[0221] Linker is either absent or is any cleavable or non-cleavable linker;

[0222] Ctx is any cytotoxic agent described herein;

[0223] n is 0, 1, 2, or 3; and

[0224] m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In certain embodiments, an antibody drug conjugate comprises an anti-BCMA antigen binding protein, such as an anti-BCMA antibody, and a drug, such as a toxin, such as a chemotherapeutic agent. The drug can be modified (e.g., via standard synthetic chemistry) to allow its chemical attachment (e.g., to contain a reaction handle to allow its chemical attachment) to a reactive end of a linker that joins the drug to the antigen binding protein.

[0225] Drugs, such as chemotherapeutic agents, useful in the generation of antibody drug conjugates are described herein. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. See, e.g., WO 93 / 21232 published Oct.

[0226] 28, 1993.

[0227] In addition to toxins, a radioactive material, such as a radionucleotide, may be used as the drug in an antibody drug conjugate. A variety of radionucleotides are available for the production of radioconjugated antibodies. Examples include 212Bi, 1311, 131 In, 90Y, and 186Re.

[0228] Anti-BCMA antigen binding proteins (such as anti-BCMA antibodies) can also be conjugated to one or more toxins, including, but not limited to, a calicheamicin, a maytansinoid, a dolastatin, an auristatin, a trichothecene, and CC1065, and a derivative of these toxins that have toxin activity. Suitable cytotoxic agents include, but are not limited to, an auristatin including dovaline-valine-dolaisoleunine-dolaproine-phenylalanine (MMAF) and monomethyl auristatin E (MMAE) as well as an ester form of MMAE, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a lexitropsin, a duocarmycin, a taxane (such as paclitaxel and docetaxel), a puromycin, a dolastatin, a maytansinoid, and a vinca alkaloid. Specific cytotoxic agents include topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin-10, echinomycin, combretatstatin, chalicheamicin, maytansine, DM-1, DM-4, and netropsin. Other suitable cytotoxic agents include anti-tubulin agents, such as an auristatin, a vinca alkaloid, a podophyllotoxin, a taxane, a baccatin derivative, a cryptophysin, a maytansinoid, a combretastatin, or a dolastatin. Antitubulin agents include dimethylvaline-valine-dolaisoleuine-dolaproine-phenylalanine-p-phenylenediamine (AFP), MMAF, MMAE, auristatin E, vincristine, vinblastine, vindesine, vinorelbine, VP-16, camptothecin, paclitaxel, docetaxel, epothiloneA, epothilone B, nocodazole, colchicines, colcimid, estramustine, cemadotin, discodermolide, maytansine, DM-1, DM-4, and eleutherobin.

[0229] In some embodiments, the immunoconjugate comprises an antigen binding protein (such as an antibody) conjugated to a dolastatin or a dolostatin peptidic analog or derivative, an auristatin (U. S. Pat. Nos. 5,635,483; 5,780,588). Dolastatins and auristatins have been shown to interfere with microtubule dynamics, GTP hydrolysis, and nuclear and cellular division (Woyke et al. (2001) Antimicrob. Agents and Chemother. 45(12):3580-3584) and have anticancer (U. S. Pat. No. 5,663,149) and antifungal activity (Pettit et al. (1998) Antimicrob. Agents Chemother. 42:2961-2965). The dolastatin or auristatin (a pentapeptide derivative of dolastatin) drug moiety may be attached to the antibody through the N (amino) terminus or the C (carboxyl) terminus of the peptidic drug moiety (WO 02 / 088172).

[0230] Exemplary auristatin embodiments include the N-terminus linked monomethylauristatin drug moieties DE and DF, disclosed in "Monomethylvaline Compounds Capable of Conjugation to Ligands," U. S. Patent No. 7,498,298. As used herein, the abbreviation "MMAE" refers to monomethyl auristatin E. As used herein the abbreviation "MMAF" refers to dovaline-valine-dolaisoleuine-dolaproine-phenylalanine or monomethyl auristatin F.

[0231] Typically, peptide-based drug moieties can be prepared by forming a peptide bond between two or more amino acids and / or peptide fragments. Such peptide bonds can be prepared, for example, according to the liquid phase synthesis method (see E. Schroder and K. Lubke, "The Peptides," volume 1, pp 76-136, 1965, Academic Press) that is well known in the field of peptide chemistry. The auristatin / dolastatin drug moieties can be prepared according to the methods of: U. S. Pat. No. 5,635,483; U. S. Pat. No. 5,780,588; Pettit et al. (1989) J. Am. Chem. Soc. 111:5463-5465; Pettit et al. (1998) Anti-Cancer Drug Design 13:243-277; Pettit, G. R., et al. Synthesis, 1996, 719- 725; and Pettit et al. (1996) J. Chem. Soc. Perkin Trans. 15:859-863. See also Doronina (2003) Nat Biotechnol 21(7):778-784; "Monomethylvaline Compounds Capable of Conjugation to Ligands," U. S. Patent No. 7,498,298, (disclosing, e.g., linkers and methods of preparing monomethylvaline compounds such as MMAE and MMAF conjugated to linkers). Biologically active organic compounds that act as cytotoxic agents, specifically pentapeptides, are disclosed in US Patent Nos. 6,884,869;

[0232] 7,498,298; 7,098,308; 7,256,257; and 7,423,116.

[0233] In one embodiment, the cytotoxic agent is an auristatin, such as MMAE or MMAF.

[0234] In one embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF:

[0235]

[0236] In one embodiment, an anti-BCMA antibody is conjugated to a cytotoxic agent via a linker. Exemplary linkers include cleavable and non-cleavable linkers. A cleavable linker may be susceptible to cleavage under intracellular conditions. Suitable cleavable linkers include, for example, a peptide linker cleavable by an intracellular protease, such as lysosomal protease or an endosomal protease. In exemplary embodiments, the linker can be a dipeptide linker, such as a valine-citrulline (val-cit) or a phenylalaninelysine (phe-lys) linker. Other suitable linkers include, for example, linkers hydrolyzable at a pH of less than 5.5, such as a hydrazone linker. Additional suitable cleavable linkers include, for example, disulfide linkers. Yet other exemplary linkers include 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alaninephenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4-(2- pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1 carboxylate (SMCC), and N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB).

[0237] In one embodiment, a linker can comprise a thiol-reactive maleimide, a caproyl spacer, dipeptide valine-5 citrulline, a p-aminobenzyloxycarbonyl, a self-immolative fragmenting group, ora protease-resistant maleimidocaproyl.

[0238] An anti-BCMA antibody described herein can contain any anti-BCMA antigen binding protein described herein, such as any anti-BCMA antibody described herein, conjugated to any cytotoxic agent described herein.

[0239] In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA antibody conjugated to a cytotoxic agent, wherein the cytotoxic agent is MMAE or MMAF. In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA monoclonal antibody conjugated to a cytotoxic agent, wherein the cytotoxic agent is MMAE or MMAF. In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA antibody conjugated to a cytotoxic agent, wherein the cytotoxic agent is MMAF. In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA monoclonal antibody conjugated to a cytotoxic agent, wherein the cytotoxic agent is MMAF.

[0240] In some embodiments, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA antibody conjugated to a cytotoxic agent via a non-cleavable linker, wherein the cytotoxic agent is MMAE or MMAF. In some embodiments, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA antibody conjugated to a cytotoxic agent via a cleavable linker, wherein the cytotoxic agent is MMAE or MMAF. In one embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA monoclonal antibody conjugated to a cytotoxic agent via a non-cleavable linker, wherein the cytotoxic agent is MMAE or MMAF. In another embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA antibody conjugated to a cytotoxic agent via a non-cleavable linker, wherein the cytotoxic agent is MMAF. In another embodiment, an anti-BCMA antigen binding protein is an antibody drug conjugate comprising an anti-BCMA monoclonal antibody conjugated to a cytotoxic agent via a non-cleavable linker, wherein the cytotoxic agent is MMAF.

[0241] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF via a non-cleavable linker, wherein the non-cleavable linker is 6- maleimidocaproyl (MC). In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a non-cleavable linker, wherein the non-cleavable linker is 6- maleimidocaproyl (MC). In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF by an MC linker as depicted in the following structures:

[0242]

[0243] wherein mAb is the anti-BCMA antibody; and p is an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

[0244] In one embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6.

[0245] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 8.

[0246] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0247] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 10.

[0248] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

[0249] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody is belantamab.

[0250] In one embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6.

[0251] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0252] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 8.

[0253] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0254] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 10.

[0255] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10, wherein the antibody is afucosylated.

[0256] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody is belantamab.

[0257] In one embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6-maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6.

[0258] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6-maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

[0259] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6-maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 8.

[0260] In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6-maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0261] In yet another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises a heavy chain (HC) compromising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising an amino acid sequence with at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence of SEQ ID NO: 10.

[0262] In yet another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6-maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 10. In yet another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), wherein the anti-BCMA antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 10, and wherein the anti-BCMA antibody is afucosylated.

[0263] In yet another embodiment, an anti-BCMA antibody drug conjugate is belantamab mafodotin. Belantamab mafodotin comprises the anti-BCMA antibody belantamab conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), and wherein belantamab comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

[0264] Such antibody drug conjugates (or immunoconjugates) can be produced by conjugating the anti-tubulin agent MMAE or MMAF to an antigen binding protein (such as an antibody). In the case of MMAE, the linker can contain a thiol-reactive maleimide, a caproyl spacer, the dipeptide valine-citrulline, or p-aminobenzyloxycarbonyl, a self-immolative fragmenting group. In the case of MMAF, a protease-resistant maleimidocaproyl linker can be used. The conjugation process leads to heterogeneity in drug-antibody attachment, varying in both the number of drugs bound to each antibody molecule (drug to antibody ratio, or DAR), and the site of attachment. The most prevalent species is the material with a DAR of 4. Other less prevalent species include material with a DAR of 0, 2, 6, and 8. The overall average drug-to-antibody (DAR) is approximately 4.

[0265] Methods of Treatment, Uses, and Combinations for Use

[0266] Described herein are methods of treating multiple myeloma using an anti-BCMA antigen binding protein as described herein in combination with lenalidomide, pomalidomide, bortezomib, carfilzomib, and / or dexamethasone, such as (i) lenalidomide and dexamethasone, (ii) bortezomib and dexamethasone, (iii) pomalidomide and dexamethasone, (iv) carfilzomib and dexamethasone, and (v) bortezomib, lenalidomide, and dexamethasone. According to embodiments of the invention, the multiple myeloma can be relapsed and / or refractory multiple myeloma, newly-diagnosed multiple myeloma, transplant-ineligible multiple myeloma, or transplant-ineligible newly diagnosed multiple myeloma.

[0267] In one aspect, provided is a method of treating multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient comprising administering to the human patient an anti-BCMA antigen binding protein, lenalidomide and dexamethasone. In another aspect, provided is a combination comprising an anti-BCMA antigen binding protein, lenalidomide and dexamethasone for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient. In another aspect, provided is use of a combination comprising an anti-BCMA antigen binding protein, lenalidomide and dexamethasone in the manufacture of a medicament for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient.

[0268] In one aspect, provided is a method of treating multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient comprising administering to the human patient an anti-BCMA antigen binding protein, pomalidomide and dexamethasone. In another aspect, provided is a combination comprising an anti-BCMA antigen binding protein, pomalidomide and dexamethasone for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient. In another aspect, provided is use of a combination comprising an anti-BCMA antigen binding protein, pomalidomide and dexamethasone in the manufacture of a medicament for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient.

[0269] In another aspect, provided is a method of treating multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib and dexamethasone. In another aspect, provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib and dexamethasone for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient. In another aspect, provided is use of a combination comprising an anti-BCMA antigen binding protein, bortezomib and dexamethasone in the manufacture of a medicament for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient.

[0270] In one aspect, provided is a method of treating multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient comprising administering to the human patient an anti-BCMA antigen binding protein, carfilzomib and dexamethasone. In another aspect, provided is a combination comprising an anti-BCMA antigen binding protein, carfilzomib and dexamethasone for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient. In another aspect, provided is use of a combination comprising an anti-BCMA antigen binding protein, carfilzomib and dexamethasone in the manufacture of a medicament for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient.

[0271] In one aspect, provided is a method of treating multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, lenalidomide and dexamethasone. In another aspect, provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, lenalidomide and dexamethasone for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient. In another aspect, provided is use of a combination comprising an anti-BCMA antigen binding protein, bortezomib, lenalidomide and dexamethasone in the manufacture of a medicament for use in the treatment of multiple myeloma (e.g., relapsed and / or refractory multiple myeloma or TI-NDMM) in a human patient.

[0272] As used herein, “newly-diagnosed multiple myeloma” or “NDMM” refers to a diagnosis of multiple myeloma in patient who has not been previously treated for multiple myeloma or smoldering myeloma. As used herein, “transplant-ineligible newly-diagnosed multiple myeloma” or “TI-NDMM” refers to a diagnosis of multiple myeloma in a patient who has not been previously treated for multiple myeloma or smoldering myeloma and who is ineligible for autologous stem cell transplantation (ASCT) at the time of diagnosis or treatment initiation. Patients can be ineligible for ASCT due to factors such as age (e.g., over 70 years of age), frailty, and / or other comorbidities.

[0273] The term “treating,” and derivatives thereof as used herein, is meant to include therapeutic therapy. In reference to a particular condition, treating means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition; (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition; (3) to alleviate one or more of the symptoms, effects or side effects associated with the condition or one or more of the symptoms, effects or side effects associated with the condition or treatment thereof; (4) to slow the progression of the condition or one or more of the biological manifestations of the condition and / or (5) to cure said condition or one or more of the biological manifestations of the condition by eliminating or reducing to undetectable levels one or more of the biological manifestations of the condition for a period of time considered to be a state of remission for that manifestation without additional treatment over the period of remission. One skilled in the art will understand the duration of time considered to be remission for a particular disease or condition.

[0274] In particular, “treating” as used herein with reference to treating or treatment of multiple myeloma, such as NDMM, TI-NDMM or RRMM, refers to: (1) ameliorating multiple myeloma or one or more of the biological manifestations of multiple myeloma; (2) interfering with (a) one or more points in the biological cascade that leads to or is responsible for multiple myeloma or (b) one or more of the biological manifestations of multiple myeloma; (3) alleviating one or more of the symptoms, effects or side effects associated with multiple myeloma or one or more of the symptoms, effects or side effects associated with multiple myeloma or treatment thereof; (4) slowing the progression of multiple myeloma or one or more of the biological manifestations of multiple myeloma and / or (5) curing multiple myeloma or one or more of the biological manifestations of multiple myeloma by eliminating or reducing to undetectable levels one or more of the biological manifestations of multiple myeloma for a period of time considered to be a state of remission for that manifestation without additional treatment over the period of remission. Examples of biological manifestations of multiple myeloma include, but are not limited to urine and / or serum M-protein, serum free light chain (FLC), and presence of plasma cells in bone marrow aspirates.

[0275] The term “progression” of tumor growth or a “progressive disease” (“PD”) as used herein in reference to cancer (e.g., multiple myeloma) status indicates an increase in soluble markers, for example serum M-protein and urine M-protein. In some embodiments, progressive disease is measured and defined as per International Myeloma Working Group (IMWG) criteria (see, e.g., Kumar S, Paiva B, Anderson KC., et al. International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-46.). In some embodiments, progressive disease refers to an increase of at least 25% from lowest confirmed response value in one or more of the following criteria: (1) serum M-protein (absolute increase of > 0.5 g / dL); (2) serum M-protein increase > 1 g / dL, if the lowest M component is > 5 g / dL; (3) urine M-protein (absolute increase of > 200 mg / 24 hours); (4) in patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved free light chain (FLC) levels (absolute increase of > 10 mg / dL); (5) in patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase of > 10%); (6) appearance of a new lesion(s), > 50% increase from nadir in the sum of the products of the maximal perpendicular diameters of measured lesions of >1 lesion, or >50% increase in the longest diameter of a previous lesion >1 cm in short axis; and / or (7) > 50% increase in circulating plasma cells (minimum of 200 cells per pL) if this is the only measure of disease.

[0276] In one embodiment, treating or treatment of multiple myeloma refers to ameliorating or slowing the progression of multiple myeloma or one or more biological manifestations of multiple myeloma as measured by progression free survival (PFS). The term “progression free survival” or “PFS” is defined as the time from the date of randomization (when treatment is in the context of a clinical study) or start of a treatment regimen (when treatment is in the real world setting) to the date of first documented disease progression per International Myeloma Working Group (IMWG) criteria or death from any cause in the absence of progression, whichever occurs first.

[0277] In one embodiment, treating or treatment of multiple myeloma refers to eliminating or reducing biological manifestations of multiple myeloma to undetectable levels as measured by achievement of minimal residual disease (MRD) negative status. The term “minimal residual disease negative status” or “MRD negative status” is defined as achieving MRD negativity at 10’5sensitivity threshold (1 nucleated tumor cell in 100,000 normal cells) assessed by next-generation sequencing (NGS) at least once during the time of confirmed complete response (CR), or better response per IMWG criteria. The MRD negativity rate is defined as the percentage of subjects who are MRD negative or have achieved MRD negative status determined by NGS based on sensitivity of 10-5.

[0278] In another embodiment, treating or treatment of multiple myeloma refers to ameliorating or slowing the progression of multiple myeloma or one or more biological manifestations of multiple myeloma as measured by overall survival (OS), complete response or better (CR+), very good partial response or better (VGPR+), duration of response (DoR), and / or time to second or next line of therapy (TSST). “Overall survival” or “OS” is defined as time from the date of randomization (when treatment is in the context of a clinical study) or start of a treatment regimen (when treatment is in the real world setting) to the date of death due to any cause. “Complete response or better” or “CR+” is defined as confirmed complete response or better per International Myeloma Working Group (IMWG) criteria. “Very good partial response or better” or “VGPR+” is defined as confirmed VGPR or better per IMWG criteria. “Duration of response” or “DoR” is defined as the time from first documented evidence of partial response (PR) or better until progressive disease (PD) or death due to PD, among participants who achieve confirmed PR. “Time to second or next line of therapy” or “TSST” is defined as the time from the date of randomization (when treatment is in the context of a clinical study) or start of a treatment regimen (when treatment is in the real world setting) until the start date of second subsequent line of anti-myeloma therapy (irrespective of PD) or death due to any cause, whichever is earlier.

[0279] In one embodiment, a method of treatment and / or combination for use as described herein increases progression free survival (PFS) in a human patient diagnosed with multiple myeloma, such as TI-NDMM or RRMM. In some embodiments, PFS is increased relative to PFS observed with other anti-myeloma therapies or treatment regimens, such as treatment with daratumamab in combination with standard of care (e.g., lenalidomide in combination with dexamethasone; or lenalidomide in combination with bortezomib and dexamethasone).

[0280] In one embodiment, PFS in a NDMM patient population is at least double the PFS as compared to the PFS observed for standard of care therapy for the same patient population. In one embodiment, PFS is at least 60 months to at least 110 months, such as at least 60 months, at least 65 months, at least 70 months, at least 75 months, at least 80 months, at least 85 months, at least 90 months, at least 95 months, at least 100 months, at least 105 months, or at least 110 months. In another embodiment, PFS is 60 months to 70 months, 70 months to 80 months, 80 months, to 90 months, 90 months to 100 months, or 100 months of 110 months. In one embodiment, PFS is 60 months to 110 months, such as 60 months, 65 months, 70 months, 75 months, 80 months, 85 months, 90 months, 95 months, 100 months, 105 months, or 110 months. In some embodiments, the observed PFS shows a 50% reduction to 60% reduction in the risk of disease progression or death compared to standard of care therapy for the same NDMM patient population, such as a 50% reduction, 51% reduction, 52% reduction, 53% reduction, 54% reduction, 55% reduction, 56% reduction, 57% reduction, 58% reduction, 59% reduction, or 60% reduction in the risk of disease progression or death compared to standard of care therapy for the same NDMM patient population. In one embodiment, PFS in a RRMM patient population is at least triple the PFS as compared to the PFS observed for standard of care therapy for the same patient population. In one embodiment, PFS is at least 35 months to 50 months, such as at least 35 months, at least 40 months, at least 45 months, or at least 50 months. In another embodiment, PFS is 35 months to 40 months, such as 35 months, 36 months, 37 months, 38 months, 39 months, or 40 months. In one embodiment, PFS is 35 months to 36 months, 35 months to 37 months, 38 months to 39 months, or 39 months to 40 months. In some embodiments, the observed PFS shows at least a 50% reduction in the risk of disease progression or death compared to standard of care therapy for the same RRMM patient population, such as at least a 50% reduction, at least a 55% reduction, at least a 60% reduction, at least a 65% reduction or at least a 70% reduction in the risk of disease progression or death compared to standard of care therapy for the same patient population. In some embodiments, the observed PFS shows a 50% reduction to 60% reduction in the risk of disease progression or death compared to standard of care therapy for the same patient population, such as a 50% reduction, 51% reduction, 52% reduction, 53% reduction, 54% reduction, 55% reduction, 56% reduction, 57% reduction, 58% reduction, 59% reduction, or 60% reduction in the risk of disease progression or death compared to standard of care therapy for the same RRMM patient population.

[0281] In one embodiment, a method of treatment and / or combination for use as described herein results in minimal residual disease (MRD) negative status in a human patient diagnosed with multiple myeloma, such as TI-NDMM or RRMM. In some embodiments, the MRD negative rate in patients treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) according to the methods described herein is at least double the MRD negative rate observed in patients treated with other antimyeloma therapies or treatment regimens, such as treatment with daratumamab in combination with standard of care (e.g., lenalidomide in combination with dexamethasone or lenalidomide in combination with bortezomib and dexamethasone). In some embodiments, the MRD negative rate is at least 10%, at least 15 %, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, or at least 50%. In some embodiments, the MRD negative rate is 10% to 15%, 15% to 20%, 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, 40% to 45%, or 45% to 50%. In some embodiments, the MRD negative rate is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, there is at least a 5%, at least 10%, at least 15%, at least 20% or at least 25% difference in the MRD negative rate between patients treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) in combination with lenalidomide, pomalidomide, bortezomib, carfilzomib and / or dexamethasone according to the methods described herein versus patients treated with standard of care therapy (e.g., daratumumab containing regimens).

[0282] Subjects (e.g., human patients) may have had at least one prior therapy for multiple myeloma before being treated for multiple myeloma according to the methods described herein. In one embodiment, the subject (e.g., human patient) has been treated with at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 prior lines of therapy for multiple myeloma before being treated according to the methods described herein. In another embodiment, the subject (e.g., human patient) has been treated with 1 or 2 prior lines of therapy for multiple myeloma before being treated according to the methods described herein.

[0283] In an embodiment, a subject (e.g., human patient) has relapsed and / or refractory multiple myeloma, newly-diagnosed multiple myeloma, transplant-ineligible multiple myeloma, or transplant-ineligible newly-diagnosed multiple myeloma. In an embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has been treated with at least one prior line of treatment, at least 2 prior lines of treatment, at least three prior lines of treatment, or at least 4 prior lines of treatment. In another embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has previously been treated with 1 or 2 prior lines of therapy. In another embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has previously been treated with 1 prior line of therapy. In another embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has previously been treated with 2 prior lines of therapy. Lines of therapy may be defined by consensus panel of the International Myeloma Workshop (IMWG). The prior treatments to treat the multiple myeloma can be selected from an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or a combination thereof.

[0284] In another embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has previously been treated with at least 3 prior lines of therapy that may include the following: an immunomodulatory drug (I MiD), a proteasome inhibitor (PI) and anti-CD38 treatment (e.g., daratumumab) or combinations thereof. In another embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has previously been treated with at least two prior lines of therapy including a proteasome inhibitory and immunomodulatory agent. In another embodiment, the subject (e.g., human patient) has relapsed and / or refractory multiple myeloma and has previously treated with at least one prior line of therapy including lenalidomide.

[0285] In another embodiment, the subject (e.g., human patient) has newly diagnosed multiple myeloma. Subjects (e.g., human patients) with newly diagnosed multiple myeloma have had 0 prior therapies for multiple myeloma or smoldering myeloma before being treated according to the methods described herein. In some embodiments, a subject (e.g., human patient) that is newly diagnosed with multiple myeloma is ineligible for autologous stem cell transplantation (ASCT) at the time of diagnosis or treatment initiation (TI-NDMM). In some embodiments, a subject (e.g., human patient) that is newly diagnosed with multiple myeloma is eligible for autologous stem cell transplantation (ASCT) at the time of diagnosis or treatment initiation (TE-NDMM). Transplant eligible subjects may choose to defer or delay undergoing to ASCT, such as due to the availability of other treatment options. Subjects (e.g., human patients) diagnosed with NDMM, including TI-NDMM and TE-NDMM can be treated according to the methods described herein.

[0286] According to embodiments of the invention, anti-BCMA antigen binding proteins can be administered by any suitable route of administration, such as oral, parenteral (including subcutaneous, intramuscular, intravenous, intrathecal, and epidural) and intratumorally. The terms "administering" and “administer” as used herein are meant to refer to the delivery of a therapeutic agent to a human patient herein to achieve a therapeutic objective. The therapeutic agents can be administered at an administration interval for a period sufficient to achieve clinical benefit. In one embodiment, an anti-BCMA antigen binding protein is administered intravenously.

[0287] The term "therapeutically effective amount" or "therapeutically effective dose" when used with reference to an anti-BCMA antigen binding protein as described herein refers to an amount effective in the treatment of multiple myeloma, such as relapsed and / or refractory multiple myeloma or TI-NDMM.

[0288] According to the methods and combinations described herein, an anti-BCMA antigen binding protein is co-administered to a subject (e.g., a human patient) with one or more additional cancer therapeutic agents, particularly anti-multiple myeloma agents. The additional cancer therapeutic agents include, but are not limited to, immunomodulatory imide drugs (IMiD) (e.g., thalidomide and analogs thereof), proteasome inhibitors, and corticosteroids. Examples of immunomodulatory imide drugs include lenalidomide and pomalidomide. Examples of proteasome inhibitors include bortezomib and carflizomib. Examples of corticosteroids include dexamethasone.

[0289] "Co-administered" or “administered in combination with” mean the administration of two or more different pharmaceutical compositions or treatments that are administered to a subject by combination in the same pharmaceutical composition or separate pharmaceutical compositions. Thus, co-administration involves administration at the same time of a single pharmaceutical composition comprising two or more pharmaceutical agents or administration of two or more different compositions to the same subject at the same or different times.

[0290] In some embodiments, an anti-BCMA antigen binding protein is administered to a subject (e.g., a human patient) in combination with lenalidomide and dexamethasone. In some embodiments, an anti-BCMA antigen binding protein administered to a subject (e.g., a human patient) in combination with pomalidomide and dexamethasone. In some embodiments, an anti-BCMA antigen binding protein is administered to a subject (e.g., a human patient) in combination with bortezomib and dexamethasone. In some embodiments, an anti-BCMA antigen binding protein is administered to a subject (e.g., a human patient) in combination with carflizomib and dexamethasone. In some embodiments, an anti-BCMA antigen binding protein is administered to a subject (e.g., a human patient) in combination with bortezomib, lenalidomide and dexamethasone.

[0291] Lenalidomide is an immunomodulatory imide drug (I MiD) useful in the treatment of multiple myeloma. Lenalidomide is registered under the trade name REVLIMID®.

[0292] Lenalidomide has the following structure:

[0293]

[0294] . Lenalidomide is typically administered orally.

[0295] Dexamethasone is a corticosteroid registered under the trade names DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, and MAXIDEX®.

[0296]

[0297] Dexamethasone is typically administered orally.

[0298] Pomalidomide is an immunomodulatory imide drug (I MiD) useful in the treatment of multiple myeloma. Pomalidomide is registered under the trade name POMALYST®.

[0299] Pomalidomide has the following structure:

[0300]

[0301] Pomalidomide is typically administered orally.

[0302] Bortezomib is a proteasome inhibitor useful in the treatment of multiple myeloma. Bortezomib is registered under the trade name VELCADE®. Bortezomib has the

[0303] following structure:

[0304]

[0305] . Bortezomib is typically administered subcutaneously. Carflizomib is a proteasome inhibitor useful in the treatment of multiple myeloma. Carflizomib is registered under the trade name KYPROLIS®. Carflizomib has the

[0306] following structure:

[0307]

[0308] Carflizomib is typically administered intravenously.

[0309] In some embodiments, the methods and combinations provided herein are for treatment of relapsed and / or refractory multiple myeloma, newly-diagnosed multiple myeloma, transplant-ineligible multiple myeloma, or transplant-ineligible newly diagnosed multiple myeloma.

[0310] In some embodiments, the methods and combinations provided herein are for treatment of newly diagnosed multiple myeloma, including transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM). A human patient newly diagnosed multiple myeloma, including TI-NDMM has not received any prior line of anti-myeloma therapy.

[0311] In some embodiments, the methods and combinations provided herein are for treatment of relapsed and / or refractory multiple myeloma (RRMM). A human patient diagnosed with RRMM has received at least one prior line of therapy for multiple myeloma, such as one or two prior lines of therapy.

[0312] In one embodiment of the methods and combinations described herein, the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, a CDRH2 of SEQ ID NO: 2, a CDRH3 of SEQ ID NO: 3, a CDRL1 of SEQ ID NO: 4, a CDRL2 of SEQ ID NO: 5, and a CDRL3 of SEQ ID NO: 6. In one embodiment, the anti-BCMA antigen binding protein comprises a variable heavy chain (VH) region comprising the amino acid sequence of SEQ ID NO: 7 and a variable light chain (VL) region comprising the amino acid sequence of SEQ ID NO: 8. In one embodiment, the anti-BCMA antigen binding protein comprises a light chain (LC) having the amino acid sequence of SEQ ID NO: 9 and a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 10. In one embodiment, the anti-BCMA antigen binding protein is afucosylated. In another embodiment, the anti-BCMA antigen binding protein is belantamab.

[0313] In other embodiments of the methods and combinations described herein, the anti-BCMA antigen binding protein is an anti-BCMA antibody conjugated to a cytotoxic agent to form an antibody drug conjugate (ADC). In one embodiment, the anti-BCMA ADC comprises an anti-BCMA antibody conjugated to MMAE or MMAF. In one embodiment, the anti-BCMA ADC comprises an anti-BCMA antibody conjugated to MMAE or MMAF via a non-cleavable linker. In one embodiment, the anti-BCMAADC comprises an anti-BCMA antibody conjugated to MMAE or MMAF via a non-cleavable linker, wherein the non-cleavable linker is 6-maleimidocaproyl (MC).

[0314] In one embodiment of the methods and combinations described herein, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAE or MMAF, wherein the anti-BCMA antibody is belantamab.

[0315] In one embodiment of the methods and combinations described herein, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF, wherein the anti-BCMA antibody is belantamab.

[0316] In one embodiment of the methods and combinations described herein, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises any one or a combination of the following CDRs: CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and / or CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6. In another embodiment, an anti-BCMA antibody drug conjugate comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 7 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 8.

[0317] In yet another embodiment of the methods and combinations described herein, an anti-BCMA antibody drug conjugate is belantamab mafodotin. Belantamab mafodotin comprises an anti-BCMA antibody conjugated to MMAF via a linker, wherein the linker is 6- maleimidocaproyl (MC), and wherein the anti-BCMA antibody comprises a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) having the amino acid sequence of SEQ ID NO: 10.

[0318] In one embodiment of the methods and combinations described herein, the anti-BCMA antigen binding protein is administered to the human patient at a dose of 1.0 mg / kg to 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg to 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks.

[0319] In one embodiment, the anti-BCMA antigen binding protein is administered to the human patient at a dose of 1.0 mg / kg, 1.4 mg / kg, 1.9 mg / kg, or 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg, 1.4 mg / kg, 1.9 mg / kg, or 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks.

[0320] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.0 mg / kg Q12W after the initial 24 week period.

[0321] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.4 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.4 mg / kg Q12W after the initial 24 week period.

[0322] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.9 mg / kg Q12W after the initial 24 week period. In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 2.5 mg / kg Q12W after the initial 24 week period.

[0323] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.9 mg / kg Q12W after the initial 24 week period.

[0324] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.4 mg / kg Q12W after the initial 24 week period.

[0325] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.0 mg / kg Q12W after the initial 24 week period.

[0326] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.4 mg / kg Q12W after the initial 24 week period.

[0327] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.0 mg / kg Q12W after the initial 24 week period.

[0328] In one embodiment, belantamab mafodotin is administered at a dose of 1.0 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.0 mg / kg Q12W after the initial 24 week period.

[0329] In one embodiment, belantamab mafodotin is administered at a dose of 1.4 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.4 mg / kg Q12W after the initial 24 week period.

[0330] In one embodiment, belantamab mafodotin is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.9 mg / kg Q12W after the initial 24 week period.

[0331] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 2.5 mg / kg Q12W after the initial 24 week period. In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.9 mg / kg Q12W after the initial 24 week period.

[0332] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.4 mg / kg Q12W after the initial 24 week period.

[0333] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.0 mg / kg Q12W after the initial 24 week period.

[0334] In one embodiment, belantamab mafodotin is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.4 mg / kg Q12W after the initial 24 week period.

[0335] In one embodiment, belantamab mafodotin is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.0 mg / kg Q12W after the initial 24 week period.

[0336] In some embodiments of the methods and combinations described herein, the anti-BCMA antigen binding protein is administered to the human patient at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0337] In some embodiments, the anti-BCMA antigen binding protein is administered to the human patient at a dose of 1.0 mg / kg, 1.4 mg / kg, 1.9 mg / kg or 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0338] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0339] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.4 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0340] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0341] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0342] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.9 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0343] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.4 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0344] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.0 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0345] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.4 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0346] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.0 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days. In one embodiment, belantamab mafodotin is administered at a dose of 1.0 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0347] In one embodiment, belantamab mafodotin is administered at a dose of 1.4 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0348] In one embodiment, belantamab mafodotin is administered at a dose of 1.9 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0349] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0350] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.9 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0351] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.4 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0352] In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.0 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0353] In one embodiment, belantamab mafodotin is administered at a dose of 1.9 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.4 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0354] In one embodiment, belantamab mafodotin is administered at a dose of 1.9 mg / kg on day 1 of treatment cycles 1, 3 and 5 and at a dose of 1.0 mg / kg on day 1 of every third treatment cycle from treatment cycle 8 onward, wherein each treatment cycle is 28 days.

[0355] In other embodiments of the methods and combinations described herein, the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0356] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg, 1.4 mg / kg, 1.9 mg / kg, or 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.0 mg / kg, 1.4 mg / kg, 1.9 mg / kg, or 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0357] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.0 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0358] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.4 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0359] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0360] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0361] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0362] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0363] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.0 mg / kg on day 1 of an 84-day treatment cycle thereafter. In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0364] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.0 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0365] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a first 56-day treatment cycle and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, and then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0366] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a first 56-day treatment cycle and at a dose of 1.4 mg / kg on day 1 of the second and third 56-day treatment cycles, and then at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0367] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.4 mg / kg on day 1 of a first 56-day treatment cycle and at a dose of 1.0 mg / kg on day 1 of the second and third 56-day treatment cycles, and then at a dose of 1.0 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0368] In some embodiments of the methods and compositions described herein, a patient has newly diagnosed multiple myeloma, and the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0369] In some embodiments of the methods and compositions described herein, a patient has transplant ineligible newly diagnosed multiple myeloma, and the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0370] In some embodiments of the methods and compositions described herein, a patient has relapsed and / or refractory multiple myeloma and the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a first 56-day treatment cycle and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, and then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter.

[0371] In some embodiments of the methods and compositions described herein, the anti-BCMA antigen binding protein is administered at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle starting at week 52 of treatment (1 year).

[0372] In some embodiments of the methods and compositions described herein, the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, then at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle for two to three cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In one embodiment, the anti-BCMA antigen binding protein is administered at dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, then at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle for two cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In one embodiment, the anti-BCMA antigen binding protein is administered at dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, then at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle for three cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

[0373] In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle for two to three cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In one the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle for two cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In another embodiment, the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle for three cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In one embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a first 56-day treatment cycle, then at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle for two to three cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In another embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a first 56-day treatment cycle, then at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle for two cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter. In another embodiment, the anti-BCMA antigen binding protein is administered at a dose of 2.5 mg / kg on day 1 of a first 56-day treatment cycle, then at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, then at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle for three cycles, and then at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

[0374] Combinations of anti-BCMA antigen binding protein, lenalidomide and dexamethasone In one aspect, an anti-BCMA antigen binding protein is administered in combination with lenalidomide and dexamethasone. The anti-BCMA antigen binding protein can be administered according to any of the embodiments described herein in combination with lenalidomide and dexamethasone.

[0375] In some embodiments, lenalidomide is administered to a human patient at a dose of 25 mg, 10 mg, or 7.5 mg on each of days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 25 mg on each of days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 7.5 mg on each of days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 15 mg every other day on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, the human patient has an estimated glomerular filtration rate (eGFR) of 30-60 mL / min / 1.73 m2and is administered lenalidomide at a dose of 10 mg on each of days 1 -21 of each 28-day lenalidomide treatment cycle. In some embodiments, the human patient has an estimated glomerular filtration rate (eGFR) of <30 mL / min / 1.73 m2and is administered lenalidomide at a dose of (i) 7.5 mg on each of days 1-21 of each 28-day lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days.

[0376] In some embodiments, dexamethasone is administered to a human patient at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In one embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, the human patient is less than 75 years old and is administered dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient is at least 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient has a body mass index (BMI) of less than 18.5, poorly controlled diabetes mellitus, comorbidities and / or prior intolerance / adverse event to steroid therapy and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle.

[0377] In some embodiments, an initial dose of the anti-BCMA antigen binding protein is administered to the human patient on day 1 of both the first lenalidomide treatment cycle and the first dexamethasone treatment cycle. In other words, treatment with the anti-BCMA antigen binding protein, lenalidomide, and dexamethasone is started on the same day and treatment with each agent is administered according to the respective dosing regimen / schedule for each agent. For example, the anti-BCMA antigen binding protein, lenalidomide and dexamethasone can be administered over the course of a treatment period as described in Table 3A below.

[0378] Table 3A: Dosing schedule during treatment period

[0379]

[0380] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone, or provided is a combination comprising an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma, wherein:

[0381] (d) the anti-BCMA antigen binding protein is administered:

[0382] iii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0383] iv. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0384] (e) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0385] (f) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).

[0386] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient belantamab mafodotin, lenalidomide, and dexamethasone, or provided is a combination comprising belantamab mafodotin, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma, wherein:

[0387] (a) the belantamab mafodotin is administered:

[0388] i. at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0389] ii. at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0390] (b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”) at a dose of 25 mg, 10 mg, or 7.5 mg on each of days 1-21 of each lenalidomide treatment cycle; and (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”) at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

[0391] Combinations of anti-BCMA antigen binding protein, pomalidomide and dexamethasone In one aspect, an anti-BCMA antigen binding protein is administered in combination with pomalidomide and dexamethasone. The anti-BCMA antigen binding protein can be administered according to any of the embodiments described herein in combination with pomalidomide and dexamethasone.

[0392] In some embodiments, pomalidomide is administered to a human patient at a dose of 4 mg on each of days 1-21 of each pomalidomide treatment cycle, wherein each pomalidomide treatment cycle is 28 days.

[0393] In some embodiments, dexamethasone is administered to a human patient at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In one embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, the human patient is less than 75 years old and is administered dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient is at least 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, a human patient has a body mass index (BMI) of less than 18.5, poorly controlled diabetes mellitus, comorbidities and / or prior intolerance / adverse event to steroid therapy and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle.

[0394] In some embodiments, an initial dose of the anti-BCMA antigen binding protein is administered to the human patient on day 1 of both the first pomalidomide treatment cycle and the first dexamethasone treatment cycle. In other words, treatment with the anti-BCMA antigen binding protein, pomalidomide, and dexamethasone is started on the same day and treatment with each agent is administered according to the respective dosing regimen / schedule for each agent. For example, anti-BCMA antigen binding protein, pomalidomide and dexamethasone can be administered over the course of a treatment period as described in Table 3B below.

[0395] Table 3B: Dosing schedule during treatment period

[0396]

[0397] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone, or provided is a combination comprising an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone for use in the treatment of multiple myeloma, wherein:

[0398] (a) the anti-BCMA antigen binding protein is administered: i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0399] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0400] (b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and

[0401] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).

[0402] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient belantamab mafodotin, pomalidomide, and dexamethasone, or provided is a combination comprising belantamab mafodotin, pomalidomide, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0403] (a) the belantamab mafodotin is administered on a 56-day treatment cycle, wherein:

[0404] i. the belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle, and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, and then ii. the belantamab mafodotin is administered at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0405] (b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”) at a dose of 4 mg on each of days 1 -21 of each pomalidomide treatment cycle; and

[0406] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”) at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

[0407] Combinations of anti-BCMA antigen binding protein, bortezomib and dexamethasone In one aspect, an anti-BCMA antigen binding protein is administered in combination with bortezomib and dexamethasone. The anti-BCMA antigen binding protein can be administered according to any of the embodiments described herein in combination with bortezomib and dexamethasone. In one embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each bortezomib treatment cycle, wherein each bortezomib treatment cycle is 28 days. In another embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, and 15 of each bortezomib treatment cycle, wherein each bortezomib treatment cycle is 28 days. In some embodiments, bortezomib is administered for the first six 28-day bortezomib treatment cycles. In some embodiments, bortezomib is administered for the first eight 28-day bortezomib treatment cycles. In another embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each 28-day bortezomib treatment cycle for the first six 28-day bortezomib treatment cycles. In another embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, and 15 of each 28-day bortezomib treatment cycle, for the first eight 28-day bortezomib treatment cycles.

[0408] In some embodiments, dexamethasone is administered to a human patient at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In one embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle. In one embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle. In one embodiment, the human patient is less than 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient is at least 75 years old and is administered dexamethasone at a dose of 10 mg on days 11, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient has a body mass index (BMI) of less than 18.5, poorly controlled diabetes mellitus, comorbidities and / or prior intolerance / adverse event to steroid therapy and is administered dexamethasone at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle.

[0409] In some embodiments, dexamethasone is administered for the first six 28-day dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first six dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first six dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first six dexamethasone treatment cycles.

[0410] In some embodiments, dexamethasone is administered for the first eight 28-day dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first eight dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first eight dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first eight dexamethasone treatment cycles.

[0411] In some embodiments, an initial dose of the anti-BCMA antigen binding protein is administered to the human patient on day 1 of both the first bortezomib treatment cycle and the first dexamethasone treatment cycle. In other words, treatment with the anti-BCMA antigen binding protein, bortezomib, and dexamethasone is started on the same day and treatment with each agent is administered according to the respective dosing regimen / schedule for each agent. For example, anti-BCMA antigen binding protein, bortezomib and dexamethasone can be administered over the course of a treatment period as described in Table 3C below.

[0412] Table 3C: Dosing schedule during treatment period

[0413]

[0414]

[0415] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib and dexamethasone, or provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0416] (a) the anti-BCMA antigen binding protein is administered:

[0417] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0418] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0419] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and

[0420] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).

[0421] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient belantamab mafodotin, pomalidomide, and dexamethasone, or provided is a combination comprising belantamab mafodotin, bortezomib, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0422] (a) the belantamab mafodotin is administered on a 56-day treatment cycle, wherein: i. the belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle, and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, and then ii. the belantamab mafodotin is administered at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0423] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”) at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each bortezomib treatment cycle for the first six bortezomib treatment cycles; and

[0424] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”) at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each dexamethasone treatment cycle for the first six dexamethasone treatment cycles.

[0425] Combinations of anti-BCMA antigen binding protein, carflizomib and dexamethasone In one aspect, an anti-BCMA antigen binding protein is administered in combination with carflizomib and dexamethasone. The anti-BCMA antigen binding protein can be administered according to any of the embodiments described herein in combination with carflizomib and dexamethasone.

[0426] In some embodiments, carflizomib is administered to a human patient at a dose of 20 mg / m2or 70 mg / m2on days 1, 8, and 15 of each carflizomib treatment cycle, wherein each carflizomib treatment cycle is 28 days. In some embodiments, carfilzomib is administered at a dose of 20 mg / m2on day 1 and at a dose of 70 mg / m2on days 8 and 15 of the first 28-day carfilzomib treatment cycle; and carfilzomib is administered at a dose of 70 mg / m2on days 1, 8, and 15 of each 28-day carfilzomib treatment cycle thereafter.

[0427] In some embodiments, dexamethasone is administered to a human patient at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In one embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, the human patient is less than 75 years old and is administered dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient is at least 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, a human patient has a body mass index (BMI) of less than 18.5, poorly controlled diabetes mellitus, comorbidities and / or prior intolerance / adverse event to steroid therapy and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle.

[0428] In some embodiments, an initial dose of the anti-BCMA antigen binding protein is administered to the human patient on day 1 of both the first carflizomib treatment cycle and the first dexamethasone treatment cycle. In other words, treatment with the anti-BCMA antigen binding protein, carflizomib, and dexamethasone is started on the same day and treatment with each agent is administered according to the respective dosing regimen / schedule for each agent. For example, anti-BCMA antigen binding protein, carflizomib and dexamethasone can be administered over the course of a treatment period as described in Table 3D below.

[0429] Table 3D: Dosing schedule during treatment period

[0430]

[0431] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti- BCMA antigen binding protein, carfilzomib and dexamethasone, or provided is a combination comprising an anti-BCMA antigen binding protein, carflizomib, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0432] (a) the anti-BCMA antigen binding protein is administered:

[0433] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0434] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0435] (b) the carflizomib is administered on a 28-day treatment cycle (“carflizomib treatment cycle”); and

[0436] (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).

[0437] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient belantamab mafodotin, carflizomib, and dexamethasone, or provided is a combination comprising an belantamab mafodotin, carflizomib, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0438] (a) the belantamab mafodotin is administered on a 56-day treatment cycle, wherein:

[0439] i. the belantamab mafodotin is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle, and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles, and then ii. the belantamab mafodotin is administered at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0440] (b) the carflizomib is administered on a 28-day treatment cycle (“carflizomib treatment cycle”), wherein:

[0441] i. the carfilzomib is administered at a dose of 20 mg / m2on day 1 and at dose of 70 mg / m2on days 8 and 15 of the first carfilzomib treatment cycle; and

[0442] ii. the carfilzomib is administered at dose of 70 mg / m2on days 1, 8, and 15 of each carfilzomib treatment cycle thereafter; and (c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”) at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

[0443] Combinations of anti-BCMA antigen binding protein, bortezomib, lenalidomide and dexamethasone

[0444] In one aspect, an anti-BCMA antigen binding protein is administered in combination with bortezomib, lenalidomide and dexamethasone. The anti-BCMA antigen binding protein can be administered according to any of the embodiments described herein in combination with bortezomib, lenalidomide and dexamethasone.

[0445] In one embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each bortezomib treatment cycle, wherein each bortezomib treatment cycle is 28 days. In another embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, and 15 of each bortezomib treatment cycle, wherein each bortezomib treatment cycle is 28 days. In some embodiments, bortezomib is administered for the first six 28-day bortezomib treatment cycles. In some embodiments, bortezomib is administered for the first eight 28-day bortezomib treatment cycles. In another embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each 28-day bortezomib treatment cycle for the first six 28-day bortezomib treatment cycles. In another embodiment, bortezomib is administered to a human patient at a dose of 1.3 mg / m2on days 1, 8, and 15 of each 28-day bortezomib treatment cycle for the first eight 28-day bortezomib treatment cycles.

[0446] In some embodiments, lenalidomide is administered to a human patient at a dose of 25 mg, 15 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 25 mg on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 7.5 mg on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 15 mg every other day on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 10 mg every other day on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered to a human patient at a dose of 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, the human patient has an estimated glomerular filtration rate (eGFR) of 30-60 mL / min / 1.73 m2and is administered lenalidomide at a dose of 10 mg on days 1-21 of each 28-day lenalidomide treatment cycle. In some embodiments, the human patient has an estimated glomerular filtration rate (eGFR) of <30 mL / min / 1.73 m2and is administered lenalidomide at a dose of (i) 7.5 mg on days 1-21 of each 28-day lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days. In some embodiments, lenalidomide is administered for the first six 28-day lenalidomide treatment cycles. In some embodiments, lenalidomide is administered for the first eight 28-day lenalidomide treatment cycles. In some embodiments, lenalidomide is administered for the first nine 28-day lenalidomide treatment cycles.

[0447] In some embodiments, dexamethasone is administered to a human patient at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In one embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In one embodiment, the human patient is less than 75 years old and is administered dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient is at least 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In another embodiment, a human patient has a body mass index (BMI) of less than 18.5, poorly controlled diabetes mellitus, comorbidities and / or prior intolerance / adverse event to steroid therapy and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle. In some embodiments, dexamethasone is administered for the first six 28-day dexamethasone treatment cycles. In some embodiments, dexamethasone is administered for the first eight 28-day dexamethasone treatment cycles. In some embodiments, dexamethasone is administered for the first nine dexamethasone treatment cycles.

[0448] In some embodiments, dexamethasone is administered to a human patient at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle for the first four 28-day dexamethasone treatment cycles, and then at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle for the next five dexamethasone treatment cycles. In some embodiments, the human patient is at least 75 years old and dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 for the first four 28-day dexamethasone treatment cycles, and then at a dose of 10 mg or 12 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle for the next five dexamethasone treatment cycles.

[0449] In some embodiments, dexamethasone is administered to a human patient at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In one embodiment, the human patient is less than 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle. In another embodiment, the human patient is at least 75 years old and is administered dexamethasone at a dose of 10 mg on days 11, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle. In another embodiment, a human patient has a body mass index (BMI) of less than 18.5, poorly controlled diabetes mellitus, comorbidities and / or prior intolerance / adverse event to steroid therapy and is administered dexamethasone at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle.

[0450] In some embodiments, dexamethasone is administered for the first six 28-day dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first six dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first six dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first six dexamethasone treatment cycles.

[0451] In some embodiments, dexamethasone is administered for the first eight 28-day dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg or 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first eight dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first eight dexamethasone treatment cycles. In some embodiments, the dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day dexamethasone treatment cycle for the first eight dexamethasone treatment cycles.

[0452] In some embodiments, lenalidomide is administered to a human patient at a dose of 10 mg or 15 mg on days 1-21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; bortezomib is administered at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each bortezomib treatment cycle for the first eight bortezomib treatment cycles, wherein each bortezomib treatment cycle is 28 days; and dexamethasone is administered at a dose of 20 mg or 40 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. In some embodiments, dexamethasone is administered for the first eight 28-day dexamethasone treatment cycles.

[0453] In some embodiments, an initial dose of the anti-BCMA antigen binding protein is administered to the human patient on day 1 of the first bortezomib treatment cycle, the first lenalidomide treatment cycle, and the first dexamethasone treatment cycle. In other words, treatment with the anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone is started on the same day and treatment with each agent is administered according to the respective dosing regimen / schedule for each agent.

[0454] In one embodiment, provided herein is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, lenalidomide and dexamethasone, or provided is a combination comprising an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0455] (a) the anti-BCMA antigen binding protein is administered:

[0456] i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles, and then

[0457] ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;

[0458] (b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);

[0459] (c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and

[0460] (d) the dexamethasone is administered on a 28-day treatment cycle (“the dexamethasone treatment cycle”) thereafter.

[0461] In one embodiment, provided is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient belantamab mafodotin, bortezomib, lenalidomide, and dexamethasone, or provided is a combination comprising belantamab mafodotin, bortezomib, lenalidomide, and dexamethasone for use in the treatment of multiple myeloma wherein:

[0462] (a) the belantamab mafodotin is administered:

[0463] i. at a dose of 1.9 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then

[0464] ii. at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle

[0465] thereafter; (b) the bortezomib is administered at a dose of 1.3 mg / m2on days 1, 8, and 15 of each bortezomib treatment cycle for the first eight bortezomib treatment cycles;

[0466] (c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”) at a dose of 25 mg, 10 mg, or 7.5 mg on each of days 1-21 of each lenalidomide treatment cycle; and (d) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”) at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

[0467] Dose Modification

[0468] In some embodiments, the dose and / or dosing frequency, or dosing regimen, of the anti-BCMA antigen binding protein is modified due to ocular toxicity or an ocular adverse event. “Ocular toxicity” and “ocular adverse event” as used herein refer to any unintended exposure of a therapeutic agent to ocular tissue, and include changes in corneal epithelium, which may manifest with various symptoms including, but not limited to, dry eyes, irritation, redness, blurred vision, dry eyes, photophobia, and / or changes in visual acuity. Detection of ocular toxicity or an ocular adverse event may be determined by ophthalmic examination by an ophthalmologist or optometrist before, during and / or after treatment. An ophthalmic examination may include one or more of the following: best corrected visual acuity (BCVA); documentation of manifest refraction and the method used to obtain BCVA; current glasses prescription (if applicable); intraocular pressure measurement; anterior segment (slit lamp) examination including fluorescein staining of the cornea and lens examination; dilated funduscopic examination; and / or an ocular surface disease index (OSDI) which is visual function questionnaire that assess the impact of potential ocular change in vision on function and health-related quality of life.

[0469] Ocular toxicity or an ocular adverse event can also be determined by grading corneal events based on the keratopathy visual acuity (KVA) grading scale. The KVA grading scale incorporates corneal examination findings and the change in best corrected visual acuity (BCVA) from baseline. Corneal events are graded as either Grade 1, Grade 2, Grade 3, or Grade 4 based on a corneal examination finding and / or a change in BCVA. A corneal examination finding and / or a change in BCVA is then used to determine the grade per the KVA scale. The KVA scale for treatment-related corneal events is shown in Table 4 below.

[0470] Table 4: KVA scale for treatment-related corneal events

[0471]

[0472] Mild superficial keratopathy is documented worsening from baseline, with or without symptoms. Moderate superficial keratopathy is defined as any one or a combination of the following: moderate superficial punctate keratopathy, patchy microcyst-like deposits, sub-epithelial haze (peripheral), and / or a new peripheral stromal opacity. Severe superficial keratopathy is defined as any one or a combination of the following: severe superficial punctate keratopathy, diffuse microcyst-like deposits, sub-epithelial haze (central), and / or a new central stromal opacity. Corneal epithelial defect is an epithelial defect without concomitant stroma infiltration or infection. A corneal ulcer is an epithelial defect with underlying stromal infiltration, and infection.

[0473] A patient treated according to the methods and combinations described herein can experience an ocular adverse event as a result of treatment with an anti-BCMA antigen binding protein (e.g., anti-BCMA antibody drug conjugate). When a patient experiences an ocular adverse event, the dose and / or dosing frequency of the anti-BCMA antigen binding protein (e.g., anti-BCMA antibody drug conjugate) can be modified, depending on the grade of the ocular adverse event per the KVA scale. For corneal events related to treatment with an anti-BCMA antigen binding protein, determination of the recommended dose modification should be based on the most severe corneal event per the KVA scale. In some embodiments, the Grade of the ocular adverse event is determined based on an ophthalmic examination finding. In some embodiments, the ophthalmic examination finding comprises a corneal examination finding and / or a change in best-corrected visual acuity (BCVA) finding.

[0474] In some embodiments, a patient treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) according to the methods and combinations described herein experiences a Grade 1 ocular adverse event, as determined per the KVA scale. In such embodiments, the patient continues treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) at the current dose and dosing schedule.

[0475] In some embodiments, a patient treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) according to the methods and combinations described herein experiences a Grade 2, Grade 3, or Grade 4 ocular adverse event, as determined per the KVA scale. For management of a Grade 2, 3, or 4 ocular adverse event that occurs during treatment with the anti-BCMA antigen binding protein on a 56-day treatment cycle (Q8W), the dosage and / or dosing frequency of the anti-BCMA antigen binding protein can be reduced, e.g., from 1.9 mg / kg Q8W to 1.9 mg / kg on day 1 of an 84-day treatment cycle (Q12W) or from 2.5 mg / kg Q8W to 1.9 mg / kg on day 1 of a 56-day treatment cycle (Q8W). For management of persistent ocular toxicity (i.e., a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event after a first Grade 2, Grade 3, or Grade 4 ocular adverse event), the dosage and / or dosing frequency of the anti-BCMA antigen binding protein can be further reduced, e.g., from 1.9 mg / kg Q8W to 1.9 mg / kg on day 1 of an 84-day treatment cycle (Q12W) or from 1.9 mg / kg Q12W to 1.4 mg / kg on day 1 of a 112-day treatment cycle (Q12W). For management of a Grade 2, 3, or 4 ocular adverse event that occurs during treatment with the anti-BCMA antigen binding protein on an 84-day treatment cycle (Q12W), the dosage and / or dosing frequency of the anti-BCMA antigen binding protein can be reduced e.g., from 1.9 mg / kg Q12W to 1.4 mg / kg on day 1 of an 84-day treatment cycle (Q12W) or from 1.4 mg / kg Q12W to 1.4 mg / kg on day 1 of a 112-day treatment cycle (Q16W). In some embodiments, the patient continues treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) (i) at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle (Q12W) if the Grade 2, Grade 3, or Grade 4 ocular adverse event occurred during treatment with the anti-BCMA antigen binding protein at a dose of 1.9 mg / kg on a 56-day treatment cycle (Q8W), (ii) at a dose of 1.4 mg / kg on an 84-day treatment cycle (Q12W) if the Grade 2, Grade 3, or Grade 4 ocular adverse event occurred during treatment with the anti-BCMA antigen binding at a dose of 1.9 mg / kg on an 84-day treatment cycle (Q12W), or (iii) at a dose of 1.4 mg / kg on a 112-day treatment cycle (Q16W) if the Grade 2, Grade 3, or Grade 4 ocular adverse event occurred during treatment with the anti-BCMA antigen binding protein at a dose of 1.4 mg / kg on 84-day treatment cycle (Q12W).

[0476] In some embodiments, a patient has a subsequent ocular adverse event of Grade 2, Grade 3 or Grade 4 during treatment with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) at dose of 1.4 mg / kg on an 84-day treatment cycle (Q12W). In such embodiments, treatment with the anti-BCMA antigen binding protein can be resumed at an extended dosing schedule. In one embodiment, treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is resumed at a dose of 1.0 mg / kg to 1.4 mg / kg on day of an 84-day treatment cycle (Q12W) to day 1 of a 116-day treatment cycle (Q16W). In one embodiment, treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is resumed at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle (Q16W). In another embodiment, treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is resumed at a dose of 1.0 mg / kg on day 1 of an 84-day treatment cycle (Q12W). In another embodiment, treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is resumed at a dose of 1.0 mg / kg on day1 of a 112-day treatment cycle (Q16W).

[0477] Depending on the severity of the ocular adverse event (i.e., whether a Grade 2, 3 or 4 ocular adverse event), treatment with belantamab mafodotin can be withheld or delayed until there is an improvement in the ocular events before treatment with belantamab mafodotin is resumed according to the modified dose / dosing schedule, e.g., either at a reduced dose and / or extended dosing interval. In some embodiments, when a patient experiences a Grade 2, 3 or 4 ocular adverse event, treatment with belantamab mafodotin is withheld and not restarted again until the ocular adverse event resolves to a Grade 1 or lower, per the KVA scale. Resolution of the ocular adverse event can be based on an improvement in corneal examination findings and / or changes in BCVA.

[0478] According to embodiments of the invention, dosing of the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) can be adjusted (e.g., by reducing the dosage and / or dosing frequency) as described herein due to an ocular adverse event that occurs during treatment with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) in combination with lenalidomide / dexamethasone, pomalidomide / dexamethasone, bortezomib / dexamethasone, carfilzomib / dexamethasone, or bortezomib / lenalidomide / dexamethasone.

[0479] In one embodiment, an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is administered to a patient at a dose of 1.9 mg / kg on day 1 of each 56-day treatment cycle for three cycles, and the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first, second, or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle (Q12W) thereafter. In some embodiments, the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle, administration of the anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein (e.g., belantamamb mafodotin) to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle (Q12W) thereafter. In some embodiments, the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of (i) 1.4 mg / kg on day 1 of a 112-day treatment cycle (Q16W) thereafter; (ii) 1.0 mg / kg on day 1 of an 84-day treatment cycle (Q12W) thereafter; or (iii) 1.0 mg / kg on day 1 of a 112-day treatment cycle (Q16W) thereafter. In one embodiment, an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) is administered to a patient at dose of 2.5 mg / kg on day 1 of a first 56-day treatment cycle and has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first 56-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient is resumed at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles. In one embodiment, the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the second or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.9 mg / kg on day 1 of an 84-day treatment cycle thereafter. In one embodiment, the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle, administration of the anti-BCMA antigen binding protein to the patient is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter. In one embodiment, the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated is initiated at a dose of (i) 1.4 mg / kg on day 1 of a 112-day treatment cycle (Q16W) thereafter; (ii) 1.0 mg / kg on day 1 of an 84-day treatment cycle (Q12W) thereafter; or (iii) 1.0 mg / kg on day 1 of a 112-day treatment cycle (Q16W) thereafter.

[0480] According to embodiments of the invention, methods of treatment and / or combinations for use as described herein result in reduced rates of ocular adverse events and / or a reduced percentage of Grade 3 and / or Grade 4 ocular adverse events observed in patients during treatment with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) as compared to more frequent dosing with the anti-BCMA antigen binding protein (e.g., belantamab mafodotin), such as dosing at on a 21 -day treatment cycle (Q3W) or a 28-day treatment cycle (Q4W), or continued dosing on a 56-day treatment cycle (Q8W). In some embodiments, such reduced rates of ocular adverse events are observed while maintaining efficacy as measured by progression free survival (PFS), minimal residual disease (MRD) negativity, and / or overall survival (OS).

[0481] In one embodiment, Grade 4 ocular adverse events are observed in 5% or less of patients treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) according to the methods described herein. In one embodiment, Grade 4 ocular adverse events are observed in 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less of patients. In one embodiment, Grade 4 ocular adverse events are observed in 5%, 4%, 3%, 2%, or 1 % of patients.

[0482] In one embodiment, Grade 3 ocular adverse events are observed in 20% or less of patients treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) according to the methods described herein. In one embodiment, Grade 3 ocular adverse events are observed in 20% or less, 15% or less, 10% or less, or 5% or less of patients. In one embodiment, Grade 3 ocular adverse events are observed in 20%, 15%, 10%, or 5% of patients.

[0483] In one embodiment, Grade 2 ocular adverse events are observed in less than 20% of patients treated with an anti-BCMA antigen binding protein (e.g., belantamab mafodotin) according to the methods described herein. In one embodiment, Grade 2 ocular adverse events are observed in 20% or less, 15% or less, 10% or less, or 5% or less of patients. In one embodiment, Grade 2 ocular adverse events are observed in 20%, 15%, 10%, or 5% of patients.

[0484] In other embodiments, methods of treatment and / or combinations for use as described herein result in a reduced percentage of dose holds or dose delays of an anti-BCMA antigen binding protein. A “dose hold” or “dose delay” used herein with respect to treatment with an anti-BCMA antigen binding protein refers to withholding treatment of the anti-BCMA antigen binding protein from a patient upon observing an ocular adverse event in the patient during treatment with the anti-BCMA antigen binding protein. Typically, observance of a Grade 2, Grade 3, or Grade 4 ocular adverse event in a patient will result in a dose hold or dose delay, and treatment with the anti-BCMA antigen binding protein following a dose hold or dose delay will not be resumed until the ocular adverse event resolves to a Grade 1 or lower. In one embodiment, 35% or less of patients experience a dose hold or dose delay. In one embodiment, 20% or less of patients experience a dose hold or dose delay. In one embodiment, 35% or less, 30% or less, 25% or less, 20% or less, 15% or less, or 10% or less of patients experience a dose hold or dose delay. In one embodiment, 35%, 30%, 25%, 20%, 15%, or 10% of patients experience a dose hold or dose delay.

[0485] EMBODIMENTS

[0486] Embodiment 1 is a method of treating multiple myeloma in a human patient, the method comprising administering to the human patient:

[0487] (a) an anti-BCMA antigen binding protein at a dose of 1.0 mg / kg to 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg to 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks, wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6;

[0488] (b) lenalidomide at a dose of (i) 25 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; and

[0489] (c) dexamethasone at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days.

[0490] Embodiment 2 is the method of embodiment 1, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma, newly-diagnosed multiple myeloma, transplant-ineligible multiple myeloma, or transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM).

[0491] Embodiment 3 is the method of embodiments 1 or 2, wherein the multiple myeloma is transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM). Embodiment 4 is the method of any one of embodiments 1 -3, wherein an initial dose of the anti-BCMA antigen binding protein is administered to the human patient on day 1 of both the lenalidomide treatment cycle and the dexamethasone treatment cycle.

[0492] Embodiment 5 is the method of any one of embodiments 1 -4, wherein the anti-BCMA antigen binding protein comprises a variable heavy chain (VH) region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7 and a variable light chain (VL) region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 8.

[0493] Embodiment 6 is the method of any one of embodiments 1 -5, wherein the anti-BCMA antigen binding protein comprises a variable heavy chain (VH) region comprising the amino acid sequence of SEQ ID NO: 7 and a variable light chain (VL) region comprising the amino acid sequence of SEQ ID NO: 8.

[0494] Embodiment 7 is the method of any one of embodiments 1 -6, wherein the anti-BCMA antigen binding protein comprises a light chain (LC) having the amino acid sequence of SEQ ID NO: 9 and a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 10.

[0495] Embodiment 8 is the method of any one of embodiments 1 -7, wherein the anti-BCMA antigen binding protein is belantamab.

[0496] Embodiment 9 is the method of any one of embodiments 1 -8, wherein the anti-BCMA antigen binding protein is an anti-BCMA antibody conjugated to a cytotoxic agent to form an antibody drug conjugate (ADC).

[0497] Embodiment 10 is the method of embodiment 9, wherein the cytotoxic agent is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

[0498] Embodiment 11 is the method of embodiment 9 or embodiment 10, wherein the anti-BCMA antibody is conjugated to the cytotoxic agent via a non-cleavable linker, wherein the non-cleavable linker is 6-maleimidocaproyl (MC).

[0499] Embodiment 12 is the method of any one of enmbodiments 1-11, wherein the anti-BCMA antigen binding protein is belantamab mafodotin.

[0500] Embodiment 13 is the method of any one of embodiments 1-12, wherein the anti-BCMA antigen binding protein is administered at a dose of 1.0 mg / kg, 1.4 mg / kg, 1.9 mg / kg or 2.5 mg / kg. Embodiment 14 is the method of any one of embodiments 1-13, wherein the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg.

[0501] Embodiment 15 is the method of any one of embodiments 1-14, wherein the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.9 mg / kg Q12W after the initial 24 week period.

[0502] Embodiment 16 is the method of any one of embodiments 1-15, wherein (i) the human patient is less than 75 years old and is administered dexamethasone at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle; or (ii) the human patient is at least 75 years old and is administered dexamethasone at a dose of 20 mg on days 1, 8, 15, and 22 of each 28-day dexamethasone treatment cycle.

[0503] Embodiment 17 is the method of any one of embodiments 1-16, wherein the patient has (i) an estimated glomerular filtration rate (eGFR) of 30-60 mL / min / 1.73 m2and is administered lenalidomide at a dose of 10 mg on days 1-21 of each 28-day lenalidomide treatment cycle; or (ii) an estimated eGFR of <30 mL / min / 1.73 m2and is administered lenalidomide at a dose of 7.5 mg on days 1 -21 of each 28-day lenalidomide cycle ora dose of 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each 28-day lenalidomide treatment cycle.

[0504] Embodiment 18 is a method of treating transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM) in a human patient, the method comprising administering to the human patient:

[0505] (a) belantamab mafodotin at a dose of 1.9 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.9 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks;

[0506] (b) lenalidomide at a dose of (i) 25 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; and

[0507] (c) dexamethasone at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days. Embodiment 19 is a method of increasing progression free survival (PFS) in a human patient diagnosed with multiple myeloma, the method comprising administering to the human patient:

[0508] (a) an anti-BCMA antigen binding protein at a dose of 1.0 mg / kg to 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg to 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks, wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6;

[0509] (b) lenalidomide at a dose of (i) 25 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; and

[0510] (c) dexamethasone at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days,

[0511] wherein the PFS is increased as compared to the PFS in a human patient diagnosed with multiple myeloma who is administered daratumamab in combination with lenalidomide and dexamethasone.

[0512] Embodiment 20 is a method of increasing minimal residual disease (MRD) negativity rate in human patients diagnosed with multiple myeloma, the method comprising administering to the human patients:

[0513] (a) an anti-BCMA antigen binding protein at a dose of 1.0 mg / kg to 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg to 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks, wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6; (b) lenalidomide at a dose of (i) 25 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; and

[0514] (c) dexamethasone at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days,

[0515] wherein the MRD negativity rate is increased as compared to the MRD negativity rate in human patients diagnosed with multiple myeloma who are administered daratumamab in combination with lenalidomide and dexamethasone.

[0516] Embodiment 21 is the method of embodiment 19 or embodiment 20, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma, newly-diagnosed multiple myeloma, transplant-ineligible multiple myeloma, or transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM).

[0517] Embodiment 22 is the method of any one of embodiments 19-21, wherein the multiple myeloma is transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM).

[0518] Embodiment 23 is the method of any one of embodiments 19-22, wherein the anti-BCMA antigen binding protein is belantamab mafodotin.

[0519] Embodiment 24 is a combination of an anti-BCMA antigen binding protein, lenalidomide and dexamethasone for use in the treatment of multiple myeloma in a human patient, wherein:

[0520] (a) the anti-BCMA antigen binding protein is administered to the human patient at a dose of 1.0 mg / kg to 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg to 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks, wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6; (b) lenalidomide is administered to the human patient at a dose of (i) 25 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; and

[0521] (c) dexamethasone is administered to the human patient at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days.

[0522] Embodiment 25 is use of a combination comprising an anti-BCMA antigen binding protein, lenalidomide and dexamethasone in the manufacture of a medicament for use in the treatment of multiple myeloma in a human patient, wherein

[0523] (a) the anti-BCMA antigen binding protein is administered to the human patient at a dose of 1.0 mg / kg to 2.5 mg / kg once every 8 weeks (Q8W) for an initial 24 weeks, followed by administration at a dose of 1.0 mg / kg to 2.5 mg / kg once every 12 weeks (Q12W) after the initial 24 weeks, wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6;

[0524] (b) lenalidomide is administered to the human patient at a dose of (i) 25 mg, 10 mg, or 7.5 mg on days 1-21 of each lenalidomide treatment cycle or (ii) 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle, wherein each lenalidomide treatment cycle is 28 days; and

[0525] (c) dexamethasone is administered to the human patient at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle, wherein each dexamethasone treatment cycle is 28 days.

[0526] Embodiment 26 is the combination or use according to embodiment 24 or embodiment 25, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma, newly-diagnosed multiple myeloma, transplant-ineligible multiple myeloma, or transplant-ineligible newly diagnosed multiple myeloma (TI-NDMM). Embodiment 27 is the combination or use according to any one of embodiments 24 to 26, wherein the multiple myeloma is transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM).

[0527] Embodiment 28 is the combination or use according to any one of embodiments 24 to 27, wherein the anti-BCMA antigen binding protein is an anti-BCMA antibody conjugated to a cytotoxic agent to form an antibody drug conjugate (ADC).

[0528] Embodiment 29 is the combination or use according to any one of embodiments 24 to 28, wherein the anti-BCMA antigen binding protein is belantamab mafodotin.

[0529] Embodiment 30 is the combination or use according to any one of embodiments 24 to 29, wherein the anti-BCMA antigen binding protein is administered at a dose of 1.9 mg / kg Q8W for an initial 24 week period followed by administration at a dose of 1.9 mg / kg Q12W after the initial 24 week period. SEQUENCE LISTING

[0530] SEQ ID NO: 1 (CDRH1)

[0531] NYWMH SEQ ID NO: 2 (CDRH2)

[0532] ATYRGHSDTYYNQKFKG SEQ ID NO: 3 (CDRH3)

[0533] GAIYDGYDVLDN SEQ ID NO: 4 (CDRH4)

[0534] SASQDISNYLN SEQ ID NO: 5 (CDRH5)

[0535] YTSNLHS SEQ ID NO: 6 (CDRH6)

[0536] QQYRKLPWT SEQ ID NO: 7 (VH) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGA TYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLD NWGQGTLVTVSS SEQ ID NO: 8 (VL) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR SEQ ID NO: 9 (HC) QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGA TYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLD NWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 10 (LC) DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNL HSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC EXAMPLES

[0537]

[0538] Phase 3 Study to Evaluate the Safety and Efficacy of Belantamab Mafodotin Administered in Combination with Lenalidomide and Dexamethasone in Participants with Newly-Diagnosed Multiple Myeloma who are Ineligible for Autologous Stem Cell Transplantation (DREAMM-10 Study)

[0539] Study Design

[0540] The DREAMM-10 study is a randomized, open-label, active controlled, parallel group, multicenter, Phase 3 study in participants with NDMM who are ineligible for autologous stem cell transplantation (ASCT) (TI-NDMM). The primary objective is to evaluate the efficacy and safety of belantamab mafodotin (B) in combination with lenalidomide (R) and dexamethasone (d) compared to daratumumab (D) in combination with lenalidomide (R) and dexamethasone (d). The combination of belantamab mafodotin, lenalidomide, and dexamethasone is referred to as BRd and the combination of daratumumab, lenalidomide, and dexamethasone is referred to as DRd.

[0541] The study consists of two arms including Treatment Arm A in which patients are administered BRd and Treatment Arm B in which patients are administered DRd at the following doses and dosing schedule. Approximately 520 patients will be randomized into the study in a 1:1 ratio between the two arms:

[0542] • Treatment Arm A: Belantamab mafodotin 1.9 mg / kg intravenously (IV) is administered once every 8 weeks (Q8W) for the first 24 weeks (Cycles 1 to 3 Q8W), then 1.9 mg / kg Q12W (Cycles 4+ Q12W) thereafter.

[0543] Lenalidomide is administered at 25 mg once a day orally (PO) on Day 1 to Day 21 of every 28-day lenalidomide treatment cycle. Dexamethasone is administered PO at a dose of 40 mg on Days 1, 8, 15, and 22 of each 28- day cycle.

[0544] • Treatment Arm B: Daratumumab 1800 mg subcutaneously (SC) is administered weekly from Week 1 to 8, Q2Wfrom Week 9 to 24, and Q4W from Week 25 onwards. Lenalidomide is administered at 25 mg once a day PO on Day 1 to Day 21 of every 28-day lenalidomide treatment cycle. Dexamethasone is administered PO at a dose of 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

[0545] The start of a cycle is defined by when a participant takes the first dose of a drug for the given cycle. This study is assessing 3 drugs given in combination; thus, within the context of this protocol "cycle" refers to the planned cycle of doses for the 3 drugs per their individual planned dosing schedules.

[0546] Cycle length for each drug in reference to C1 D1:

[0547] • Each belantamab mafodotin cycle is 56 days for the first 24 weeks and 84 days thereafter

[0548] • Each lenalidomide cycle is 28 days (i.e., 4 weeks)

[0549] • Each dexamethasone cycle is 28 days (i.e., 4 weeks)

[0550] • Each daratumumab cycle is 28 days (i.e., 4 weeks)

[0551] If administration of 1 or 2 of the drugs are delayed for any reason, the dosing of the other drug(s) should continue within the cycle as per the planned dosing schedule. If drug(s) that were delayed can be administered again during an ongoing planned cycle, dosing would resume according to what day it is relative to Day 1 of the planned cycle, and only the remaining planned doses for that cycle would be given. See below for dose modifications guidelines for management of common toxicities associated with the study interventions.

[0552] An overview of the study arms is provided in Table 5. An overview of the study is also provided in FIG. 1.

[0553] Table 5: Overview of Study Arms

[0554]

[0555]

[0556] 1 For participants with eGFR 30-60 mL / min / 1.73 m2lenalidomide should be administered at 10 mg on the days indicated. For participants with eGFR <30 mL / min / 1.73 m2lenalidomide should be administered at 7.5 mg on the days indicated or at 15 mg on every other day of days 1-21 of the 28-day lenalidomide treatment cycle.

[0557] 2 For participants who are >75 years old, are underweight (BMI< 18.5), have poorly controlled diabetes mellitus, or have prior intolerance / AE to steroid therapy, dexamethasone may be administered at the lower dose of 20 mg at the discretion of the investigator.

[0558] Treatment will continue in both arms until progressive disease, death, unacceptable toxicity, withdrawal of consent, or end of study, whichever occurs first. Dose delays or reductions may be required following potential drug-associated toxicities.

[0559] Objectives and Endpoints

[0560] The study’s dual primary objectives are to demonstrate superiority of BRd over DRd in terms of minimal residual disease (MRD) negative rate and / or progression free survival (PFS). The primary and secondary objectives and endpoints are shown in Table 6.

[0561] Table 6: Primary and Secondary Endpoints

[0562]

[0563]

[0564]

[0565] Eligibility Criteria

[0566] Inclusion Criteria:

[0567] Participants are eligible to be included in the study only if all the following criteria are met:

[0568] 1. Is at least 18 or the legal age of consent in the jurisdiction in which the study is taking place, at the time of signing the informed consent. 2. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.

[0569] 3. NDMM with a requirement for treatment as documented per IMWG criteria. 4. Must have at least 1 aspect of measurable disease, as assessed by the central laboratory, defined as 1 of the following: a) Urine M-protein excretion >200 mg / 24 hours (>0.2 g / 24 hours) And / or b) Serum M-protein concentration >0.5 g / dL (>5.0 g / L) And / or c) Serum free light-chain (FLC) assay: involved FLC level >10 mg / dL (>100 mg / L) and an abnormal serum FLC ratio (<0.26 or >1.65).

[0570] 5. Newly diagnosed and not considered candidate for high-dose chemotherapy with autologous stem cell transplant (ASCT) due to any of the following: a) >70 years of age, OR b) Age 18 to 69 years with presence of comorbid condition(s) likely to have a negative impact on tolerability of high-dose chemotherapy with ASCT, (or for whom national guidelines do not permit transplant due to a cut-off age below 70 years), OR c) Who refuse high-dose chemotherapy with ASCT as an initial treatment.

[0571] 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (see Table 12 in Example 2 below).

[0572] 7. Adequate organ system function as defined by the laboratory assessments. Exclusion Criteria

[0573] Participants are excluded from the study if any of the following criteria are met: 1. Diagnosis of systemic amyloid light chain amyloidosis, Waldenstrom’s disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or Primary Plasma Cell Leukemia (defined as circulating plasma cells >5%).

[0574] 2. Prior systemic therapy for multiple myeloma, or smoldering multiple myeloma.

[0575] 3. Signs of meningeal or central nervous system involvement with multiple myeloma. 4. Major surgery within 2 weeks prior to the first dose of study drugs or has not recovered fully from surgery. Kyphoplasty is not considered major surgery.

[0576] 5. Any serious and / or unstable pre-existing medical, psychiatric disorder or other conditions (including lab abnormalities) that could interfere with participant's safety, obtaining informed consent, or compliance with study procedures.

[0577] 6. Current active liver or biliary disease (except for Gilbert's syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease as per the investigator's assessment).

[0578] 7. Participants with previous or concurrent malignancies other than multiple myeloma are excluded. Exceptions are any other malignancy that has been considered medically stable for at least 2 years, after discussion with the Medical Monitor. The participant must not be receiving active therapy, other than hormonal therapy for this disease.

[0579] 8. Evidence of cardiovascular risk including any of the following: a) Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram abnormalities including second-degree (Mobitz Type II) or third-degree atrioventricular block, b) Recent history (within 3 months of screening) of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty or stenting, or bypass grafting, c) Class III or IV heart failure as defined by the New York Heart Association functional classification system.

[0580] 9. Known human immunodeficiency virus (HIV) infection, unless the participant can meet all of the following criteria: a) Established antiretroviral therapy for at least 4 weeks and HIV viral load <400 copies / mL within Screening Period, b) CD4+ T-cell (CD4+) counts ≥350 cells / µL. c) No history of acquired immune deficiency syndromedefining opportunistic infections within the last 12 months.

[0581] 10. Positive hepatitis C antibody test result or positive hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention unless the participant can meet the following criteria: a) RNA test negative, b) Successful antiviral treatment (usually 8 weeks duration) is required, followed by a negative hepatitis C viral load RNA test after a washout period of at least 4 weeks.

[0582] 11. Participants with hepatitis B will be excluded unless the participant can meet the defined criteria

[0583] 12. Current corneal epithelial disease except for mild punctate keratopathy.

[0584] 13. Intolerance or contraindications to antiviral prophylaxis.

[0585] 14. Unable to tolerate antithrombotic prophylaxis.

[0586] 15. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, or any of the components of the study intervention.

[0587] 16. Plasmapheresis within 7 days prior to the first dose of study intervention. 17. Participants must not have received a live or live-attenuated vaccine within 30 days prior to first dose of belantamab mafodotin.

[0588] Dose Modifications

[0589] All belantamab mafodotin dose modifications and stopping criteria for corneal events are based on the KVA scale. For corneal events related to belantamab mafodotin, determination of the recommended dose modification should be based on the most severe corneal events per the KVA scale as shown in Table 7. Dose modification guidelines for belantamab mafodotin based on the KVA scale are shown in Table 8 and recommendations for dose modification of belantamab mafodotin are shown in Table 9.

[0590] Table 7: KVA scale for treatment-related corneal events

[0591]

[0592] 1. Grade 0 will indicate clear cornea and that BCVA shows no change from baseline or re-baseline. The recommended dose for Grade 0 is to start or continue treatment at current dose.

[0593] 2. Mild superficial keratopathy (documented worsening from baseline), with or without symptoms.

[0594] 3. Moderate superficial keratopathy = any / or a combination of moderate superficial punctate keratopathy, patchy microcyst-like deposits, sub-epithelial haze (peripheral), or a new peripheral stromal opacity.

[0595] 4. Severe superficial keratopathy = any / or a combination of severe superficial punctate keratopathy, diffuse microcyst-like deposits, sub-epithelial haze (central), or a new central stromal opacity.

[0596] 5. Corneal epithelial defect such as corneal ulcers. Corneal ulcer by definition means an epithelial defect with underlying stromal infiltration.

[0597] Table 8: Dose modification for Belantamab Mafodotin based on the KVA scale

[0598]

[0599] Note: Changes in VA due to treatment-related corneal findings:

[0600] For participants who have BCVA worse than 20 / 20 in either eye at baseline, dose modification for that eye will be determined by the worsening of vision from baseline only (not by absolute BCVA at the visits).

[0601] If a participant has a baseline BCVA of 20 / 200 or worse in 1 eye, then belantamab mafodotin-related changes in vision in the other eye will drive the change in BCVA grading.

[0602] If a participant has baseline BCVA of 20 / 200 or worse in both eyes, then the decision to delay or reduce belantamab mafodotin dose will be based on Pl’s assessment of benefit vs. risk based on corneal exam findings following a discussion with the qualified eye care specialist.

[0603] If already on the lowest allowed dose level, the participant should resume treatment at that dose.

[0604] 1. Dose modification should be based on the most severe grade. If eyes differ in severity, dose modification guideline should be applied based on the more severe eye. Table 9: Recommendations for dose modification of Belantamab mafodotin

[0605]

[0606] Treatment of TI-NDMM patients with the triplet regimen of belantamab mafodotin plus Rd provides additional therapeutic benefit over the DRd triplet regimen by improving outcomes of depth and durability of response, without negatively impacting safety.

[0607] Example 2: Phase 2 Study to Evaluate the Safety and Efficacy of Belantamab Mafodotin Administered in Combination with Standard of Care Regimens in Participants with Relapsed-Refractory Multiple Myeloma (DREAMM-15 Study)

[0608] Study Design

[0609] The DREAMM-15 study is a non-randomized, open-label, multicenter Phase 2 study in participants with relapsed and / or refractory multiple myeloma (RRMM) to determine the efficacy and safety of a proactively extended dosing schedule of belantamab mafodotin in combination with: (a) pomalidomide and dexamethasone (BPd), or (b) bortezomib and dexamethasone (BVd), or (c) carfilzomib and dexamethasone (BKd).

[0610] The study consists of three arms including Treatment Group A (BPd), Treatment Group B (BVd), and Treatment Group C (BKd). Treatment is administered to patients as described below and in Table 10. An overview of the study is provided in FIG. 2.

[0611] • Treatment Group A (BPd): belantamab mafodotin 2.5 mg / kg in cycle 1 (C1) and 1.9 mg / kg in C2-C3 (Q8W) and C4+ (Q12W). Pomalidomide will be administered at 4 mg once a day orally (PO) on Day 1 to Day 21 of every 28-day pomalidomide treatment cycle. Dexamethasone will be administered PO at a dose of 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle. • Treatment Group B (BVd): belantamab mafodotin 2.5 mg / kg in C1 and 1.9 mg / kg in C2-C3 (Q8W), and C4+ (Q12W); Bortezomib will be administered at 1.3 mg / m2subcutaneously (SC) on Days 1, 8, 15, and 22 of every 28-day bortezomib treatment cycle. Dexamethasone will be administered PO at a dose of 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. Both bortezomib and dexamethasone will be discontinued after six 28-day cycles (i.e., after 24 weeks of treatment).

[0612] • Treatment Group C (BKd): belantamab mafodotin 2.5 mg / kg in C1 and 1.9 mg / kg in C2-C3 (Q8W), and C4+ (Q12W); Carfilzomib will be administered intravenously (IV) at 20 mg / m2on Day 1 and then IV at 70 mg / m2on Day 8 and Day 15 of the first carfilzomib cycle. Carfilzomib will be administered IV at 70 mg / m2on Days 1, 8 and 15 of each 28-day carfilzomib cycle thereafter.

[0613] Dexamethasone will be administered PO at a dose of 40 mg on Days 1, 8, 15, and 22 of each 28-day cycle.

[0614] Treatment will continue in each Treatment Group until progressive disease (PD), death, unacceptable toxicity, withdrawal of consent, or end of study (EoS), whichever occurs first. Dose delays or reductions may be required following potential drug-associated toxicities.

[0615] The start of a cycle is defined by when a participant takes the first dose of a drug for the given cycle. This study is assessing 3 drugs given in combination; thus, within the context of this protocol "cycle" refers to the planned cycle of doses for the 3 drugs per their individual planned dosing schedules.

[0616] Cycle length for each drug in reference to C1 D1:

[0617] • Each belantamab mafodotin cycle is 56 days for the first 24 weeks and 84 days thereafter;

[0618] • Each pomalidomide cycle is 28 days; pomalidomide will be administered PO at 4 mg once a day on Day 1 to Day 21 of every 28-day pomalidomide treatment cycle. • Each bortezomib cycle is 28 days; bortezomib will be administered SC at 1.3 mg / m2on Day 1, 8, 15, 22 of every 28-day bortezomib treatment cycle.

[0619] • Each carfilzomib cycle is 28 days; Carfilzomib will be administered IV at 20 mg / m2on Day 1 and then at 70 mg / m2on Day 8, and Day 15 of the first carfilzomib cycle. Carfilzomib will be administered IV at 70 mg / m2on Days 1, 8, 15 of each 28-day carfilzomib cycle thereafter.

[0620] • Each dexamethasone cycle is 28 days. See Table 10 below for dexamethasone dosing in each Treatment Group.

[0621] If administration of 1 or 2 of the drugs are delayed for any reason, the dosing of the other drug(s) should continue within the cycle as per the planned dosing schedule. If drug(s) that were delayed can be administered again during an ongoing planned cycle, dosing would resume according to what day it is relative to D1 of the planned cycle, and only the remaining planned doses for that cycle would be given.

[0622] Table 10: Treatment Schedule

[0623]

[0624] 1 = Belantamab mafodotin will be administered as an IV infusion over at least 30 minutes. A window of ±3 days is acceptable for administration of study intervention after C1D1.

[0625] 2 = Pomalidomide 4 mg PO daily on Days 1 to 21 of each 28-day cycle to be taken after the 1 hour rest period after belantamab mafodotin. Platelet count must be ≥50 000 per μL to initiate new cycle. If dose(s) are held within a cycle they will be skipped and will not be made up later in the cycle. The 7-day break Q4W should be observed.

[0626] 3 = For participants who are >75 years of age, have comorbidities, or are intolerant to 40 mg, the dose of dexamethasone can be reduced to 20 mg. On days where only pomalidomide and dexamethasone are taken at home, they should be taken in the morning approximately at the same time each day. On belantamab mafodotin dosing days, dexamethasone should be administered 1 to 3 hours prior to the first administration of belantamab mafodotin.

[0627] 4= If a bortezomib dose was delayed, subsequent doses should be adjusted to account for delay as all bortezomib doses must be at least 72 hours / 3 calendar days apart. Doses that need to be withheld are skipped and will not be made up later in the cycle. Individual doses within a cycle have a ±1-day window. Bortezomib should be administered approximately 1 hour after the belantamab mafodotin infusion is complete, assuming the participant is clinically stable.

[0628] 5 = The starting dose of dexamethasone may be reduced to 10 mg for participants >75 years of age, who have a body mass index of less than 18.5, who had previous unacceptable side effects associated with glucocorticoid therapy, or who are unable to tolerate the starting dose. On days where bortezomib and dexamethasone administration coincides with administration of belantamab mafodotin, dexamethasone should be administered PO prior to the infusion of belantamab mafodotin. 6 = Carfilzomib is administered intravenously as a 30-minute infusion once weekly for 3 weeks followed by a 13-day rest period. For frail patients, a lower carfilzomib dose may be considered after discussion with the Medical Monitor.

[0629] 7 = Dexamethasone 40 mg PO on Days 1, 8, 15, and 22 of every 28-day cycle. For participants who are >75 years, have comorbidities, or are intolerant to 40 mg, the dose of dexamethasone can be reduced to 20 mg in Group A. On days where only pomalidomide and dexamethasone are taken at home, they should be taken in the morning approximately at the same time each day. On belantamab mafodotin dosing days, dexamethasone should be administered 1 to 3 hours prior to the first administration of belantamab mafodotin. Administer dexamethasone 30 minutes to 4 hours before carfilzomib.

[0630] Objectives and Endpoints

[0631] The primary objective is to evaluate the ORRs for BPd or BVd or BKd in participants with RRMM with 1-2 prior lines of therapy. The key secondary objectives are to further assess CRR, MRD negative status, DoR, and safety for each 1 of these combinations. Moreover, the study will assess the concordance of participant reported ocular symptoms and ocular CTCAEs with ophthalmic examination findings. The primary and secondary objectives and endpoints are shown in Table 11.

[0632] Table 11: Objectives and Endpoints

[0633]

[0634]

[0635] AE = adverse event; BPd = belantamab mafodotin + pomalidomide + dexamethasone; BKd = belantamab mafodotin + carfilzomib + dexamethasone; BVd = belantamab mafodotin + bortezomib + dexamethasone; CR = complete response; CRR = complete response rate; CTCAEs = Common Terminology Criteria for Adverse Events; DoR = duration of response; EORTC QLQ-C30= European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire 30; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire Multiple Myeloma 20; FACT-GP5 = Functional Assessment of Chronic Illness Therapy - Item GP5; HRQoL = health-related quality of life; IMWG = International Myeloma Working Group; MRD = minimal residual disease; NGS = next generation sequencing; ORR = objective response rate; OSDI = ocular surface disease index; PD = progressive disease;

[0636] PGIC = patient global impression of change; PGIS = patient global impression of symptoms; PFS = progression-free survival; PR = partial response; PRO-CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PROSIM-Q = Patient-Reported Symptom and Impact Monitoring - Questionnaire;

[0637] RRMM = relapsed / refractory multiple myeloma; SAE = serious adverse event; sCR = stringent complete response;

[0638] TTBR = time to best response; TTP = time to progression; TTR = time to response; VA = visual acuity; VGPR = very good partial response.

[0639] Eligibility Criteria

[0640] Inclusion Criteria (BPd, BVd, and BKd Treatment Groups): Patients are eligible to be included in the study only if all of the following criteria are met:

[0641] • Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

[0642] • Male or female, 18 years or older (at the time consent is obtained).

[0643] • Have a confirmed diagnosis of MM as defined by the IMWG criteria.

[0644] • ECOG performance status of zero to 2 per Table 12 below.

[0645] Table 12 ECOG performance status grading

[0646]

[0647] • Have been previously treated with at least 1, but no more than 2, prior lines of MM therapy and must have documented disease progression during or after their most recent therapy

[0648] o Note: induction +ASCT + maintenance is 1 line of therapy).

[0649] o ForBPd group: Previously treated with at least 1, but no more than 2, prior lines of MM therapy including a lenalidomide-containing regimen (lenalidomide must have been administered for at least 2 consecutive cycles). Patients treated with lenalidomide >10 mg daily for at least 2 consecutive cycles are eligible.

[0650] • Must have at least 1 aspect of measurable disease, defined as one the following:

[0651] o Urine M-protein excretion >200 mg / 24 h, or

[0652] o Serum M-protein concentration >0.5 g / dL (>5.0 g / L), or

[0653] o Serum FLC assay: involved FLC level >10 mg / dL (>100 mg / L) and an abnormal serum free light chain ratio (<0.26 or >1.65) only if patient has no measurable urine or serum M spike • Patients with a history of ASCT are eligible for study participation provided the following eligibility criteria are met:

[0654] o ASCT was >100 days prior to the first dose of study medication o No active bacterial, viral, or fungal infection(s) present

[0655] • All prior treatment-related toxicities (defined by National Cancer Institute- Common Terminology Criteria for Adverse Events v5.0) must be Grade <1 at the time of enrollment, except for alopecia.

[0656] • Adequate organ system functions as defined by laboratory assessments.

[0657] Exclusion Criteria (BPd, B Vd and BKd Treatment Groups)

[0658] Participants are excluded from the study if any of the following criteria apply: • Active plasma cell leukemia at Screening. Symptomatic amyloidosis, active POEMS syndrome.

[0659] • Previous or concurrent invasive malignancy other than MM, except:

[0660] o the disease must be considered medically stable for at least 2 years; or o the patient must not be receiving active therapy, other than hormonal therapy for this disease

[0661] • Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment.

[0662] • Evidence of active mucosal or internal bleeding.

[0663] • Active infection requiring treatment.

[0664] • Any major surgery within 4 weeks prior to the first dose of study drug. Exception allowed for bone stabilizing surgery after consultation with Medical Monitor. • Intolerance or contraindications to anti-viral prophylaxis.

[0665] • Presence of active renal conditions (e.g., infection, severe renal impairment requiring dialysis or any other condition that could affect participant’s safety). Patients with isolated proteinuria resulting from MM are eligible, provided they fulfill certain criteria.

[0666] • Current corneal epithelial disease except for mild punctate keratopathy.

[0667] • Any serious and / or unstable pre-existing medical, psychiatric disorder or other conditions (including laboratory abnormalities) that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures.

[0668] • Patients after prior allogeneic stem cell transplant.

[0669] • Systemic anti-myeloma therapy (including chemotherapy and systemic steroids);

[0670] prior treatment with an anti-MM monoclonal antibody drug within 30 days of receiving the first dose of study intervention.

[0671] • Plasmapheresis within 7 days prior to the first dose of study intervention.

[0672] • Received prior BCMA targeted therapy.

[0673] • Is currently enrolled or has participated in any other clinical study involving an investigational drug within 14 days or 5 half-lives (whichever is shorter) preceding the first dose of study intervention.

[0674] • Known HIV infection, unless the participant can meet all of the following criteria:

[0675] o Established anti-retroviral therapy for at least 4 weeks and HIV viral load <400 copies / mL;

[0676] o CD4+ T-cell counts >350 cells / µL; and

[0677] o No history of AIDS-defining opportunistic infections within the last 12 months.

[0678] • Pregnant or lactating female.

[0679] • Has an alanine aminotransferase (ALT) value >2.5x upper limit of normal (ULN).

[0680] • Has a total bilirubin value >1,5x ULN.

[0681] • Has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice.

[0682] • Has a positive HCV antibody test result at screening or within 3 months prior to the first dose of study intervention unless HCV RNA is negative, indicating past resolved HCV infection, including participants who have undergone curative treatment.

[0683] • Has a positive HCV RNA test result at screening or within 3 months prior to the first dose of study intervention (note: the HCV RNA test is optional, and participants with a negative HCV antibody test are not required to undergo HCV RNA testing as well). • Has documented presence of HBsAg and / or HBcAb at screening or within 3 months prior to the first dose of study intervention. Participants with hepatitis B will be excluded unless certain criteria can be met.

[0684] • Evidence of cardiovascular risk including any of the following:

[0685] o Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular block.

[0686] o History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening

[0687] o Class III or IV heart failure as defined by the NYHA functional classification system.

[0688] o Uncontrolled hypertension, defined as an average systolic blood pressure >159 mmHg or diastolic >99 mmHg despite optimal treatment • Has QTc >450 msec or QTc >480 msec for participants with bundle branch block. Additional Exclusion Criteria for BPd Treatment Group

[0689] • Active or history of venous and arterial thromboembolism within the past 3 months.

[0690] • Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis.

[0691] • Received prior treatment with or intolerant to pomalidomide.

[0692] Additional Exclusion Criteria for BVd Treatment Group

[0693] • Intolerant to bortezomib, or refractory to bortezomib (defined as progressive disease during treatment with a bortezomib-containing regimen of 1.3 mg / m2twice weekly, or within 60 days of completing that treatment). Participants with progressive disease during treatment with a weekly bortezomib regimen are allowed.

[0694] • Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain.

[0695] Additional Exclusion Criteria for BKd Treatment Group • Intolerant to carfilzomib, or refractory to carfilzomib (defined as progressive disease during treatment with a carfilzomib-containing regimen, or within 60 days of completing that treatment).

[0696] • Active infection within 14 days prior to enrollment requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents. Such infection must be fully resolved prior to initiating study intervention

[0697] • Pleural effusions requiring thoracentesis within 14 days prior to enrollment;

[0698] Ascites requiring paracentesis within 14 days prior to enrollment; Intolerance to hydration due to pre-existing pulmonary or cardiac impairment; Known pulmonary hypertension.

[0699] • Known history of allergy to captisol (i.e., a cyclodextrin) derivatives used to solubilize carfilzomib.

[0700] • Evidence of cardiovascular risk including left ventricular ejection fraction <40% as assessed by transthoracic echocardiogram.

[0701] • Pericardial disease, including pericarditis, pericardial effusion, cardiac tamponade, and constrictive pericarditis, as assessed by ECG abnormalities, echocardiography, chest X-ray, and / or computed tomography / magnetic resonance imaging

[0702] Dose Modifications

[0703] Detailed guidance for belantamab mafodotin dose levels and AE-related dose modifications including dose modification guidelines for belantamab mafodotin treatment-related corneal events based on KVA scale are shown in Table 13, Table 14, and Table 15. All belantamab mafodotin dose modifications and stopping criteria for corneal events are based on the KVA scale (see Table 15).

[0704] Table 13: Recommendations for dose reduction of belantamab mafodotin

[0705]

[0706]

[0707] QXW = every X weeks.

[0708] Table 14: Dose modifications guidelines for belantamab mafodotin treatment-related AEs

[0709]

[0710]

[0711] ANC=absolute neutrophil count; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events v05;

[0712] TLS = tumor lysis syndrome; ULN = upper limit of normal.

[0713] a = Medical Monitor may consult renal safety panel about plans to continue therapy.

[0714] b = If symptoms resolve within 1 h of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL / h to 50 mL / h). Otherwise dosing will be held until symptoms resolve and the participant should be premedicated at the next scheduled dose.

[0715] Table 15: KVA scale and dose modification guidelines for belantamab mafodotin treatment-related corneal events

[0716]

[0717]

[0718] BCVA=best-corrected visual acuity; KVA=keratopathy visual acuity.

[0719] 1 = Mild superficial keratopathy=mild superficial punctate keratopathy (documented worsening from baseline), with or without symptoms.

[0720] 2 = Moderate superficial keratopathy=any / or a combination of: moderate superficial punctate keratopathy, patchy microcyst like deposits, subepithelial haze (peripheral), or a new peripheral stromal opacity.

[0721] 3 = Severe superficial keratopathy=any / or a combination of: severe superficial punctate keratopathy, diffuse microcyst like deposits involving the central cornea, subepithelial haze (central), or a new central stromal opacity

[0722] 4 = The term ’corneal epithelial defect’ refers to and includes only corneal erosions and corneal ulcers. Corneal ulcer by definition means an epithelial defect with underlying stromal infiltration. In the presence of only a corneal epithelial defect without erosion or ulcer, the grading depends on the presence of other corneal examination findings such as: superficial keratopathy, microcysts, sub-epithelial haze and stromal opacity.

[0723] 5 = Changes in visual acuity due to treatment-related corneal findings.

[0724] o For participants who have BCVA worse than 20 / 20 in either eye at baseline, dose modification for that eye will be determined by the worsening of vision from baseline only (not by absolute BCVA at the visits).

[0725] o If a participant has a baseline BCVA of 20 / 200 or worse in an eye, then belantamab mafodotin related changes in vision in the other eye will drive the dose modification. If a participant has baseline BCVA of 20 / 200 or worse in both eyes, then the decision to delay or reduce belantamab mafodotin dose will be based on principal investigator’s assessment of benefit versus, risk based on corneal examination findings following a discussion with the qualified eye care specialist such as ophthalmologist / optometrist.

[0726] o Dose modification should be based on the most severe grade. If eyes differ in severity, dose modification guideline should be applied based on the more severe eye.

[0727] 6 = Snellen-equivalent BCVA is recommended to be tested on a visual acuity chart which has an approximately equal number of letters per line and equal spacing between lines.

[0728] 7 = If a participant has cataract surgery during the study the BCVA should be re-baselined (after the BCVA stabilizes if there are no corneal findings but prior to any further belantamab mafodotin administration) and subsequent visual acuity must then be assessed from this new “best’ baseline value (see details in Ocular Study Reference Manual).

[0729] 8 = Dose modification should be based on the most severe finding. If eyes differ in severity, dose modification guideline should be applied based on the more severe eye. Dose reductions of belantamab mafodotin will be triggered by Grade 2 or worse events of ocular examination findings or decrease in BCVA on day of dosing. Response Evaluation

[0730] Patients are evaluated for response according to the IMWG Uniform Response Criteria for MM as presented in Table 16 and described in Kumar et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328-46.

[0731] Table 16 Response evaluation criteria

[0732]

[0733] CR = complete response; CT = computed tomography; FLC = free light chain; h = hour(s); PD = progressive disease;

[0734] PR = partial response; sCR = stringent complete response; SD = stable disease; SPD = sum of the product of the diameters; VGPR = very good partial response.

[0735] Note: VGPR and CR response categories require both serum and urine evaluations.

[0736] a = All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are based on results obtained with the validated Freelite test (The Binding Site Group, Birmingham, UK). b = Presence / absence of clonal cells on immunohistochemistry is based upon the K / A / L ratio. An abnormal K / A ratio by immunohistochemistry 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.

[0737] c = Plasmacytoma measurements should be taken from the CT portion of the PET-CT, or MRI scans, or dedicated CT scans where applicable. For patients with only skin involvement, skin lesions should be measured with a ruler. Measurement of tumor size will be determined by the SPD.

[0738] d = Positive immunofixation alone in a patient previously classified as achieving a complete response will not be considered progression. For purposes of calculating time to progression and progression-free survival, patients who have achieved a complete response and are MRD negative should be evaluated using criteria listed for PD. Criteria for relapse from a complete response or relapse from MRD should be used only when calculating disease-free survival.

[0739] e = In the case where a value is felt to be a spurious result per physician discretion (e.g., a possible laboratory error), that value will not be considered when determining the lowest value.

[0740] Example 3: Phase I Study of Belantamab Mafodotin in Combination with Standard of Care in Transplant-Ineligible Newly Diagnosed Multiple Myeloma

[0741] DREAMM-9 (NCT04091126) is an ongoing randomized Phase 1 dose optimization study evaluating belantamab mafodotin in addition to standard of care (bortezomib, lenalidomide, and dexamethasone; VRd) over a range of doses (1.0-1.9 mg / kg) and schedules with fixed or step-down (S / D) dosing in autologous stem cell transplant (ASCT)-ineligible patients (pts) with newly diagnosed multiple myeloma (Tl-NDMM).

[0742] Study Design

[0743] A schematic of the study design is shown in FIG. 3. Patients >18 years of age ineligible for ASCT and with no prior MM treatment were dosed in one of 8 cohorts (C1-8) with differing belantamab mafodotin (belamaf) doses (mg / kg) and schedules. All cohorts received belantamab mafodotin with VRd for Cycles 1-8 (21 -day cycle), followed by belantamab mafodotin with Rd for Cycles 9+ (28-day cycle). The belantamab mafodotin regimens tested in the various cohorts included: cohort 1, 1.9 mg / kg Q3 / 4W (N=12); cohort 2, 1.9 mg / kg Q6 / 8W (N=12); cohort 3, 1.4 mg / kg Q3 / 4W (N=13); cohort 4, 1.4 mg / kg Q6 / 8W (N=12); cohort 5, 1.9 mg / kg for 1 dose and then 1.4 mg / kg Q9 / 12W (N=19); cohort 6, 1.0 mg / kg Q3 / 4W (N=15); cohort 7, 1.4 mg / kg for 1 dose and then 1.0 mg / kg Q9 / 12W (N=15); cohort 8, 1.0 mg / kg Q12W(N=10). Cohorts with lower doses and longer schedules were opened to inform on the potential to improve tolerability while maintaining efficacy. The primary endpoint was safety / tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Efficacy endpoints included overall response rate (ORR, % of pts with a confirmed partial response or better); complete response rate (CRR, % of pts with a complete response or better [CR+]); and minimal residual disease negativity rate (MRD[-], % of pts with very good partial response or better [VGPR+] and reached MRD negativity at 10’5threshold evaluated by next generation sequencing). Responses were assessed per International Myeloma Working Group criteria.

[0744] Ocular examination findings (OEF) were measured using the Keratopathy and Visual Acuity (KVA) scale comprising changes in best corrected visual acuity (BCVA) and slit lamp findings. OEFs were managed through dose reductions and schedule extensions. Changes in bilateral BCVA to 20 / 50 or worse in patients who had BCVA of 20 / 25 or better in at least 1 eye at baseline were assessed.

[0745] Results

[0746] As of 4 March 2024, 108 pts were treated in 8 cohorts. Median age (range) was 74.0 (51-88) years; 44% (n=47) were >75 yrs old, 86% were White, and 46% female. Overall duration of follow-up ranged from 0.1-49.8 months, and by cohort (months, interquartile range) was: cohort 1, 37.6 (21.9-43.1); cohort 2, 32.3 (31.4-33.4); cohort 3, 20.2 (14.0-33.0); cohort 4, 32.4 (18.8-33.6); cohort 5, 17.1 (2.8-20.3); cohort 6, 31.0 (16.3-33.4); cohort 7, 18.2 (8.7-20.6); cohort 8, 7.8 (7.0-8.7).

[0747] Safety: Overview

[0748] Of the patients who received >1 dose of belantamab mafodotin, 100% (n=105) experienced AEs. Rates of Grade 3 / 4 AEs were the lowest among cohorts with lower doses and longer dosing intervals. Of the 105 patients who received more than 1 dose of belantamab mafodotin, all had an AE with 33% having a Grade 3 / 4 AE considered by the investigator to be related to be related to belantamab mafodotin. The most common non-ocular Gr3+ AEs ( [n]) across all cohorts were thrombocytopenia, 30% (32), neutropenia, 26% (27), and COVID-19 pneumonia, 14% (15), similar to previous studies. Fewer Grade 3 / 4 AEs were reported during the maintenance phase (50%) than the induction phase (87%). Safety: Ocular Events

[0749] Cohorts with lower doses and longer dosing intervals generally had lower rates of Grade 3 / 4 KVA events. Maximum Grade 1 KVA events were reported in 11% of patients, maximum Grade 2 KVA events in 19%, and maximum Grade 3 / 4 KVA events in 55% of patients. Of 2142 KVA assessments, only 15% were Grade 3 / 4 events. Grade 3+ (Gr3+) belantamab mafodotin -related AEs ranged from 67% (n=8) for cohort 1 to 10% (n=1) for cohort 8. Ocular events (Gr3+) based on keratopathy and visual acuity scale (KVA) were reported in 55% (n=58) of pts across cohorts; dose interruptions / delays were seen in 95% (n=55) and dose reductions in 33% (n=19) of affected pts.

[0750] Cohorts 1-3 had the highest proportion of pts with Gr3+ KVA events ([n]): cohort 1, 83% (10); cohort 2, 92% (11); and cohort 3, 85% (11). The lowest was reported for cohort 7, 7% (1) and cohort 8, 20% (2). A total of 28 patients (27%) had a decrease in best correct visual acuity (BCVA) score from baseline (20 / 25 or better) to 20 / 50 or worse, with a median (range) time of 194 (42-713) days to onset of the first occurrence, of which 89% (n=25) resolved in a median (range) of 85 (22-421) days. The longest median time to onset was reported for the cohorts with the longer dosing intervals ([n]): cohort 7 (Q9 / 12W), 337 days (1); cohort 4 (Q6 / 8W), 263.5 days (6); cohort 2 (Q6 / 8W), 245.5 days (6). The shortest median time to onset was 76 days for cohort 1 (Q3 / 4W).

[0751] Grade (Gr) >2 OEF were seen in 74% of patients and decrease in BCVA to 20 / 50 or worse was seen in 27% of patients overall. Both Gr>2 OEF and decrease in BCVA to 20 / 50 or worse in pts with 20 / 25 or better in >1 eye at baseline had a trend towards lower incidence in lower-dose-intensity cohorts. The first Gr>2 OEF resolved in 90% of total affected pts. Resolution rates were: 92% for cohort 1; 91 % for cohort 2; 91 % for cohort 4; 92% for cohort 3; 100% for cohort 5; 91% for cohort 6; 100% for cohort 7; 40% for cohort 8 (shorter follow-up than the other cohorts). The first decrease in BCVA to 20 / 50 or worse resolved in 89% of patients overall; resolution rates were: 100% for cohort 1; 100% for cohort 2; 67% for cohort 4; 100% for cohort 3; 100% for cohort 5; 100% for cohort 6; 0% in cohort 7 (only 1 patient had an event); in cohort 8, no patient had an event. Discontinuation rates due to Gr>2 OEF events were low at 6% across the study (range: 0% [cohorts 2, 4, 5, and 8] to 15% [cohort 3]).

[0752] Dose and schedule affected the time to, and resolution of, BCVA decreases. Extending the dosing interval between the 1.9 mg / kg or 1.4 mg / kg doses from Q3 / 4W to Q6 / 8W was associated with longer time to BCVA decrease to 20 / 50 or worse.

[0753] Resolution of BCVA decreases was generally faster in cohorts with lower initial doses of belantamab mafodotin (FIG. 4).

[0754] Efficacy Results

[0755] Across the cohorts ORR was 90% and ranged from 71-100%; CRR was 63% and ranged from 30-92%. VGPR+ was 100% in 3 cohorts including those with lower doses and less frequent schedules. Time to achieve VGPR+ was consistent across the cohorts (median 2.1-3.2 months) and response deepened overtime. In cohorts 1-4, CR+ was 62-92%. ORR % (CRR %) by cohort was cohort 1, 100% (75%); cohort 2, 100% (92%); cohort 3, 92% (62%); cohort 4, 100% (91%); cohort 5, 71% (41%); cohort 6, 86% (71%); cohort 7, 87% (53%); cohort 8, 100% (30%). See FIG. 5.

[0756] Higher belamaf starting doses were associated with deeper and faster MRD[-] rates. MRD[-] rate in pts with VGPR+ ranged from 10% (cohort 8) to 83% (cohort 1). MRD[-] rate in pts with CR+ ranged from 0% (cohort 8) to 75% (cohort 1) and was highest in (% [n]): cohort 1, 75% (9); cohort 2, 67% (8), and cohort 3, 54% (7). MRD[-] rate continued to increase into the Maintenance phase, regardless of dose modifications used to manage KVA Grade 2+ events (30%). Longer belamaf dosing intervals allowed for a higher mg / kg / cycle to be given. See FIG. 6A and FIG. 6B.

[0757] Efficacy in patients with EMD, high-risk cytogenetics, or who were >80 years of age were comparable to the ITT population (data not shown). At the data cut, 72% of patients completed the Induction phase and entered the Maintenance phase. Overall, 19% of patients discontinued treatment in the Induction phase.

[0758] Sub-analysis of selected cohorts

[0759] Three cohorts were selected based on their efficacy and safety profiles for further sub-analysis to support belamaf dose recommendations in TI-NDMM, in particular cohort 1 (1.9 mg / kg Q3 / 4W), cohort 2 (1.9 mg / kg Q6 / 8W), and cohort 4 (1.4 mg / kg Q6 / 8W). Twelve patients were enrolled in each of the selected cohorts, o Patient demographics were comparable across cohorts, but the 1.9 mg / kg Q3 / 4W cohort had a higher rate of high-risk cytogenetics and the 1.9 mg / kg Q6 / 8W cohort had more patients with EMD than the other cohorts. The median (range) duration of follow-up for each of cohorts 1, 2, and 4 was 37.6 months (7-50 months), 32.3 months (6-38 months), and 32.4 months (5-37 months), respectively. Response rates of 100% were observed in all 3 cohorts. The 1.9 mg / kg cohorts had the deepest responses, with the highest MRD[-] rates (>73% of patients with CR+) and shorter times to MRD[-] (threshold 10-5 per nextgeneration sequencing). See FIG. 5 and FIG. 6A for a summary of responses.

[0760] Of the patients who received >1 dose of belamaf, 67% (n=8) / 25% (n=3) / 33% (n=4) of patients in cohorts 1, 2, and 4, respectively, had Grade 3+ (Gr3+) belamaf-related AEs. Ocular exam findings (Gr3+) based on keratopathy and visual acuity scale were reported in 83% (n=10) / 92% (n=11 ) / 75% (n=9) of patients, respectively, comprising 26% / 10% / 18% of all assessments. AEs led to belamaf dose interruptions / delays in 83% (n=10) / 75% (n=9) / 83% (n=10). Belamaf dose reductions were seen in 42% (n=5) / 83% (n=10) / 42% (n=5) of affected patients. Median (days) time to first bilateral decrease in BCVA to 20 / 50 or worse in patients with 20 / 25 or better in >1 eye at baseline was longer with Q6 / 8W schedules (cohort 2, 245.5 days; cohort 4, 263.5 days) than Q3 / 4W (cohort 1, 76.0 days): these BCVA decreases resolved in a median of 70.0 days (cohort 4), 135.0 days (cohort 2), and 163.0 days (cohort 1).

[0761] Lower rates of grade 3 / 4 AEs related to belamaf were observed in the cohorts with a Q6 / 8W schedule, and Aes were manageable and reversible in all cohorts with appropriate dose modifications. Median time to onset of first bilateral decrease in BCVA from 20 / 25 or better to 20 / 50 or worse was longer in the Q6 / 8W cohorts, and resolution occurred faster.

[0762] Summary and Conclusion

[0763] Across all dosing schedules, belantamab + VRd delivered highly effective tumor responses and MRD negativity in patients with Tl NDMM. ORR was 71-100% across cohorts with 4 cohorts having 100% ORR. CR+ was 30-92% across cohorts. MRD[-] was 0-75% across cohorts: MRD[-] was 75% in 1.9 mg / kg Q3 / 4W and 67% in 1.9 mg / kg Q6 / 8W cohorts. MRD[-] continued to increase into the Maintenance phase. Higher starting doses of belamaf were generally associated with higher and faster rates of MRD[-] across dosing intervals. Regardless of dosing interval, higher belamaf doses were associated with higher rates of MRD negativity. Of the cohorts described, deeper MRD[-] responses were induced at the higher initial dose (1.9 mg / kg), with improved tolerability at the longer schedules (Q6 / 8W).

[0764] In cohorts with comparable follow-up durations, longer dosing intervals were associated with fewer ocular events and increased time to onset of clinically meaningful BCVA changes. Ocular events were effectively managed with dose modification, including extending the dosing interval or dose reduction, while maintaining patients on treatment across all cohorts. These data are consistent with prior clinical studies of belamaf in the relapsed / refractory MM setting. Follow-up is ongoing.

[0765] Example 4: Population Pharmacokinetics Analysis for Belantamab Mafodotin in Combination with Standard of Care in Transplant-Ineligible Newly Diagnosed Multiple Myeloma (DREAMM-9)

[0766] The population pharmacokinetics (popPK) of belantamab mafodotin when administered in combination with VRd in patients with Tl NDMM and the exposure- response (E-R) relationships for efficacy and select safety endpoints were characterized from the DREAMM-9 (NCT04091126) Phase I clinical study described above in Example 3 to inform the clinical dosing regimen selection for the first-line setting. The pharmacokinetics (PK) of belantamab mafodotin has been found to be associated with baseline disease factors and to vary over time.

[0767] Methods

[0768] PK samples from patients evaluated in the DREAMM-9 study were collected at different times and analyzed for concentration of belantamab mafodotin and concentration of the free payload cys-mcMMAF. Serial PK samples were obtained after the first dose, with pre-dose and EOI samples collected on some subsequent dosing days. The PK profiles, individual dosing history, and baseline characteristics of the participants were evaluated using a qualified popPK model developed in patients with refractory or relapsed multiple myeloma. The MAXEVALS option was set to zero in NONMEM to obtain the post hoc estimates and derive the exposure measures. The exposure measures included: (i) cycle 1: peak concentration (Cmax), average concentration (Cavg) and concentration at day 21; first 6 months average concentration (only for participants who stayed on trial for 6 months). Individual PK parameters were computed for all patients.

[0769] E-R analyses focused on selected safety and efficacy endpoints and investigated the impact of different exposure metrics for belantamab mafodotin (ADC) and cys-mcMMAF (safety endpoints only) along with selected covariates, including key disease factors (Table 17). Logistic regression models were used to assess probability of efficacy or safety endpoints. Cox proportional hazard models were used to assess time-to-event endpoints. Univariate covariate search followed by a stepwise covariate selection procedure were used to identify significant covariates (a 0.01 for forward addition; a 0.001 for backward elimination).

[0770] Table 17: Covariates evaluated for E-R analysis

[0771]

[0772] Results

[0773] The PopPK models developed in later-line patients adequately described belamaf and cys-mcMMAF PK in Tl NDMM patients, showing that PK is similar across different LOTs and treatments. Belantamab mafodotin PK values were impacted by disease-related clinical factors (e.g. baseline sBCMA, IgG and albumin). Belantamab mafodotin clearance (CL) was reduced overtime, potentially linked to reduction in disease burden. In DREAMM-9, CL was reduced by 49% following combination therapy, resulting in the average elimination half-life of belamaf increasing from 12 days to 20 days. The time to 50% change in CL was 60 days, with time to 95% change approximately 24 weeks.

[0774] With cycle 1 exposures, a Q6 / 8W dosing schedule was significantly associated with probability of sCR / CR, while a Q9 / 12W dose was associated with lower probability. IgG myeloma was associated with longer time to sCR / CR and time to MRD- negativity with Cycle 1 and 6-month exposures. See FIGs. 7A-7B. A positive relationship between belantamab mafodotin average concentration exposure metrics and probability of MRD negativity was observed across all average exposure metrics, including cycle 1 exposure and landmark exposure over 6 months (FIG. 8A). A positive correlation was observed between cycle 1 and 6-months belantamab mafodotin exposure and probability of sCR / CR, with higher average concentrations associated with increased likelihood of sCR / CR (FIG. 8B).

[0775] Logistic regression also showed a trend for reduced probability of Grade >2 corneal events in the Q9 / 12W cohort using Cycle 1 exposure metrics or the 6-month average concentration. Probability of Grade >2 corneal events did not appear to be associated with exposure. Of the covariates included in the E-R model for corneal events, only dose schedule was retained as a significant predictor in the final models using Cycle-1 and 6-month exposure metrics, with the Q9 / Q12Wdose schedule associated with reduced incidence and longer time to an event. This suggests that extending the dosing interval could reduce the incidence and delay onset of corneal events. Final models for Grade >3 thrombocytopenia, Grade >3 neutropenia, Grade >3 anemia, and SAEs, as well as dose reductions and delays / interruptions due to TEAEs or KVA events showed no association with the covariates evaluate. The final dose modification model included Q9 / Q12W schedule as a significant predictor for reduced probability when the entire population was evaluated at Cycle 1, but not at the 6-month landmark analysis.

[0776] Conclusions Belantamab mafodotin and cys-mcMMAF PK in Tl NDMM patients from

[0777] D REA MM -9 were well-described by the PopPK model developed with data from patients with RRMM who received belantamab mafodotin as monotherapy or in combinations, showing that PK is similar across different lines of therapy and treatments. Belantamab mafodotin demonstrated time-dependent clearance, with lower clearance over time potentially associated with a reduction in disease burden. Across all dosing schedules, there was a trend for increased probability of achieving CR+ and MRD negativity with increased Cycle-1 and 6-months average exposures, suggesting that higher early belamaf exposure may lead to deeper responses. While probabilities of Grade >2 corneal events were not associated with PK exposures in E-R analyses, the more stretched dosing schedule cohort, Q9 / 12W in Tl NDMM patients was associated with reduced probability and later occurrence of Grade >2 corneal events using Cycle-1 and 6-month exposure metrics, indicating that longer dosing intervals reduce the probability of these events.

[0778] Taken together, these results suggest that belantamab mafodotin can be dosed at longer intervals after 24 weeks of treatment, the switch to longer dosing intervals being proportional to the increase in half-life.

[0779] Example 5: Phase 3 Study to Evaluate the Safety and Efficacy of Belantamab Mafodotin Administered in Combination with Bortezomib and Dexamethasone in Participants with Relapsed or Refractory Multiple Myeloma

[0780] Belantamab mafodotin, bortezomib, and dexamethasone (BVd), as compared with daratumumab, bortezomib, and dexamethasone (DVd), was evaluated in patients who had progression of multiple myeloma after at least one line of therapy in a phase 3, open-label, randomized trial (DREAMM-7 ClinicalTrials.gov number, NCT04246047; EudraCT number, 2018 -003993-29). The primary end point was progression-free survival. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status. This study is described in Hungria et al., Belantamab Mafodotin, Bortezomib and Dexamethasone for Multiple Myeloma, N Engl J Med 2024;391:393-407, which is incorporated by reference herein in its entirety, including the Supplementary Material for this article available at https: / / www.nejm. Org / doi / full / 10.1056 / NEJMoa2405090#supplementary-materials (last accessed October 31, 2025).

[0781] Study Design

[0782] A Phase 3, open-label, global, randomized trial involving patients with multiple myeloma who had received at least one line of therapy and had disease progression during or after the most recent therapy was conducted. The study is ongoing.

[0783] Patients were excluded from the trial if they had disease that was refractory to anti-CD38 therapy or had had exposure to anti-BCMA therapy. Patients were randomly assigned in a 1:1 ratio to receive either BVd or DVd. Both treatment groups received bortezomib (administered subcutaneously at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11 of 21-day cycles) and dexamethasone (administered orally or intravenously at a dose of 20 mg on the day of and the day after bortezomib administration) for the first eight cycles. The BVd group received belantamab mafodotin (administered intravenously at a dose of 2.5 mg per kilogram of body weight on day 1 of 21-day cycles [every 3 weeks]) until the occurrence of disease progression. The belantamab mafodotin dose was reduced to 1.9 mg per kilogram or delayed to manage adverse events. The DVd group received daratumumab (administered intravenously at a dose of 16 mg per kilogram every week in cycles 1 through 3, every 3 weeks in cycles 4 through 8, and every 4 weeks in cycle 9 and beyond) until the occurrence of disease progression. Treatment was continued until the occurrence of progressive disease, unacceptable toxic effects, withdrawal of consent, or death (whichever occurred first). Patients were stratified according to Revised International Staging System stage at screening (I vs. II or III), previous exposure to bortezomib (yes vs. no), and the number of previous lines of therapy (one vs. two or three vs. four or more). Up to 50% of the patients enrolled could have received two or more previous lines of therapy. Crossover between treatment groups was not permitted. End Points and Assessments

[0784] The primary end point was progression-free survival (PFS), defined as the time from randomization to the occurrence of documented disease progression or death from any cause. Disease progression was assessed by an independent review committee with the use of International Myeloma Working Group criteria. A post hoc supplementary analysis was performed in which any occurrence of disease progression or death was considered to be an event, regardless of whether the patient had started a new antimyeloma therapy or had extended loss to follow-up. Key secondary end points were overall survival, response duration, and minimal residual disease (MRD)-negative status, which was assessed by means of next-generation sequencing at a sensitivity of 10-5or lower. Additional secondary end points were adverse events, which were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, and findings on ocular examination, which were graded with the use of the Keratopathy and Visual Acuity (KVA) scale. The KVA grade is a composite grade that is based on findings on corneal examination and changes in the best corrected visual acuity (BCVA). In the BVd group, an ocular examination was performed at screening, every 3 weeks before treatment administration up to at least the sixth dose of belantamab mafodotin, and then every 3 months if there were no ocular findings. In the DVd group, an ocular examination was performed at screening, at cycle 6, and then every 6 months. To assess the change from baseline in health-related quality of life, the scores on the global health status and quality-of- life domains of the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire were obtained at each visit.

[0785] Statistical Analysis

[0786] The sample size was driven by the analysis of the primary end point, progression-free survival. It was estimated that a sample of approximately 478 patients, with approximately 280 events (disease progression or death) in the intention-to-treat population, would provide the trial with approximately 92% power to detect a significant difference between the BVd group and the DVd group in progression-free survival, at a one-sided significance level of 2.5%. The estimate was based on an assumed hazard ratio for disease progression or death of 0.67. One interim analysis of progression-free survival was to be performed when approximately 250 events had occurred. The familywise type I error was controlled at 2.5% (one-sided) across hypotheses for progression-free survival, overall survival, response duration, and MRD-negative status; for the interim and final analyses of progression-free survival and overall survival, efficacy boundaries were defined with the Lan-DeMets O’Brien-Fleming spending function.

[0787] Progression-free survival and overall survival were compared between treatment groups with a stratified log-rank test. Hazard ratios and corresponding 95% confidence intervals were estimated with a stratified Cox proportional-hazards model, with treatment as the only explanatory variable. The Kaplan-Meier method was used to estimate the median progression-free survival and overall survival; corresponding 95% confidence intervals were calculated with the Brookmeyer-Crowley method. The methods used in the primary analysis incorporate the missing-at-random assumption, which specifies that missingness does not depend on the unobserved data. A stratified Cochran-Mantel-Haenszel test was used in the analysis of MRD-negative status. The main analysis of response duration involved the use of the restricted mean response duration. A conventional analysis of response duration, involving a method similar to that used for progression-free survival and overall survival, was performed as a sensitivity analysis. Prespecified subgroup analyses of progression-free survival were performed.

[0788] Results are reported from the successful interim analysis for progression-free survival, which was performed after 249 events had occurred (data cutoff, October 2, 2023). This interim analysis was performed with a multiplicity-adjusted boundary for significance of P<0.017. The boundary was one-sided according to the statistical analysis plan; two-sided P values are reported (Table S3). The two-sided (alpha level, 0.05) 95% confidence intervals reported were not adjusted for multiplicity and cannot be used in place of hypothesis testing to infer definitive treatment effects.

[0789] Results

[0790] In sum, At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [Cl], 28.4 to not reached) in the BVd group and 13.4 months (95% Cl, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% Cl, 0.31 to 0.53; P<0.001). Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group. An analysis of the restricted mean response duration favored BVd over DVd (P<0.001). A complete response or better plus MR D-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group. Ocular events were more common in the BVd group than in the DVd group (79% vs. 29%); such events were managed with dose modifications, and events of worsening visual acuity mostly resolved.

[0791] Patients and Treatment

[0792] From May 7, 2020, through June 28, 2021, a total of 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients); these patients were included in the intention-to-treat population. At the time of the data cutoff, all the patients were in the monotherapy phase. Overall, 81 of the 243 patients (33%) in the BVd group and 51 of the 251 patients (20%) in the DVd group were receiving the trial treatment; 161 patients (66%) had discontinued belantamab mafodotin, and 195 patients (78%) had discontinued daratumumab. One patient in the BVd group and 5 patients in the DVd group had undergone randomization but had not received the trial treatment.

[0793] Progressive disease was the most common reason for discontinuation of belantamab mafodotin or daratumumab; 24% of the patients in the BVd group had discontinued belantamab mafodotin and 59% in the DVd group had discontinued daratumumab for this reason.

[0794] The trial population was closely representative of the population of patients with multiple myeloma in terms of the sex and age distribution. However, the trial population had more White patients than patients in other racial groups, with an underrepresentation of Black patients. The characteristics of the patients and previous treatments at baseline were well balanced between the treatment groups. Overall, 250 of the 494 patients (51%) had received one previous line of therapy, 257 (52%) had had exposure to lenalidomide, 166 (34%) had disease that was refractory to lenalidomide, and 136 (28%) had high cytogenetic risk.

[0795] Efficacy At a median follow-up of 28.2 months (range, 0.1 to 40.0), median progression-free survival was 36.6 months (95% confidence interval [Cl], 28.4 to not reached [NR]) in the BVd group and 13.4 months (95% Cl, 11.1 to 17.5) in the DVd group (hazard ratio for disease progression or death, 0.41; 95% Cl, 0.31 to 0.53; P<0.001) (FIG. 9A). Of the 249 total events (disease progression or death), 91 (37%) had occurred in the BVd group and 158 (63%) had occurred in the DVd group. The investigators and the independent review committee were largely in agreement in their assessment of progressive disease. A post hoc analysis showed that follow-up for patients with censored data was balanced between the treatment groups. The results of prespecified subgroup analyses of progression-free survival are shown in. The results of a post hoc supplementary analysis in which any occurrence of disease progression or death was considered to be an event, regardless of whether the patient had started a new antimyeloma therapy or had extended loss to follow-up, are shown in FIG. 9B. The results of further supplementary analyses were all consistent with the results of the primary analysis (data not shown).

[0796] At the time of the data cutoff, 54 patients (22%) in the BVd group and 87 patients (35%) in the DVd group had died. Overall survival at 18 months was 84% in the BVd group and 73% in the DVd group (FIG. 9C). The 25th percentile of the distribution of overall survival was 33.9 months (95% Cl, 21.9 to NR) in the BVd group and 15.2 months (95% Cl, 12.3 to 21.1) in the DVd group. At the data cutoff, the results for overall survival did not meet the significance criterion; follow-up for overall survival is ongoing.

[0797] The percentage of patients who had a response to treatment (partial response or better) was 83% (95% Cl, 77 to 87) in the BVd group and 71% (95% Cl, 65 to 77) in the DVd group (Table 18). The depth of response was greater with BVd than with DVd; 35% of the patients in the BVd group had a complete response or better, as compared with 17% of the patients in the DVd group. A complete response or better plus MRD-negative status occurred in 25% of the patients in the BVd group and 10% of those in the DVd group. The median response duration was 35.6 months (95% Cl, 30.5 to NR) in the BVd group and 17.8 months (95% Cl, 13.8 to 23.6) in the DVd group; the 25th percentile of the distribution of response duration was 18.8 months (95% Cl, 13.2 to 23.5) in the BVd group and 9.0 months (95% Cl, 6.4 to 10.4) in the DVd group. However, because more than half the responses in the BVd group were still ongoing at the time of the interim analysis, the data regarding the median response duration were not fully mature. A separate analysis of the restricted mean response duration favored BVd over DVd (P<0.001).

[0798] Table 18: Treatment Response and Minimal Residual Disease (intent-to-treat population)

[0799]

[0800]

[0801] MRD denotes minimal residual disease, and NR not reached,

[0802] † Duration of response is defined as the time from the first documented evidence of a partial response or better to the occurrence of disease progression or death from any cause.

[0803] ‡ Time to first response is defined as the time from the date of randomization to the first documented evidence of a partial response or better among patients who had a confirmed partial response or better

[0804] § Time to best response is defined as the time from the date of randomization to the earliest date of achieving the best response among patients who had a confirmed partial response or better.

[0805] 1 Minimal residual disease (MRD)-negative status was assessed by means of next-generation sequencing at a sensitivity of 10−5or lower.

[0806] The most common therapies administered after DVd were glucocorticoids, immunomodulators, and proteasome inhibitors; the most common therapies administered after BVd were glucocorticoids, immunomodulators, and monoclonal antibodies. In a post hoc analysis, among the 110 patients in the DVd group who had received any subsequent antimyeloma therapy, the first treatment after DVd was lenalidomide in 32 patients (29%), carfilzomib in 30 (27%), pomalidomide in 24 (22%), and belantamab mafodotin in 15 (14%). Among the 62 patients in the BVd group who had received any subsequent anti-myeloma therapy, the first treatment after BVd was daratumumab in 25 patients (40%), pomalidomide in 18 (29%), and lenalidomide in 13 (21%). The benefits of treatment with BVd were maintained, as shown by the time to the occurrence of disease progression or death from any cause after subsequent antimyeloma therapy.

[0807] Among the 67 patients in the BVd group who had disease progression, 36 had samples available for a post hoc analysis of soluble BCMA levels. All 36 patients had detectable soluble BCMA at baseline and at the time of disease progression. For the 32 patients with available soluble BCMA data who had a confirmed response, the analysis showed that soluble BCMA levels were numerically lower than baseline levels while the patients were having a response (median relative decrease from baseline, 78%) but increased when disease progression occurred. This finding, which suggests that there was no BCMA target loss, is similar to previously reported findings.

[0808] Safety

[0809] The safety population included the 488 patients (242 in the BVd group and 246 in the DVd group) who had received at least one dose of any trial drug. The median duration of exposure to any trial drug was 15.9 months (range, 0.7 to 40.2) in the BVd group and 12.9 months (range, 0.2 to 40.5) in the DVd group. All the patients had at least one adverse event (Table 19). Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group and 78% of those in the DVd group, and serious adverse events occurred in 50% and 37%, respectively. Discontinuation of any trial drug due to adverse events that were considered by the investigator to be related to treatment occurred in 64 patients (26%) in the BVd group and 36 patients (15%) in the DVd group. The following adverse events led to discontinuation of any trial drug in at least 2% of the patients in either treatment group: peripheral sensory neuropathy (5% in the BVd group and 2% in the DVd group), peripheral neuropathy (2% and 4%, respectively), polyneuropathy (3% and 2%), pneumonia (4% and none), coronavirus disease 2019 (Covid-19) (1% and 2%), Covid-19 pneumonia (<1% and 2%), thrombocytopenia (2% and <1%), and blurred vision (2% and none) (Table S13). In addition, 23 patients (10%) in the BVd group and 19 patients (8%) in the DVd group died from serious adverse events; the serious adverse event that led to death was considered to be related to treatment in 7 patients (3%) and 2 patients (1%), respectively.

[0810] In both treatment groups, the most common adverse events according to system organ class were blood disorders and infections. Although the incidence of thrombocytopenia was higher in the BVd group than in the DVd group (69% vs. 50%), there was no substantial difference between the treatment groups in the percentage of patients with a concomitant grade 3 or 4 platelet-count decrease and grade 2, 3, or 4 bleeding event (7% with BVd and 6% with DVd). The incidence of anemia was 19% in the BVd group and 26% in the DVd group. The incidence of infections was similar in the two groups (70% with BVd and 67% with DVd), although grade 3 or higher pneumonia was more common in the BVd group than in the DVd group (12% vs. 4%). Data regarding opportunistic infections were not collected systematically; however, when an analysis was performed with the use of the adverse-event terms “aspergillus infection,” “cyto-megalovirus reactivation,” and “pneumonia fungal,” the incidence of these three opportunistic infections was low and balanced between the treatment groups (<1% in each group). In a post hoc analysis, immunoglobulin replacement was more common with BVd than with DVd (8% vs. 4%). Other nonocular adverse events that occurred in at least 20% of the patients in either treatment group included diarrhea, peripheral sensory neuropathy, peripheral neuropathy, constipation, and fatigue.

[0811] Because belantamab mafodotin has known ocular toxic effects, patients underwent regular ocular assessments. Ocular adverse events were more common in the BVd group than in the DVd group (any grade, 79% vs. 29%; grade 3 or 4, 34% vs.

[0812] 3%). The most common grade 3 or 4 ocular adverse events with BVd were blurred vision, dry eyes, and cataract, whereas cataract was the most common with DVd.

[0813] Among the patients with a normal BCVA (defined as 20 / 25 or better in at least one eye) at baseline, a decrease in the BCVA to 20 / 50 or worse in both eyes occurred in 34%, and a decrease to 20 / 200 in both eyes occurred in 2% (Table 20). In 98% of the patients who had a decrease to 20 / 50 in both eyes, and in all the patients who had a decrease to 20 / 200 in both eyes, the BCVA improved after the first occurrence of worsening. In the remaining 2% of the patients who had a decrease to 20 / 50 in both eyes, the BCVA did not improve, treatment was discontinued, and no further examinations were performed to assess for resolution. In a post hoc analysis, the BCVA returned to the baseline level (20 / 25 or better in at least one eye) after the first occurrence of worsening in 94% of the patients who had a decrease to 20 / 50 in both eyes and in 80% of those who had a decrease to 20 / 200 in both eyes. The median time to resolution after the first occurrence was 9 weeks among patients with a decrease to 20 / 50 and 12 weeks among those with a decrease to 20 / 200.

[0814] Modifications of the belantamab mafodotin dose were based on the overall KVA grade. KVA events occurred in 84% of the patients; 7% had grade 2 events, and 74% had grade 3 or higher events. For the first occurrence of a grade 2 or higher KVA event, the median time to onset was 58.0 days, and the median duration was 106.0 days. At the time of the data cutoff, the first occurrence of a KVA event had resolved, whether before or after the end of treatment exposure, in 85% of the patients. Ocular events led to reductions, delays, and discontinuations of the belantamab mafodotin dose in 44%, 78%, and 9% of the patients in the BVd group, respectively. Although more ocular events occurred in the BVd group than in the DVd group, there was no substantial difference between the treatment groups in the overall patient-reported quality of life over time.

[0815] The median relative dose intensity of belantamab mafodotin was 51% for the full duration of treatment. In a post hoc analysis, the value was 77% in the first 6 months, 68% after 6 months to 12 months, and 28% after 12 months. The median relative dose intensity of daratumumab was 95% or higher during each dosing period (i.e., cycles 1 through 3, cycles 4 through 8, and cycle 9 onward through treatment discontinuation. The median dose intensities of bortezomib and dexamethasone were similar in the two treatment groups (>75% in the first eight cycles).

[0816] Table 19: Adverse Events Reported in at Least 15% of Patients in Either Group (Safety Population)*

[0817]

[0818]

[0819] ’ Adverse events were graded with rhe use of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 0.

[0820] † If platelet-count decrease is also included, the percentage of patients with a thrombocytopenia event of any grade is 87% with BVd and 65% with DVd, and the percentage of patients with a grade 3 or higher thrombocytopenia event is 73% and 46%, respectively.

[0821] ‡ Decreased red-cell count was not reported.

[0822] § Infusion-related reactions are based on a hybrid of terms identified in the electronic case report form and a list of terms identified by GSK internal review. The event had to start within 24 hours after the infusion and lead to dose interruption or delay or to discontinuation of the trial drug

[0823] Table 20: Worsening of BCVA in Both Eyes Among Patients in the BVd Group with Normal BCVA at Baseline*

[0824]

[0825] Conclusion

[0826] The interim analysis of the DREAMM-7 trial showed that, as compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy. The hazard ratio for disease progression or death was 0.41 (95% Cl, 0.31 to 0.53; P<0.001). BVd therapy was associated with a greater depth and durability of response than DVd therapy; the percentages of patients who had a stringent complete response, a complete response, and MRD-negative status were higher and the response duration was longer in the BVd group than in the DVd group. Grade 3 or higher adverse events occurred in 95% of the patients in the BVd group, and serious adverse events occurred in half. Approximately one quarter of the patients in the BVd group discontinued any of the three drugs in BVd because of treatment-related toxic effects.

[0827] The median progression-free survival of 13.4 months (95% Cl, 11.1 to 17.5) in the DVd group is consistent with that seen in the CASTOR trial (16.7 months; 95% Cl, 13.1 to 19.4) and better than the outcome among patients with multiple myeloma in a nontrial setting (8.3 months). Although crosstrial comparisons should be interpreted with caution, the median progression-free survival of 36.6 months (95% Cl, 28.4 to NR) in the BVd group is similar to, or better than, that reported in other trials of triplet combination regimens that included anti-CD38 monoclonal antibodies and proteasome inhibitors and were used in similar populations; the median progression-free survival was 28.6 months in the CANDOR trial and 35.7 months in the IKEMA trial. In the CARTITUDE-4 trial, patients who had disease that was refractory to lenalidomide after at least one line of therapy were treated with ciltacabtagene autoleucel, a BCMA-targeting chimeric antigen receptor (CAR) T-cell therapy. Progression-free survival at 12 months was 76%, and the corresponding estimate in the DREAMM-7 trial was 78%. The broad clinical benefit observed with BVd supports its potential integration into current treatment strategies used at the time of the first relapse or later. The PERSEUS trial recently showed a benefit of frontline treatment with daratumumab, bortezomib, lenalidomide, and dexamethasone. Once this frontline regimen is adopted, disease may become refractory to maintenance therapy with daratumumab and lenalidomide after frontline treatment, and new second-line regimens may be needed. The DREAMM-7 trial included a small number of patients who had had exposure to daratumumab, and patients with disease that was refractory to anti-CD38 antibody therapies were excluded from the trial; however, BVd may offer patients an alternative to retreatment with an anti-CD38 antibody. Furthermore, the presence of soluble BCMA at the time of disease progression may indicate retained BCMA expression in tumor cells after treatment with belantamab mafodotin. Therefore, it is anticipated that patients may derive benefit from other BCMA-targeted retreatment after progression. However, this result does not rule out the presence of mutations in the tumor necrosis factor receptor superfamily member 17 gene, which encodes BCMA; further studies would be needed to confirm that soluble BCMA is a surrogate for sensitivity to subsequent BCMA- targeting agents.

[0828] Adverse events associated with the use of BVd were consistent with those described previously with belantamab mafodotin. The overall incidence of adverse events was high because the analysis included adverse events associated with all drugs in the triplet combination regimen; the incidence may also reflect the treatment duration. In addition, enrollment occurred during the Covid-19 pandemic, which may have led to a higher level of treatment discontinuation than that reported in previous studies. Ocular side effects, which are a known risk with belantamab mafodotin, were managed with dose modifications, including delays and reductions. The efficacy of BVd was maintained even with delays and reductions of the belantamab mafodotin dose, which resulted in the lower relative dose intensity reported for belantamab mafodotin. Most patients who had a decrease in the BCVA subsequently had improvement or had their vision return to the baseline level. Resolution could not be confirmed in all patients because of progressive disease, death, or loss to follow-up. Some patients had multiple occurrences of a decrease in the BCVA, but the likelihood of resolution after the first occurrence was similar to that after the last occurrence among patients with more than one occurrence of worsening. Ocular adverse events occurred in 79% of the patients in the BVd group and 29% of those in the DVd group, findings that suggest a background incidence of such events in the general population of patients with multiple myeloma and that may reflect the intense ocular monitoring mandated by the use of belantamab mafodotin. Despite the higher incidence of ocular adverse events in the BVd group, overall patient-reported health-related quality of life did not differ substantially between the treatment groups over time.

[0829] The use of BCMA-targeting bispecific T-cell engager (BITE) or CAR T-cell therapies requires more intensive monitoring and is associated with life-threatening toxic effects, including cytokine release syndrome and immune effector cell- associated neurotoxicity syndrome. Belantamab mafodotin administered as a short outpatient infusion offers a less burdensome treatment option for patients and does not require monitoring for life-threatening toxic effects. The incidence of infections, including opportunistic infections — a known risk with the use of BCMA-targeting BITE and CAR T-cell agents — was low and similar in the two treatment groups in this trial. Limitations of this trial included limited racial diversity. There was the potential for bias from the open-label design, but such bias is unlikely because the investigators and the independent review committee were largely in agreement in their assessment of progressive disease. There was reporting bias of ocular events toward the BVd group because of the higher frequency of ocular examinations.

[0830] As compared with DVd, BVd conferred a significant benefit with respect to progression-free survival among patients with relapsed or refractory multiple myeloma after at least one line of therapy. In addition, BVd was associated with serious adverse events in 50% of patients. However, the strong results for progression-free survival and the deep and durable response with BVd support the potential for BVd to become a therapeutic option for patients with multiple myeloma at or after the first relapse.

[0831] In sum, as compared with DVd therapy, BVd therapy conferred a significant benefit with respect to progression-free survival among patients who had relapsed or refractory multiple myeloma after at least one line of therapy.

[0832] Example 6: Phase 3 Study to Evaluate the Safety and Efficacy of Belantamab Mafodotin Administered in Combination with Pomalidomide and Dexamethasone in Participants with Relapsed or Refractory Multiple Myeloma

[0833] Belantamab mafodotin, pomalidomide, and dexamethasone (BPd), as compared with pomalidomide, bortezomib, and dexamethasone (PVd), in lenalidomide-exposed patients who had relapsed or refractory myeloma after at least one line of therapy were evaluated in a phase 3, randomized, open-label trial. The primary end point was progression-free survival. Disease response and safety were also assessed. This study is described in Dimopoulos, et al., Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma, N Engl J Med 2024;391:408-421, which is incorporated by reference herein in its entirety, including the Supplementary Material for this article available at https: / / www.nejm.org / doi / full / 10.1056 / NEJMoa2403407#supplementary-materials (last accessed October 31, 2025).

[0834] Study Design

[0835] Patients, Treatment, and Oversight

[0836] Patients underwent central randomization in a 1:1 ratio to receive either BPd or PVd. Patients in the BPd group received 28-day cycles of belantamab mafodotin (2.5 mg per kilogram of body weight intravenously on day 1 of cycle 1 and 1.9 mg per kilogram on day 1 of cycle 2 onward) combined with pomalidomide and dexamethasone. The dose of belantamab mafodotin could be delayed or reduced to manage adverse events. Patients in the PVd group received 21 -day cycles of bortezomib (1.3 mg per square meter of body-surface area subcutaneously on days 1, 4, 8, and 11 of cycles 1 through 8 and days 1 and 8 of cycle 9 onward) combined with pomalidomide and dexamethasone.

[0837] Treatment continued until the occurrence of progressive disease, unacceptable adverse effects, withdrawal of consent, or death (whichever occurred first). Patients were stratified according to the number of previous lines of therapy they had received (one, two or three, or four or more), previous exposure to bortezomib (yes or no), and whether anti-CD38 antibodies had been received previously (yes or no). Enrollment of patients who had received more than one previous line of therapy was capped at 50%. Crossover between groups was not permitted.

[0838] End Points and Assessments

[0839] The primary end point was progression-free survival, defined as the time from randomization to the earliest date of disease progression based on assessment by an independent review committee (per International Myeloma Working Group 2016) or death from any cause. Key secondary end points included overall survival, minimal residual disease (MRD)-negative status, and response duration. Patients in both groups underwent response assessments every 4 weeks. Additional secondary end points included adverse events (including ocular adverse events), which were graded in ac-cordance with Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Ocular examination findings were also graded with the use of the Keratopathy Visual Acuity (KVA) scale, which incorporated findings on corneal examination and changes in the best corrected visual acuity (BCVA) into a composite grade; grades range from 1 (least severe) to 4 (most severe). In accordance with the protocol, ocular examinations were performed more frequently in the BPd group than in the PVd group.9 Patient-reported outcomes from the global health status and quality-of-life domains of the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) were also assessed.

[0840] Statistical Analysis

[0841] Using a one-sided significance level of 2.5% and accounting for two interim analyses of progression-free survival — one for harm (when an information fraction of approximately 25% for progression-free survival had been reached) and one for efficacy (when an information fraction of approximately 84% for progression-free survival had been reached) — it was calculated that approximately 173 progression or death events were needed for the primary analysis of progression-free survival to detect a hazard ratio of 0.6 with at least 90% power. Type I error was controlled at 2.5% (one-sided) across end points and interim analyses of progression-free survival (first and second interim analyses and third primary analysis of progression-free survival) and overall survival (interim analyses two, three, and four and the final analysis); efficacy boundaries were defined with the use of the Lan-DeMets approach, which approximates the O’Brien and Fleming spending function. End points were tested sequentially in the following order: progression-free survival, overall survival, and MRD-negative status. Progression-free survival was estimated with the Kaplan-Meier method. The treatment effect (hazard ratio and 95% confidence interval) was estimated with the stratified Cox proportional-hazards model. The methods used in the primary analysis incorporate the missing-at-random assumption, which specifies that missingness does not depend on the unobserved data. P values were calculated with the stratified log-rank test. Prespecified subgroup analyses of progression-free survival were performed. At the first interim analysis (data cutoff, January 17, 2022), the prespecified stopping boundary for harm had not been crossed (40 progression or death events; hazard ratio >1.245), and the independent data and safety monitoring committee recommended that the trial continue as planned. The sponsor remained unaware of the treatment assignments. The analysis described in this report, which is based on the successful second interim analysis (data cutoff, January 29, 2024), was performed after 142 progression or death events, with a boundary for significance of P<0.013361 (one-sided according to the statistical analysis plan, but two-sided P values are reported). Two-sided (alpha level, 0.05) 95% confidence intervals are reported but were not adjusted for multiplicity and cannot be used in place of hypothesis testing.

[0842] Results

[0843] Patients and Treatment

[0844] From October 2020 through December 2022, a total of 302 patients at 95 sites in 18 countries were randomly assigned to receive BPd (155 patients) or PVd (147 patients); these patients made up the intention-to-treat population. At the data cutoff for the second interim analysis, 65 patients (42%) in the BPd group and 33 patients (22%) in the PVd group were receiving treatment. The median duration of follow-up was 22.4 months (range, <0.1 to 36.4) in the BPd group and 20.5 months (range, 0.1 to 39.2) in the PVd group, with a minimum ongoing follow-up of 12.8 and 13.5 months, respectively.

[0845] The patients in the trial were closely representative of patients with multiple myeloma with respect to the sex distribution and the median age; however, Black patients were not represented, which is not reflective of the epidemiologic profile for multiple myeloma. The characteristics of the patients at baseline and the previous treatments received were generally similar in the two groups; two exceptions were the percentage of patients who were 75 years of age or older, which was higher in the PVd group than in the BPd group, and the percentage of patients with baseline extramedullary disease, which was higher in the BPd group than in the PVd group. Overall, 159 patients (53%) had received one previous line of therapy, and 41 (14%) had received four or more previous lines. All the patients had previously received lenalidomide, and 236 (78%) had lenalidomide-refractory disease. A total of 80 patients (26%) had previously received anti-CD38 antibodies, and 71 (24%) had disease refractory to anti-CD38 antibodies. After discontinuation of trial treatment, subsequent antimyeloma therapy was received by 76 patients (52%) in the PVd group and 42 patients (27%) in the BPd group.

[0846] The median total duration of exposure was 16.5 months (range, 0.92 to 35.06) for BPd and 8.5 months (range, 0.26 to 39.85) for PVd. Patients in the BPd group received a median of 16.0 treatment cycles (range, 1 to 37), and patients in the PVd group received a median of 11.0 treatment cycles (range, 1 to 56). The median relative dose intensity was 52.50% for belantamab mafodotin and 87.50% for bortezomib. The majority of patients received belantamab mafodotin at a dose of 1.9 mg per kilogram from the second cycle onward; the lower dose intensity was driven by a reduction in frequency of administration because of protocol-recommended modifications. The median relative dose intensities of pomalidomide and dexamethasone were slightly lower in the BPd group than in the PVd group (84.25% and 91.73%, respectively, for pomalidomide; 81.70% and 90.34%, respectively, for dexamethasone).

[0847] Efficacy

[0848] BPd resulted in a significantly lower risk of disease progression or death than PVd (hazard ratio, 0.52; 95% confidence interval [CI], 0.37 to 0.73; two-sided P<0.001). The median progression-free survival duration was not reached in the BPd group and was 12.7 months (95% CI, 9.1 to 18.5) in the PVd group. The estimates of 12-month progression-free survival were 71% (95% CI, 63 to 78) with BPd and 51% (95% CI, 42 to 60) with PVd (FIG. 10A). Disease progression or death occurred in 62 patients (40%) in the BPd group and 80 patients (54%) in the PVd group. A post hoc supplementary analysis was performed in which any occurrence of disease progression or death was included as an event, regardless of whether new antimyeloma therapy was started or whether the patient had an extended loss to follow-up. The results of this analysis are shown in FIG. 10B; the results were consistent with those of the primary analysis.

[0849] The percentage of patients who had a response to treatment (partial response or better) was 77% (95% Cl, 70 to 84) in the BPd group and 72% (95% Cl, 64 to 79) in the PVd group; the corresponding percentages of patients with a complete response or better were 40% (95% CI, 32 to 48) and 16% (95% CI, 11 to 23) (Table 21). A complete response or better plus MRD-negative status was achieved in 24% (95% CI, 17 to 31) of the patients in the BPd group, as compared with 5% (95% CI, 2 to 10) of those in the PVd group (Table 21). The estimated percentage of patients with a response duration of 12 months was 79% (95% CI, 71 to 86) in the BPd group and 61% (95% CI, 50 to 70) in the PVd group (Table 21). Among the patients with a response, 55% of those in the BPd group and 31% of those in the PVd group had not had disease progression or died and continued to have follow-up for progression-free survival ongoing at the data cutoff. Results of the primary analyses of the duration of response in which the restricted mean duration of response was used were consistent with those of the conventional analysis.

[0850] Table 21: Treatment response and minimal residual disease (intent-to-treat population)

[0851]

[0852]

[0853] The 12-month estimate of progression-free survival during receipt of the subsequent line of therapy was 80% (95% CI, 73 to 86) with BPd and 67% (95% CI, 58 to 74) with PVd (hazard ratio, 0.61; 95% CI, 0.43 to 0.86). Data for overall survival were immature and did not reach significance at the current interim analysis; follow-up is ongoing for future prespecified analyses of overall survival. The 12-month overall survival was 83% (95% CI, 76 to 88) with BPd and 76% (95% CI, 68 to 82) with PVd (hazard ratio, 0.77; 95% CI, 0.53 to 1.14) (FIG. 10C).

[0854] Safety

[0855] The safety population included the 295 patients (150 in the BPd group and 145 in the PVd group) who received at least one dose of BPd or PVd. Patients in the BPd group continued to receive their assigned treatment for almost twice as long as those in the PVd group; therefore, data on adverse events were collected for a correspondingly longer period in the BPd group.

[0856] Adverse events of any grade were reported in 99% of the patients who received BPd and 96% of those who received PVd. The percentage of patients with grade 3 or higher adverse events was 94% in the BPd group and 76% in the PVd group, and the percentage of patients with serious adverse events was 63% and 45%, respectively (Table 22). Similar percentages of patients in the two groups had adverse events leading to permanent discontinuation of any trial treatment (15% in the BPd group and 12% in the PVd group), adverse events leading to dose reduction (61% in both groups), and fatal adverse events (11% in both groups) (Table S12). Adverse events led to dose delay in 91% of the patients who received BPd and 75% of those who received PVd. The most frequently reported adverse events in the BPd group were blurred vision (in 79% of the patients in the BPd group and 15% of those in the PVd group), dry eye (in 61% and 10%), and foreign-body sensation in the eyes (in 61% and 6%). The most frequently reported adverse events in the PVd group were neutropenia (in 48% of the patients in the BPd group and 34% of those in the PVd group), thrombocytopenia (in 36% and 30%), and anemia (in 23% and 26%). Infection occurred in 82% of the patients in the BPd group and 68% of the patients in the PVd group, and infection of grade 3 or higher occurred in 49% and 26%, respectively.

[0857] At the data cutoff, 89% of the patients who received BPd had had CTCAE-graded ocular adverse events (grade 3 or 4 in 43%), as compared with 30% of those who received PVd (grade 3 or 4 in 2%). In the BPd group, 91% of these reported events had resolved. A decrease in BCVA to 20 / 50 or worse can affect activities of daily living. A total of 51 patients (34%) in the BPd group, as compared with 4 (3%) in the PVd group, had postbaseline worsening of their BCVA from normal (defined as 20 / 25 or better in at least one eye) at baseline to 20 / 50 or worse in both eyes at the same time. The median time to onset was 112 days, and the median duration of the first occurrence was 29 days. Improvement after the first event occurred in 47 of 51 patients (92%); 2 patients had withdrawn from the trial or died before improvement, and the event was ongoing in 2 patients who were still in the trial at the data cutoff. A normal BCVA at baseline with post-baseline worsening to 20 / 200 in both eyes was reported in 2 BPd-treated patients (1%) and in 1 PVd-treated patient (1%) (Table 23). Each of the two BPd-treated patients had one such occurrence; the duration was 22 days in one and 29 days in the other. After both events, the BCVA improved to better than 20 / 200 in both eyes by the data cutoff.

[0858] Ocular events as defined according to the KVA scale were reported in 87% of the patients who received BPd, with 12% having a maximum event grade of 2 and 70% having a maximum event grade of 3 or higher. KVA-defined events led to a dose delay in 75% of the patients who received BPd, dose reduction in 57%, and treatment discontinuation in 8%. Of the 123 patients with grade 2 or higher KVA-defined events, the majority had no subsequent grade 2 or higher occurrence or had a second occurrence that was no more severe than the first. For grade 2 or higher KVA-defined events, the median time to onset was 57 days, and the median duration of the first occurrence was 90.5 days. The first occurrence resolved in 110 of 123 patients (89%) with a grade 2 or higher KVA-defined event; 8 patients (7%) had withdrawn from the trial or died before documented resolution, and the first occurrence was ongoing at the data cutoff in 5 patients (4%) who remained in the trial. Overall, ocular events (CTCAE- or KVA-defined) led to discontinuation of any trial treatment in 9% of the patients in the BPd group.

[0859] Patient-reported outcomes from the global health status and quality-of-life domains of the EORTC QLQ-C30 showed no clinically meaningful change from baseline in either treatment group over time. Similar results were also observed in domains assessing physical and role functioning, fatigue, and pain, which suggested that treatment did not lead to any decline in overall health-related quality of life.

[0860] Table 22: Adverse Events Reported in at Least 20% of Patients in Either Group (Safety Population)

[0861]

[0862]

[0863] Table 23: Worsening of BCVA in Both Eyes among Patients in the BPd Group with Normal BCVA at Baseline

[0864]

[0865] t Improvement was defined as no longer 20 / 50 (or 20 / 200) or worse in both eyes.

[0866] t One of the patients had onset of a BCVA worse than 20 / 50 in both eyes at 6 months after the last dose

[0867] of belantamab mafodotin in the presence of normal cornea.

[0868] Conclusion

[0869] In patients with relapsed or refractory myeloma who had previously been treated with lenalidomide, BPd led to a significantly greater reduction in the risk of progression or death than PVd and was associated with a higher percentage of patients with a complete response or better. The benefit was consistently observed across all efficacy end points, and health-related quality of life was not adversely affected. Follow-up for overall survival is ongoing, and assessment of this outcome will be included in the planned subsequent interim and final overall survival analyses.

[0870] Ocular events were common and were mainly characterized by high rates of resolution, low treatment discontinuation rates, and the absence of a negative effect on patient-assessed global health status-related quality-of-life measures. These events were managed by protocol-recommended modification of the belantamab mafodotin dose, which included dose delays until the KVA grade improved to 1 or lower and reductions in the frequency of administration from every 4 weeks to every 8 weeks. Ocular adverse events and examination findings were also occasionally observed in the PVd group and probably represent the background incidence in the trial population. High levels of monitoring, including protocol-mandated eye examinations and solicitation of ocular symptoms, may have led to increased reporting of ocular adverse events and findings in both treatment groups.

[0871] The median relative dose intensity of 52.50% for belantamab mafodotin was driven by the protocol-recommended dose modifications to manage corneal events, including dose delays and the reduction in dosing frequency from every 4 weeks to every 8 weeks. Measures such as initiating treatment at a dose of 2.5 mg per kilogram in cycle 1 followed by 1.9 mg per kilogram every 4 weeks and providing flexibility in reducing the frequency of administration to every 8 weeks to manage corneal events optimize the efficacy and side-effect profile of the regimen for each patient.

[0872] The utility of regimens containing lenalidomide or anti-CD38 antibodies at the first relapse is declining because of the increase in the number of patients whose disease is refractory to these agents as a result of exposure during frontline treatment. Other currently approved triplet regimens used at the first relapse include PVd, the trial comparator, and selinexor-bortezomib-dexamethasone, which is associated with considerable challenges in managing adverse events. Two chimeric antigen receptor (CAR) T-cell therapies — ciltacabtagene autoleucel and idecabtagene vicleucel — were recently approved for patients who have received at least one and at least two previous lines of therapy, respectively. Both therapies have been shown to provide a significant progression-free survival benefit and improvement in quality of life as compared with standard triplet regimens. However, access and safety issues, including the potential for cytokine release syndrome, neurotoxic effects, and an early survival detriment (thought to be related to bridging therapy challenges while the therapeutic cells are being generated in the laboratory), may limit their use. Results from phase 3 trials of BCMA-targeting bispecific antibodies, including teclistamab, elranatamab, and linvosel...

Claims

1. CLAIMS1. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone, wherein:3.(a) the anti-BCMA antigen binding protein is administered:4.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then5.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;6.(b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and7.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);8.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

2. The method of claim 1, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 1.9 mg / kg on day 1 of each 56-day treatment cycle.

3. The method of claim 1 or 2, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

4. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, lenalidomide, and dexamethasone, wherein:12.(a) the anti-BCMA antigen binding protein is administered:13.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter; (b) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and14.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);15.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

5. The method of claim 4, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 1.9 mg / kg on day 1 of each 56-day treatment cycle.

6. The method of claims 4 or 5, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

7. The method of any one of claims 4 to 6, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first, second, or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is initiated.

8. The method any one of claims 4 to 7, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle, administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

9. The method of claim 8, wherein the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

10. The method of any one of claims 4 to 9, wherein the Grade of the ocular adverse event is determined based on an ophthalmic exam finding.

11. The method of claim 10, wherein the ophthalmic exam finding comprises a corneal exam finding and / or a change in best-corrected visual acuity (BCVA) finding.

12. The method of any one of claims 1 to 11, wherein the lenalidomide is administered at a dose of 25 mg, 10 mg, or 7.5 mg on each of days 1-21 of each lenalidomide treatment cycle.

13. The method of any one of claims 1 to 11, wherein the lenalidomide is administered at a dose of 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle.

14. The method of any one of claims 1 to 11, wherein the human patient has an estimated glomerular filtration rate (eGFR) of 30-60 mL / min / 1.73 m2and is administered lenalidomide at a dose of 10 mg on days 1-21 of each lenalidomide treatment cycle.

15. The method of any one of claims 1 to 11, wherein the human patient has an estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2and is administered lenalidomide at a dose of 7.5 mg on days 1-21 of each lenalidomide treatment cycle.

16. The method of any one of claims 1 to 11, wherein the human patient has an estimated glomerular filtration rate (eGFR) of <30 mL / min / 1.73 m2and is administered lenalidomide at a dose of 15 mg on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, and 21 of each lenalidomide treatment cycle.

17. The method of any one of claims 1 to 16, wherein the dexamethasone is administered at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

18. The method of claim 17, wherein the dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

19. The method of claim 17, wherein the dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

20. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone, wherein:28.(a) the anti-BCMA antigen binding protein is administered:29.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then30.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;31.(b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and32.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);33.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

21. The method of claim 20, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles.

22. The method of claims 20 or 21, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

23. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, pomalidomide, and dexamethasone, wherein:37.(a) the anti-BCMA antigen binding protein is administered: i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then38.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;39.(b) the pomalidomide is administered on a 28-day treatment cycle (“pomalidomide treatment cycle”); and40.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);41.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

24. The method of claim 23, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles.

25. The method of claims 23 or 24, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

26. The method of any one of claims 23 to 25, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(i) is resumed.

27. The method of any one of claims 23 to 26, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the second or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is initiated.

28. The method of any one of claims 25 to 27, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle, administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

29. The method of claim 28, wherein the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

30. The method of any one of claims 23 to 29, wherein the Grade of the ocular adverse event is determined based on an ophthalmic exam finding.

31. The method of claim 30, wherein the ophthalmic exam finding comprises a corneal exam finding and / or a change in best-corrected visual acuity (BCVA) finding.

32. The method of any one of claims 20 to 31, wherein the pomalidomide is administered at a dose of 4 mg on each of days 1-21 of each pomalidomide treatment cycle.

33. The method of any one of claims 20 to 32, wherein the dexamethasone is administered at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

34. The method of claim 33, wherein the dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

35. The method of claim 33, wherein the dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

36. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, and dexamethasone, wherein:51.(a) the anti-BCMA antigen binding protein is administered:52.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then53.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;54.(b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and55.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);56.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

37. The method of claim 36, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle and a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles.

38. The method of claims 36 or 37, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

39. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, and dexamethasone, wherein:59.(a) the anti-BCMA antigen binding protein is administered:60.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;61.(b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”); and62.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);63.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

40. The method of claim 39, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle and a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles.

41. The method of claims 39 or 40, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

42. The method of any one of claims 39 to 41, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(i) is resumed.

43. The method of any one of claims 39 to 42, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the second or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is initiated.

44. The method of any one of claims 41 to 43, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle,administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

45. The method of any one of claims 41 to 44, wherein the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

46. The method of any one of claims 39 to 45, wherein the Grade of the ocular adverse event is determined based on an ophthalmic exam finding.

47. The method of claim 46, wherein the ophthalmic exam finding comprises a corneal exam finding and / or a change in best-corrected visual acuity (BCVA) finding.

48. The method of any one of claims 36 to 47, wherein the bortezomib is administered at a dose of 1.3 mg / m2on days 1, 8, 15, and 22 of each bortezomib treatment cycle for the first six bortezomib treatment cycles.

49. The method of any one of claims 36 to 48, wherein the dexamethasone is administered at a dose of 20 mg or 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each dexamethasone treatment cycle for the first six dexamethasone treatment cycles.

50. The method of claim 49, wherein the dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each dexamethasone treatment cycle for the first six dexamethasone treatment cycles.

51. The method of claim 49, wherein the dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each dexamethasone treatment cycle for the first six dexamethasone treatment cycles52. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, carfilzomib, and dexamethasone, wherein:74.(a) the anti-BCMA antigen binding protein is administered:75.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, and then76.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;77.(b) the carfilzomib is administered on a 28-day treatment cycle (“carfilzomib treatment cycle”); and78.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);79.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

53. The method of claim 52, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles.

54. The method of claims 52 or 53, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

55. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, carfilzomib, and dexamethasone, wherein:82.(a) the anti-BCMA antigen binding protein is administered:83.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of a 56-day treatment cycle for three cycles, or until an adverse ocular event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then84.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter; (b) the carfilzomib is administered on a 28-day treatment cycle (“carfilzomib treatment cycle”); and85.(c) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”);86.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

56. The method of claim 55, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 2.5 mg / kg on day 1 of the first 56-day treatment cycle and at a dose of 1.9 mg / kg on day 1 of the second and third 56-day treatment cycles.

57. The method of claims 55 or 56, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

58. The method of any one of claims 55 to 57, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(i) is resumed.

59. The method of any one of claims 55 to 58, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the second or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is initiated.

60. The method of any one of claims 57 to 59, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle, administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 orlower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

61. The method of claim 60, wherein the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

62. The method of any one of claims 55 to 61, wherein the Grade of the ocular adverse event is determined based on an ophthalmic exam finding.

63. The method of claim 62, wherein the ophthalmic exam finding comprises a corneal exam finding and / or a change in best-corrected visual acuity (BCVA) finding.

64. The method of any one of claims 52 to 63, wherein the carfilzomib is administered at a dose of 20 mg / m2or 70 mg / m2on days 1, 8, and 15 of each carfilzomib treatment cycle.

65. The method of any one of claims 52 to 64, wherein:96.i. the carfilzomib is administered at a dose of 20 mg / m2on day 1 and at a dose of 70 mg / m2on days 8 and 15 of the first carfilzomib treatment cycle; and97.ii. the carfilzomib is administered at a dose of 70 mg / m2on days 1, 8, and 15 of each carfilzomib treatment cycle thereafter.

66. The method of any one of claim 51 to 65, wherein the dexamethasone is administered at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

67. The method of claim 66, wherein the dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

68. The method of claim 66, wherein the dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

69. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone, wherein:101.(a) the anti-BCMA antigen binding protein is administered:102.i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles, and then103.ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;104.(b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);105.(c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and106.(d) the dexamethasone is administered on a 28-day treatment cycle (“the dexamethasone treatment cycle”) thereafter,107.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

70. The method of claim 69, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 1.9 mg / kg on day 1 of each 56-day treatment cycle.

71. The method of claim 69 or 70, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

72. A method of treating multiple myeloma in a human patient, the method comprising administering to the human patient an anti-BCMA antigen binding protein, bortezomib, lenalidomide, and dexamethasone, wherein:111.(a) the anti-BCMA antigen binding protein is administered: i. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of on day 1 of a 56-day treatment cycle for three cycles or until an adverse event of Grade 2, 3, or 4 in the patient is observed, whichever occurs first, and then ii. at a dose of 1.0 mg / kg to 2.5 mg / kg on day 1 of an 84-day treatment cycle thereafter;112.(b) the bortezomib is administered on a 28-day treatment cycle (“bortezomib treatment cycle”);113.(c) the lenalidomide is administered on a 28-day treatment cycle (“lenalidomide treatment cycle”); and114.(d) the dexamethasone is administered on a 28-day treatment cycle (“dexamethasone treatment cycle”).115.wherein the anti-BCMA antigen binding protein comprises CDRH1 of SEQ ID NO: 1, CDRH2 of SEQ ID NO: 2, CDRH3 of SEQ ID NO: 3, CDRL1 of SEQ ID NO: 4, CDRL2 of SEQ ID NO: 5, and CDRL3 of SEQ ID NO: 6.

73. The method of claim 72, wherein the anti-BCMA antigen binding protein in step (a)(i) is administered at a dose of 1.9 mg / kg on day 1 of each 56-day treatment cycle.

74. The method of claim 72 or 73, wherein the anti-BCMA antigen binding protein in step (a)(ii) is administered at a dose of 1.9 mg / kg on day 1 of each 84-day treatment cycle.

75. The method of any one of claims 72 to 74, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the first, second, or third 56-day treatment cycle, administration of the anti-BCMA antigen binding protein in step (a) is withheld until the ocular adverse event in the patient resolves to a Grade 1 or lower, and then administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is initiated.

76. The method of any one of claims 72 to 74, wherein the patient has a Grade 2, Grade 3, or Grade 4 ocular adverse event during the 84-day treatment cycle, administration of the anti-BCMA antigen binding protein to the patient in step (a)(ii) is terminated and, once the ocular adverse event in the patient resolves to a Grade 1 orlower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of an 84-day treatment cycle thereafter.

77. The method of claim 76, wherein the patient has a subsequent Grade 2, Grade 3, or Grade 4 ocular adverse event during the 1.4 mg / kg 84-day treatment cycle, administration of the anti-BCMA antigen binding protein is withheld and, once the ocular adverse event in the patient resolves to a Grade 1 or lower, administration of the anti-BCMA antigen binding protein to the patient is initiated at a dose of 1.4 mg / kg on day 1 of a 112-day treatment cycle thereafter.

78. The method of any one of claims 72 to 77, wherein the Grade of the ocular adverse event is determined based on an ophthalmic exam finding.

79. The method of claim 78, wherein the ophthalmic exam finding comprises a corneal exam finding and / or a change in best corrected visual acuity (BCVA) finding.

80. The method of any one of claims 69 to 79, wherein the bortezomib is administered at a dose of 1.3 mg / m2on days 1, 8, and 15 of each bortezomib treatment cycle for the first eight bortezomib treatment cycles.

81. The method of any one of claims 69 to 80, wherein the lenalidomide is administered at a dose of 25 mg, 10 mg, or 7.5 mg on each of days 1-21 of each lenalidomide treatment cycle.

82. The method of any one of claims 69 to 81, wherein the dexamethasone is administered at a dose of 40 mg or 20 mg on days 1, 8, 15, and 22 of each dexamethasone treatment cycle.

83. The method of any one of claims 1 to 82, wherein the anti-BCMA antigen binding protein comprises a variable heavy chain (VH) region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7 and a variable light chain (VL) region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 8.

84. The method of any one of claims 1 to 83, wherein the anti-BCMA antigen binding protein comprises a variable heavy chain (VH) region comprising the amino acidsequence of SEQ ID NO: 7 and a variable light chain (VL) region comprising the amino acid sequence of SEQ ID NO: 8.

85. The method of any one of claims 1 to 84, wherein the anti-BCMA antigen binding protein comprises a light chain (LC) having the amino acid sequence of SEQ ID NO: 9 and a heavy chain (HC) having the amino acid sequence of SEQ ID NO: 10.

86. The method of any one of claims 1 to 85, wherein the anti-BCMA antigen binding protein is afucosylated.

87. The method of any one of claims 1 to 86, wherein the anti-BCMA antigen binding protein is belantamab.

88. The method of any one of claims 1 to 87, wherein the anti-BCMA antigen binding protein is an anti-BCMA antibody conjugated to a cytotoxic agent to form an antibody drug conjugate (ADC).

89. The method of claim 88, wherein the cytotoxic agent is monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF).

90. The method of claim 89, wherein the cytotoxic agent is MMAF.

91. The method of any one of claims 88 to 90, wherein the anti-BCMA antibody is conjugated to the cytotoxic agent via a non-cleavable linker, wherein the non-cleavable linker is 6-maleimidocaproyl (MC).

92. The method of any one of claims 1 to 91, wherein the anti-BCMA antigen binding protein is belantamab mafodotin.

93. The method of any one of claims 1 to 92, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma or newly-diagnosed multiple myeloma.

94. The method of claim 93, wherein the multiple myeloma is newly-diagnosed multiple myeloma.

95. The method of claim 94, wherein the multiple myeloma is transplant-ineligible newly-diagnosed multiple myeloma (TI-NDMM).

96. The method of claim 93, wherein the multiple myeloma is relapsed and / or refractory multiple myeloma.

Images