Therapeutic methods using antagonists of B-cell maturation antigens

Abstract

The present disclosure provides methods of treating diseases or disorders responsive to inhibiting or blocking B-cell maturation antigen (BMCA) by administering one or more BCMA antagonists.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 430,249, filed December 5, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates generally to methods of treating diseases or disorders responsive to inhibiting or blocking B-cell maturation antigen (BMCA) by administering one or more BCMA antagonists. [Background technology]

[0003] B-cell maturation antigen (BCMA) is a cell surface receptor expressed in the plasmablast lineage and upregulated on various disease cell types, including multiple myeloma (MM) cells. MM is an incurable, malignant clonal plasma cell disorder that accounts for 1% of all cancers and 10% of all hematologic malignancies worldwide. Patients with newly diagnosed multiple myeloma (NDMM) have several available treatment options. While nearly 100% of patients respond to first-line therapy, the disease eventually recurs, requiring further treatment. With each subsequent line of treatment for this malignancy, the duration and rate of response dramatically decrease. Most patients with MM eventually develop resistance to existing therapies and die from relapse.

[0004] Belantamab mafodotin is a BCMA-directed antibody-drug conjugate (ADC) conjugated to the microtubule-disrupting agent monomethyl auristatin-F (MMAF) and has demonstrated antitumor activity in MM cells. Belantamab mafodotin is produced in an afucosylated form that enhances its interaction with the FcγRIIIa receptor. This enhanced interaction enhances antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) activity, including against MM cells. Thus, belantamab mafodotin has dual antitumor activity via delivery of the MMAF cytotoxin and through ADCC / ADCP. Ocular toxicity has been reported for belantamab mafodotin and other MMAF-containing ADCs, leading to dose delays and dose reductions. Therefore, there is a need for additional therapies with manageable toxicity for treating MM and other diseases associated with abnormal BCMA expression. Summary of the Invention

[0005] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering to the patient a dose of about 300 mg to about 2000 mg of belantamab.

[0006] In one aspect, the disclosure provides for the use of belantamab in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of a dose of about 300 mg to about 2000 mg of belantamab.

[0007] In one aspect, the disclosure provides for the use of belantamab in the manufacture of a medicament for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of a dose of about 300 mg to about 2000 mg of belantamab.

[0008] In one embodiment, the dose is about 300 mg, about 900 mg, or about 2000 mg. In one embodiment, the dose is administered at regular intervals over a period of time. In one embodiment, the dose is administered once every 1 week ± 3 days to once every 4 weeks ± 3 days. In one embodiment, the dose is administered once every 2 weeks ± 3 days. In one embodiment, the dose is administered once every 3 weeks ± 3 days. In one embodiment, the dose is administered once every 4 weeks ± 3 days. In one embodiment, the dose is administered on days 1 and 15 of a 28-day cycle. In one embodiment, the dose is administered on day 1 of a 21-day cycle.

[0009] In one embodiment, the patient has been treated with at least one line of therapy for the prior cancer. In one embodiment, the patient has been treated with one, two, three, or four lines of therapy for the prior cancer. In one embodiment, the lines of therapy for the prior cancer include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

[0010] In one embodiment, belantamab is administered via intravenous infusion or subcutaneous injection.

[0011] In one embodiment, the patient is further receiving at least one additional cancer therapy, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody. In one embodiment, the additional cancer therapy is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone. In one embodiment, the additional cancer therapy is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In one embodiment, the patient is receiving lenalidomide on days 1 to 21 of a 28-day cycle. In one embodiment, the additional cancer therapy is dexamethasone. In one embodiment, the additional cancer therapy is dexamethasone at a dose of 20 mg to 40 mg once weekly. In one embodiment, the patient is receiving dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, (i) the patient is under 75 years of age and is receiving a 40 mg dose of dexamethasone once a week; or (ii) the patient is at least 75 years of age and is receiving a 20 mg dose of dexamethasone once a week. In one embodiment, (i) the patient has a BMI of at least 18.5 and is receiving a 40 mg dose of dexamethasone once a week; or (ii) the patient has a BMI of less than 18.5 and is receiving a 20 mg dose of dexamethasone once a week.

[0012] In one embodiment, the method or use further comprises discontinuing administration of belantamab followed by administration of belantamab mafodotin. In one embodiment, the method or use further comprises administering belantamab mafodotin followed by discontinuing administration of belantamab. In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg once every 3 weeks ± 3 days.

[0013] In one embodiment, the method or use further comprises administering an induction dose of belantamab mafodotin prior to initiating administration of belantamab, wherein the induction dose of belantamab mafodotin is about 1.4 mg / kg to about 3.4 mg / kg, administered once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg to about 1.9 mg / kg, administered once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg, administered once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg, administered once during the induction period. In one embodiment, the induction period is 4 weeks ± 3 days, and belantamab mafodotin is administered on day 1 of the induction period.

[0014] In one embodiment, the method or use further comprises administering to the patient, during the lead-in period, at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody. In one embodiment, the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In one embodiment, lenalidomide is administered to the patient on days 1 to 21 of the lead-in period. In one embodiment, lenalidomide is administered to the patient on days 1 to 21 of the lead-in period, the lead-in period being 4 weeks ± 3 days. In one embodiment, lenalidomide is administered to the patient on days 1-21 of the lead-in period, and the lead-in period is 28 days. In one embodiment, the additional cancer treatment is dexamethasone. In one embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg-40 mg once weekly. In one embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period. In one embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period, and the lead-in period is 4 weeks ± 3 days. In one embodiment, dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the lead-in period, and the lead-in period is 28 days. In one embodiment, (i) the patient is under 75 years of age and dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years of age and dexamethasone is administered to the patient at a dose of 20 mg once weekly. In one embodiment, (i) the patient has a BMI of at least 18.5 and dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient has a BMI of less than 18.5 and dexamethasone is administered to the patient at a dose of 20 mg once weekly.

[0015] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient belantamab mafodotin at a dose of about 1.4 mg / kg to about 3.4 mg / kg once every 8 weeks ± 3 days, e.g., at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every 8 weeks ± 3 days.

[0016] In one aspect, the disclosure provides for the use of belantamab mafodotin in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of belantamab mafodotin at a dose of about 1.4 mg / kg to about 3.4 mg / kg once every 8 weeks ± 3 days, e.g., at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every 8 weeks ± 3 days.

[0017] In one aspect, the disclosure provides the use of belantamab mafodotin in the manufacture of a medicament for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) by administration of belantamab mafodotin at a dose of about 1.4 mg / kg to about 3.4 mg / kg once every 8 weeks ± 3 days, for example, at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every 8 weeks ± 3 days.

[0018] In one embodiment, the dose is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg once every 8 weeks ± 3 days. In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

[0019] In one aspect, the disclosure provides for the use of a combination comprising a first BCMA antagonist and a second BCMA antagonist in a patient in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).

[0020] In one aspect, the present disclosure provides the use of a combination comprising a first BCMA antagonist and a second BCMA antagonist in the manufacture of a medicament for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).

[0021] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of idecabutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712. In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In one embodiment, the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.

[0022] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising belantamab mafodotin and belantamab.

[0023] In one aspect, the disclosure provides for the use of a combination comprising belantamab mafodotin and belantamab in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).

[0024] In one aspect, the disclosure provides for the use of a combination comprising belantamab mafodotin and belantamab in the manufacture of a medicament for use in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA).

[0025] In one embodiment, the method or use further comprises administering to the patient at least one additional cancer therapy, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody. In one embodiment, the additional cancer therapy is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0026] In one aspect, the present disclosure provides a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.

[0027] In one aspect, the disclosure provides a kit comprising: (i) belantamab mafodotin; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab.

[0028] In one aspect, the disclosure provides a kit comprising: (i) belantamab; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab mafodotin.

[0029] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with a first BCMA antagonist, comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0030] In one aspect, the present disclosure provides for the use of a second BCMA antagonist in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with a first BCMA antagonist, wherein administration of the first BCMA antagonist is discontinued before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0031] In one aspect, the disclosure provides for the use of a second BCMA antagonist in the manufacture of a medicament for the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with a first BCMA antagonist, wherein administration of the first BCMA antagonist is discontinued before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0032] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of idecabutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712. In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the second BCMA antagonist is belantamab mafodotin. In one embodiment, the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In one embodiment, the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab. In one embodiment, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In one embodiment, the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712. In one embodiment, the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.

[0033] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient had discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

[0034] In one aspect, the disclosure provides for the use of belantamab in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with belantamab mafodotin, wherein administration of belantamab mafodotin has been discontinued prior to initiating administration of belantamab.

[0035] In one aspect, the disclosure provides the use of belantamab for use in the manufacture of a medicament for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with belantamab mafodotin, wherein administration of belantamab mafodotin has been discontinued prior to initiating administration of belantamab.

[0036] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab, comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient had discontinued administration of belantamab prior to initiating administration of belantamab mafodotin.

[0037] In one aspect, the disclosure provides for the use of belantamab mafodotin in the treatment of a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with belantamab, wherein administration of belantamab has been discontinued prior to initiating administration of belantamab mafodotin.

[0038] In one aspect, the disclosure provides the use of belantamab mafodotin in the manufacture of a medicament for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with belantamab, wherein administration of belantamab has been discontinued prior to initiating administration of belantamab mafodotin.

[0039] In one embodiment, the method or use further comprises administering to the patient at least one additional cancer therapy, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody. In one embodiment, the additional cancer therapy is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0040] In one aspect, the present disclosure provides a method of reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0041] In one aspect, the present disclosure provides for the use of a second B-cell maturation antigen (BCMA) antagonist for the reduction of corneal toxicity in a patient previously treated with a first BCMA antagonist, wherein administration of the first BCMA antagonist is discontinued before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0042] In one aspect, the present disclosure provides for the use of a second B-cell maturation antigen (BCMA) antagonist in the manufacture of a medicament for use in reducing corneal toxicity in a patient previously treated with a first BCMA antagonist, wherein administration of the first BCMA antagonist is discontinued before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0043] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of idecabutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712. In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the second BCMA antagonist is belantamab mafodotin. In one embodiment, the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In one embodiment, the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab. In one embodiment, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In one embodiment, the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712. In one embodiment, the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.

[0044] In one aspect, the disclosure provides a method of reducing corneal toxicity in a patient previously treated with belantamab mafodotin, comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient has discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

[0045] In one aspect, the present disclosure provides a use of belantamab for reducing corneal toxicity in a patient previously treated with belantamab mafodotin, wherein the patient had discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

[0046] In one aspect, the disclosure provides the use of belantamab in the manufacture of a medicament for use in reducing corneal toxicity in a patient previously treated with belantamab mafodotin, wherein the patient had discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

[0047] In one aspect, the disclosure provides a method of reducing corneal toxicity in a patient previously treated with belantamab, comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient had discontinued administration of belantamab prior to initiating administration of belantamab mafodotin.

[0048] In one aspect, the present disclosure provides the use of belantamab mafodotin for the reduction of corneal toxicity in a patient previously treated with belantamab, wherein the patient had discontinued administration of belantamab prior to initiating administration of belantamab mafodotin.

[0049] In one aspect, the present disclosure provides the use of belantamab mafodotin in the manufacture of a medicament for use in reducing corneal toxicity in a patient previously treated with belantamab, wherein the patient had discontinued administration of belantamab prior to initiating administration of belantamab mafodotin.

[0050] In one embodiment, the method or use further comprises administering to the patient at least one additional cancer therapy, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody. In one embodiment, the additional cancer therapy is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0051] In one aspect, the disclosure provides a method of treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

[0052] In one aspect, the disclosure provides for the use of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody in the treatment of a disease or disorder.

[0053] In one aspect, the disclosure provides the use of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody for use in the manufacture of a medicament for the treatment of a disease or disorder.

[0054] In one aspect, the disclosure provides a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, comprising administering a therapeutically effective amount of a corresponding unconjugated antibody to the patient, wherein the patient had discontinued administration of the antibody-drug conjugate prior to initiating administration of the corresponding unconjugated antibody.

[0055] In one aspect, the disclosure provides for the use of an antibody in the treatment of a disease or disorder in a patient previously treated with an antibody-drug conjugate, where the antibody is a corresponding unconjugated antibody and the patient discontinued administration of the antibody-drug conjugate before initiating administration of the corresponding unconjugated antibody.

[0056] In one aspect, the disclosure provides for the use of an antibody in the manufacture of a medicament for use in treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, where the antibody is a corresponding unconjugated antibody and the patient discontinued administration of the antibody-drug conjugate prior to initiating administration of the corresponding unconjugated antibody.

[0057] In one embodiment, the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, fam-trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, roncatuximab tesirin, tisotumab vedotin, moxetumomab pasudotox, MEDI2228, or CC99712.

[0058] In one embodiment, the disease or disorder is a plasma cell disorder or a B-cell disorder. In one embodiment, the disease or disorder is a BCMA-expressing cancer. In one embodiment, the disease or disorder is multiple myeloma (MM). In one embodiment, the MM is relapsed and / or refractory MM, newly diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly diagnosed MM. In one embodiment, the MM is relapsed and / or refractory MM, newly diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly diagnosed MM.

[0059] In one aspect, the disclosure provides a method of treating cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction attributable to administration of belantamab mafadotin, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering a therapeutically effective amount of belantamab to the patient for a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period.

[0060] In one aspect, the disclosure provides for the use of belantamab in the treatment of cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction attributable to belantamab mafadotin administration, wherein the belantamab mafadotin is temporarily discontinued during a lead-in period during which belantamab is administered, followed by resumption of administration of belantamab mafadotin after the lead-in period.

[0061] In one aspect, the disclosure provides for the use of belantamab in the manufacture of a medicament for use in treating cancer in a patient having a Grade 1 corneal adverse reaction attributable to belantamab mafadotin administration, wherein the belantamab mafadotin is temporarily discontinued during a lead-in period during which belantamab is administered, followed by resumption of administration of belantamab mafadotin after the lead-in period.

[0062] In one aspect, the disclosure provides a method of treating cancer in a patient, wherein the patient has a Grade 2 or greater corneal adverse reaction attributable to administration of belantamab mafadotin, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering a therapeutically effective amount of belantamab to the patient for a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period.

[0063] In one aspect, the disclosure provides for the use of belantamab in the treatment of cancer in a patient, wherein the patient has a Grade 2 or greater corneal adverse reaction attributable to belantamab mafadotin administration, wherein the belantamab mafadotin is temporarily discontinued during a lead-in period during which belantamab is administered, followed by resumption of administration of belantamab mafadotin after the lead-in period.

[0064] In one aspect, the disclosure provides for the use of belantamab in the manufacture of a medicament for use in treating cancer in a patient, the patient having a Grade 2 or greater corneal adverse reaction attributable to belantamab mafadotin administration, wherein the belantamab mafadotin is temporarily discontinued during a lead-in period during which belantamab is administered, followed by resumption of administration of belantamab mafadotin after the lead-in period.

[0065] It is understood that any and all embodiments of the present disclosure may be combined with any other embodiment to describe additional, more preferred embodiments. It is also understood that each individual element of a preferred embodiment is a preferred embodiment in its own right. Furthermore, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments. [Brief explanation of the drawings]

[0066] [Figure 1] FIG. 1 is a graph illustrating tumor volume growth curves for all treatment groups according to study day, as described in Example 1. [Figure 2] FIG. 2 is a graph illustrating Kaplan-Meier survival curves for all treatment groups according to study date, as described in Example 1. [Figure 3] FIG. 3 is a graph illustrating tumor volume growth at different drug-to-antibody ratios (DAR) as a function of the day of the study, as described in Example 3. [Figure 4] FIG. 4 is a graph illustrating progression-free survival of patients grouped according to sBCMA levels for the belantamab mafodotin treatment arm (left) and the pom / dex treatment arm (right), as described in Example 4. [Figure 5] FIG. 5 is a graph illustrating the level of sBCMA reduction from pre-dose to end of infusion (EOI) of belantamab mafodotin for cycle 1, day 1 of belantamab mafodotin treatment, as described in Example 4. [Figure 6]FIG. 6 is a graph illustrating sBCMA levels 24 hours after the end of infusion (EOI) of belantamab mafodotin, as described in Example 4. [Figures 7A-7B] Figures 7A and 7B are graphs illustrating sBCMA levels in patients grouped according to response to treatment with belantamab mafodotin, as described in Example 4. Figure 7A shows baseline sBCMA levels before belantamab mafodotin administration; Figure 7B shows sBCMA levels 24 hours EOI for belantamab mafodotin. CR = complete response; VGPR = very good partial response; PR = partial response; MR / SD = minimal response / stable disease; PD / NE = progressive disease / not evaluable. [Figure 8] Figure 8 is a graph illustrating the mean tumor volume curves for the vehicle control and treatment groups between randomization and the end of the study for the in vivo efficacy study of belantamab and belantamab mafodotin in human multiple myeloma xenografted NOG mice, as described in Example 5. [Figure 9] FIG. 9 is a graph showing Kaplan-Meier survival curves for all treatment groups according to study day for the in vivo efficacy study of belantamab and belantamab mafodotin in human multiple myeloma xenografted NOG mice, as described in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0067] definition As used herein and in the claims, the term "comprising" encompasses "including" or "consisting", e.g., a composition "comprising" X may consist of only X, or it may include something more, e.g., X+Y.

[0068] Unless otherwise defined, 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 belongs. In practicing or testing the methods of the present disclosure, any compositions and methods similar or equivalent to those described herein can be used, but exemplary compositions and methods are described herein. Also, any of the aspects and embodiments of the present disclosure described herein can be combined. For example, the subject matter of any dependent or independent claim disclosed herein can be combined in multiple ways (e.g., one or more statements from each dependent claim can be combined into a single claim based on the independent claim to which it depends).

[0069] The ranges provided herein include all values ​​within the particular ranges described, as well as values ​​near the endpoints of the particular ranges. The figures and tables of this disclosure also describe ranges and discrete values ​​that can constitute elements of any of the methods and uses disclosed herein.

[0070] The concentrations described herein are determined at ambient temperature and pressure. This can be, for example, room temperature or the temperature and pressure within a specific part of the process stream. Preferably, the concentrations are determined at standard conditions of 25°C and 1 bar pressure.

[0071] As used herein, the term "antigen binding protein" refers to antibodies and other protein constructs, such as domains, that are capable of binding to an antigen.

[0072] The term "antibody" is used herein in the broadest sense to refer to molecules comprising immunoglobulin-like domains (e.g., IgG, IgM, IgA, IgD, or IgE), and includes monoclonal antibodies, recombinant antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, humanized antibodies, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; single variable domains (e.g., domain antibodies (DABs)), antigen-binding antibody fragments, Fab, F(ab'), Fv, disulfide-linked Fv, single-chain Fv, disulfide-linked scFv, diabodies, TANDABS, etc., as well as modified versions of any of the foregoing (for a review of alternative "antibody" formats, see Holliger and Hudson, Nature Biotechnology, 2005, Vol. 23, No. 9, 1126-1136).

[0073] The terms "full-length antibody," "whole antibody," and "intact antibody," used interchangeably herein, refer to a heterotetrameric glycoprotein with a molecular weight of approximately 150,000 daltons. An intact antibody consists of two identical heavy chains (HC) and two identical light chains (LC) linked by covalent disulfide bonds. This H2L2 structure folds to form three functional domains, including two antigen-binding fragments known as "Fab" fragments and an "Fc" crystallizable fragment. The Fab fragment consists of an amino-terminal variable domain, a variable heavy chain (VH) or a variable light chain (VL), and a carboxyl-terminal constant domain, CH1 (heavy) and CL (light). The Fc fragment consists of two domains formed by the dimerization of paired CH2 and CH3 regions. The Fc fragment can exert effector functions by binding to receptors on immune cells or by binding to 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, designated μ, α, γ, ε, and δ, respectively, and each heavy chain can pair with either a K or a λ light chain. The majority of antibodies in serum belong to the IgG class, and there are four isotypes of human IgG (IgG1, IgG2, IgG3, and IgG4), whose sequences differ primarily in the hinge region of their sequences.

[0074] Fully human antibodies can be obtained using a variety of methods, for example, using yeast-based libraries or transgenic animals (e.g., mice) capable of producing a repertoire of human antibodies. Yeast displaying human antibodies on their surface that bind to the antigen of interest can be selected using FACS (fluorescence-activated cell sorting)-based methods or by capture on beads using labeled antigen. Transgenic animals that have been modified to express human immunoglobulin genes can be immunized with the antigen of interest, and antigen-specific human antibodies can be 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.

[0075] Alternative antibody formats include alternative scaffolds in which one or more CDRs of an antigen binding protein may be placed onto a suitable non-immunoglobulin protein scaffold or framework, such as an affibody, an SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, 2005 / 0164301), or an EGF domain.

[0076] As used herein, the term "anti-BCMA antigen binding protein" refers to antibodies and other protein constructs, such as domains, that are capable of binding to BCMA. The terms "BCMA binding protein" and "anti-BCMA antigen binding protein" are used interchangeably herein.

[0077] The anti-BCMA antigen binding proteins described herein can bind to human BCMA, for example, to human BCMA containing the amino acid sequence of GenBank Accession No. Q02223.2, or to human BCMA containing the amino acid sequence of a gene encoding human BCMA that is at least 90 percent homologous or at least 90 percent identical thereto.

[0078] Exemplary anti-BCMA antigen binding proteins and methods of making same are disclosed in International Publication No. WO 2012 / 163805, which is incorporated herein by reference in its entirety. Further exemplary anti-BCMA antigen binding proteins include WO 2016 / 014789, WO 2016 / 090320, WO 2016 / 090327, WO 2016 / 020332, WO 2016 / 079177, WO 2014 / 122143, WO 2014 / 122144, WO 2017 / 021450, WO 2016 / 014565, WO 2014 / 068079, WO 2015 / 166649, W WO2015 / 158671, WO2015 / 052536, WO2014 / 140248, WO2013 / 072415, WO2013 / 072406, WO2014 / 089335, US2017 / 165373, WO2013 / 154760, WO2018 / 201051 and WO2017 / 051068, each of which is incorporated herein by reference in its entirety.

[0079] In some embodiments, the BCMA-binding proteins disclosed herein may be derived from rat, mouse, primate (e.g., cynomolgus monkey, Old World monkey, or ape), or human. The BCMA-binding protein may be a human antibody, a humanized antibody, or a chimeric antibody. The BCMA-binding protein may comprise a constant region, which may be of any isotype or subclass. The constant region may be of an IgG isotype, e.g., IgG1, IgG2, IgG3, IgG4, or a variant thereof. The constant region of the BCMA-binding protein may be IgG1.

[0080] Thus, BCMA binding proteins are provided which may comprise any one or combination of the following CDRs: CDRH1 of SEQ ID NO: 5, CDRH2 of SEQ ID NO: 6, CDRH3 of SEQ ID NO: 7, CDRL1 of SEQ ID NO: 8, CDRL2 of SEQ ID NO: 9, CDRL3 of SEQ ID NO: 10. The CDRs may be modified by substitution, deletion or addition of at least one amino acid, in which case the variant antigen binding protein substantially retains the biological characteristics of the unmodified protein, such as binding to antigen.

[0081] In some embodiments, the anti-BCMA antigen binding protein comprises a CDRH1 according to SEQ ID NO:5, a CDRH2 according to SEQ ID NO:6, a CDRH3 according to SEQ ID NO:7, a CDRL1 according to SEQ ID NO:8, a CDRL2 according to SEQ ID NO:9, and a CDRL3 according to SEQ ID NO:10.

[0082] In some embodiments, the anti-BCMA antigen binding protein comprises a heavy chain variable region (VH) according to SEQ ID NO:3 and a light chain variable region (VL) according to SEQ ID NO:4.

[0083] In some embodiments, the anti-BCMA antigen binding protein comprises a heavy chain (H) according to SEQ ID NO: 1 and a light chain (L) according to SEQ ID NO:2.

[0084] In some embodiments, the anti-BCMA antigen binding protein is a T cell redirecting antibody (BiTE) with dual inhibition of the BCMA receptor and the CD3 receptor, such as teclistamab (Pillarisetti et al., Blood Advances 4,4538-49, 2020) and blinatumomab, AMG 424, GBR 1342, BFR4350A, AMG 420, AMG 701, erlanatamab (PF-06863135), REGN5458, or TNB-383B (Alhallak et al., Cancers 13,2853, 2021). In some embodiments, the anti-BCMA antigen binding protein is a non-fucosylated BCMA-directed antibody, such as SEA-BCMA (Van Epps et al., Cancer Res 2018;78(13 Suppl):Abstract nr 3833).

[0085] In some embodiments, the anti-BCMA antigen binding protein is a CAR-T cell therapy.

[0086] In some embodiments, the anti-BCMA antigen binding protein is used in an immunoconjugate. An "immunoconjugate" (interchangeably referred to as an "antibody-drug conjugate," "ADC," or "antigen-binding protein drug conjugate") comprises an anti-BCMA antigen binding protein conjugated to one or more drugs, such as a cytotoxic agent, for example, a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g., a protein toxin or fragment thereof, such as an enzymatically active toxin of bacterial, fungal, plant, or animal origin), an antiviral agent, a radioisotope (i.e., a radioconjugate), an antibiotic, or a small interfering RNA (siRNA).

[0087] In some instances, the anti-BCMA antigen binding protein has the following general structure: ABP-((linker)n-Ctx)m (In the formula, ABPs are antigen-binding proteins The linker may be absent or any cleavable or non-cleavable linker. Ctx is any cytotoxic agent described herein n is 0, 1, 2, or 3 m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) The immunoconjugate may be an immunoconjugate having the formula:

[0088] Exemplary linkers can include 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (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).

[0089] In some examples, the anti-BCMA antigen binding protein may be an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF. In another embodiment, the anti-BCMA antigen binding protein has the following structure:

[0090] [ka] The immunoconjugate can be an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF by an MC linker, as illustrated in Figure 1, where "p" is the drug-to-antibody ratio (DAR) and is an integer from 1 to 8, e.g., 2, 4, 6, or 8.

[0091] In some instances, the anti-BCMA antigen binding protein can be the antibody belantamab. In another embodiment, the anti-BCMA antigen binding protein can be the immunoconjugate belantamab mafodotin.

[0092] In some embodiments, the BCMA antagonist is a BCMA-targeted chimeric antigen receptor (CAR)-T cell therapy. As used herein, the term "chimeric antigen receptor" ("CAR") refers to an engineered receptor composed of an extracellular antigen-binding domain (usually derived from a monoclonal antibody or its antigen-binding fragment, e.g., the VH and VL domains in scFv form), optionally a spacer region, a transmembrane region, and one or more intracellular effector domains. CARs have also been called chimeric T cell receptors or chimeric immunoreceptors (CIRs). CARs are generally introduced into hematopoietic cells, such as T cells, to redirect the specificity of the T cells to a desired cell surface antigen, resulting in a CAR-T therapeutic.

[0093] As used herein, the term "spacer region" refers to an oligopeptide or polypeptide that serves to link the transmembrane domain to the target binding domain. This region may also be referred to as a "hinge region" or "stalk region." The size of the spacer can vary depending on the location of the target epitope to maintain a set distance (e.g., 14 nm) during CAR:target binding.

[0094] As used herein, the term "transmembrane domain" refers to the portion of the CAR molecule that crosses the cell membrane.

[0095] As used herein, the term "intracellular effector domain" (also referred to as "signaling domain") refers to a domain in a CAR that is responsible for intracellular signal transduction upon binding of the antigen-binding domain to a target. The intracellular effector domain is responsible for activating at least one of the normal effector functions of the immune cell in which the CAR is expressed. For example, the effector function of a T cell can be cytolytic activity or helper activity, including cytokine secretion.

[0096] Those skilled in the art will appreciate that the VH and / or VL domains disclosed herein can be combined into CAR-T therapeutics, for example, in the form of an scFv.

[0097] "CDR" is defined as the amino acid sequence of the complementarity determining region of an antigen-binding protein. These are the hypervariable regions of the heavy and light chains of immunoglobulins. There are three heavy chain CDRs and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Therefore, as used herein, "CDR" refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least two CDRs.

[0098] Throughout this specification, amino acid residues in variable domain sequences and variable domain regions within a full-length antigen-binding sequence, 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," and "CDRH3" follow the Kabat numbering convention. For more information, see Kabat et al., Sequences of Proteins of Immunological Interest, 4th Ed., USDapartment of Health and Human Services, National Institutes of Health (1987).

[0099] Those skilled in the art will understand that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. Alternative numbering conventions for CDR sequences also exist, such as the numbering convention described in Chothia et al. (1989) Nature 342:877-883. The structure and protein folding of antigen-binding proteins may mean that other residues are considered part of the CDR sequences, and those skilled in the art will understand this to be the case.

[0100] Other numbering conventions for CDR sequences available to those skilled in the art include the "AbM" (University of Bath) and "contact" (University College London) conventions.

[0101] Table 1 below presents one definition using each numbering convention for each CDR or binding unit. It should be noted that some of the CDR definitions may vary depending on the individual publication used.

[0102] [Table 1]

[0103] Immunoconjugates (interchangeably referred to as "antibody-drug conjugates," "ADCs," or "antigen-binding protein-drug conjugates") comprise an antigen-binding protein (e.g., an antibody or antigen-binding fragment thereof) conjugated to one or more drugs, such as a cytotoxic drug, e.g., a chemotherapeutic agent, an immunotherapeutic agent, a growth inhibitory agent, a toxin (e.g., a protein toxin or fragment thereof, such as an enzymatically active toxin of bacterial, fungal, plant, or animal origin), an antiviral agent, a radioisotope (i.e., a radioconjugate), an antibiotic, or a small interfering RNA (siRNA).

[0104] Immunoconjugates have been used in the treatment of cancer for the local delivery of cytotoxic drugs, i.e., drugs that terminate or inhibit cell growth or proliferation (Lambert, J. (2005) Curr. Opinion in Pharmacology 5:543-549; Wu et al. (2005) Nature Biotechnology 23(9):1137-1146; Payne, G. (2003) Cancer Cell 3:207-212; Syrigos and Epenetos (1999) Anticancer Research 19:605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Deliv. Rev. 26:151-172; U.S. Pat. No. 4,975,278). Immunoconjugates, in particular, enable targeted delivery of drug moieties to tumors and their intracellular accumulation within tumors, where systemic administration of unconjugated drugs can result in unacceptable levels of toxicity to normal cells (Tsuchikama and An, Protein and Cell (2018) 9:33-46). Immunoconjugates enable selective delivery of potent cytotoxic payloads to targeted cancer cells, resulting in improved efficacy, reduced systemic toxicity, and favorable pharmacokinetics (PK) / pharmacodynamics (PD) and biodistribution compared to conventional chemotherapy (Tsuchikama and An 2018; Beck A. et al., (2017) Nature Rev. Drug Disc. 16:315-337).

[0105] Both polyclonal and monoclonal antibodies have been reported to be useful in these strategies (Rowland et al., (1986) Cancer Immunol. Immunother. 21:183-87). Drugs used in these methods include daunomycin, doxorubicin, methotrexate, and vindesine (Rowland et al., (1986) supra). 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; Mandler et 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. 58:2928; Hinman et al., (1993) Cancer Res.53:3336~3342).

[0106] In certain embodiments, an immunoconjugate comprises an antigen-binding protein, such as an antibody, and a drug, such as a toxin, e.g., a chemotherapeutic agent. The drug can be modified (e.g., via standard synthetic chemistry) to allow for chemical attachment of the drug (e.g., to contain a reactive handle that allows for chemical attachment of the drug) to the reactive end of a linker that connects the drug to the antigen-binding protein.

[0107] Drugs, e.g., chemotherapeutic agents, useful in generating immunoconjugates 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 protein, dianthin protein, Phytolacca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogenin, restrictocin, phenomycin, enomycin, and trichothecenes. See, for example, WO 93 / 21232, published October 28, 1993.

[0108] In addition to toxins, radioactive substances such as radionucleotides can be used as drugs in ADCs. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.

[0109] The antigen-binding protein (e.g., an antibody) may also be conjugated to one or more toxins, including, but not limited to, calicheamicin, maytansinoids, dolastatins, auristatins, trichothecenes, and CC1065, as well as derivatives of these toxins that have toxin activity. Suitable cytotoxic agents include, but are not limited to, auristatins such as dovaline-valine-dolaisoloinine-dolaproine-phenylalanine (MMAF) and monomethylauristatin E (MMAE) and ester forms of MMAE, DNA minor groove binders, DNA minor groove alkylating agents, enediynes, lexitropsins, duocarmycins, taxanes (e.g., paclitaxel and docetaxel), puromycins, dolastatins, maytansinoids, and vinca alkaloids. Specific cytotoxic agents include topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin-10, echinomycin, combretatostatin, calicheamicin, maytansine, DM-1, DM-4, ​​and netropsin. Other suitable cytotoxic agents include antitubulin agents, such as auristatins, vinca alkaloids, podophyllotoxins, taxanes, baccatin derivatives, cryptophysins, maytansinoids, combretastatins, or dolastatins. Antitubulin agents include dimethylvaline-valine-dolaisoleuin-dolaproine-phenylalanine-p-phenylenediamine (AFP), MMAF, MMAE, auristatin E, vincristatine, vinblastine, vindesine, vinorelbine, VP-16, camptothecin, paclitaxel, docetaxel, epothilone A, epothilone B, nocodazole, colchicine, colcimid, estramustine, cemadotin, discodermolide, maytansine, DM-1, DM-4, ​​and eleutherobin.

[0110] Antibody-drug conjugates can be produced by conjugating the antitubulin agents monomethyl auristatin E (MMAE) or monomethyl auristatin F (MMAF) to an antigen-binding protein (e.g., an antibody). In the case of MMAE, the linker can be composed of a thiol-reactive maleimide, a caproyl spacer, the dipeptide valine-citrulline, or p-aminobenzyloxycarbonyl, a self-immolative fragmentation group. In the case of MMAF, a protease-resistant maleimide caproyl linker can be used. The conjugation process leads to heterogeneity in drug-antibody attachment, which varies in both the number of drugs attached to each antibody molecule (drug-antibody ratio [DAR]) and the attachment site. The most common species are those with a DAR of 4; less common are those with a DAR of 0, 2, 6, and 8. The overall average drug-to-antibody ratio (DAR) is approximately 4.

[0111] The term "progression" or "progressive disease" ("PD") of tumor growth, as used herein with respect to a cancer state, refers to an increase in the sum of the diameters of target lesions (tumors). In some embodiments, progressive disease is assessed and defined according to the criteria of the International Myeloma Working Group (IMWG) (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, tumor growth progression refers to an increase of at least 20% in the sum of the diameters of target lesions relative to the minimum total on study (which includes the baseline total if that total is the minimum on study). In some embodiments, in addition to a relative increase of 20%, the sum of the diameters of the target lesion sites must also show an absolute increase of at least 5 mm. The appearance of one or more new lesions may also be counted in determining tumor growth progression.

[0112] As used herein, "about" means ±10% of the stated value.

[0113] As used herein, "treating" refers to alleviating one or more symptoms or effects associated with a disorder and / or slowing the progression of the disorder. For example, in some embodiments, the disclosed therapies reduce ocular toxicity. "Ocular toxicity" refers to any unintended exposure of ocular tissue to a therapeutic agent, including changes in the corneal epithelium, dry eyes, irritation, redness, blurred vision, dry eyes, photophobia, and / or changes in vision. Detection of ocular toxicity can be determined by ophthalmic examination by an ophthalmologist or optometrist before, during, and / or after treatment.

[0114] An eye examination may include one or more of the following: 1. Best corrected visual acuity, 2. Records of subjective refraction and the method used to obtain best-corrected visual acuity; 3. Current eyeglass prescription (if applicable); 4. Intraocular pressure measurement, 5. Anterior segment (slit lamp) examination, including corneal fluorescein staining and lens examination; 6. Dilated eye exam, and / or 7. A visual function questionnaire, the Ocular Surface Disease Index (OSDI), which assesses the impact of potential ocular changes in vision on function and health-related quality of life.

[0115] Treatment using belantamab Described herein are methods for treating a disease or disorder in a patient that would benefit from the inhibition or blockade of B-cell maturation antigen (BCMA). Also described are the use of BCMA inhibitory or blocking therapy in treating a disease or disorder in a patient. In one aspect, the disclosure provides a method for treating a disease or disorder responsive to the inhibition or blockade of B-cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab to the patient. Belantamab is the unconjugated monoclonal antibody component of belantamab mafodotin that targets BCMA, and thus lacks the cytotoxic payload of belantamab mafodotin.

[0116] In one embodiment, belantamab is administered at a dose of about 300 mg to about 2000 mg. In one embodiment, belantamab is administered at a dose of about 300 mg to about 900 mg. In one embodiment, belantamab is administered at a dose of about 900 mg to about 2000 mg. In one embodiment, belantamab is administered at a dose of about 300 mg. In one embodiment, belantamab is administered at a dose of about 900 mg. In one embodiment, belantamab is administered at a dose of about 2000 mg.

[0117] In one embodiment, the dose of belantamab is administered at regular intervals over a period of time. In one embodiment, the dose of belantamab is administered on day 1 of the regular intervals. In one embodiment, the regular intervals are at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every 1 week ± 3 days, once every 1 week ± 3 days to once every 8 weeks ± 3 days, once every 1 week ± 3 days to once every 6 weeks ± 3 days, once every 1 week ± 3 days to once every 4 weeks ± 3 days, once every 1 week ± 3 days once every week ±3 days to once every 3 weeks ±3 days, once every 1 week ±3 days to once every 2 weeks ±3 days, once every 2 weeks ±3 days to once every 3 weeks ±3 days, once every 3 weeks ±3 days to once every 4 weeks ±3 days, once every 4 weeks ±3 days to once every 5 weeks ±3 days, once every 5 weeks ±3 days to once every 6 weeks ±3 days, once every 6 weeks ±3 days to once every 7 weeks ±3 days, and / or once every 7 weeks ±3 days to once every 8 weeks ±3 days. In one embodiment, the time period is until progressive disease occurs.

[0118] In one embodiment, the dose of belantamab is at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every 1 week ± 3 days, from once every 1 week ± 3 days to once every 8 weeks ± 3 days, from once every 1 week ± 3 days to once every 6 weeks ± 3 days, from once every 1 week ± 3 days to once every 4 weeks ± 3 days, from once every 1 week ± 3 days to once every 1 week ± 3 days. belantamab is administered once every week to once every 3 weeks ± 3 days, once every 1 week ± 3 days to once every 2 weeks ± 3 days, once every 2 weeks ± 3 days to once every 3 weeks ± 3 days, once every 3 weeks ± 3 days to once every 4 weeks ± 3 days, once every 4 weeks ± 3 days to once every 5 weeks ± 3 days, once every 5 weeks ± 3 days to once every 6 weeks ± 3 days, once every 6 weeks ± 3 days to once every 7 weeks ± 3 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days. In one embodiment, belantamab doses are administered once every 1 week ± 3 days to once every 4 weeks ± 3 days. In one embodiment, belantamab doses are administered once every 2 weeks ± 3 days to once every 4 weeks ± 3 days. In one embodiment, belantamab doses are administered once every 2 weeks ± 3 days to once every 4 weeks ± 3 days. In one embodiment, belantamab doses are administered once every 2 weeks ± 3 days. In one embodiment, the dose of belantamab is administered once every 3 weeks ± 3 days. In one embodiment, the dose of belantamab is administered once every 4 weeks ± 3 days.

[0119] In one embodiment, the dose of belantamab is administered parenterally, i.e., subcutaneously (sc or SC), intrathecally, intraperitoneally, intramuscularly (im or IM), or intravenously (iv or IV), including by intravenous infusion. In one embodiment, the dose of belantamab is administered intravenously. In one embodiment, the dose of belantamab is administered via intravenous infusion. In one embodiment, the dose of belantamab is administered subcutaneously.

[0120] In one embodiment, belantamab is administered as a first-line treatment for a disease or disorder. In one embodiment, belantamab is administered after one or more prior lines of treatment for the disease or disorder. In one embodiment, belantamab is administered after at least one prior line of treatment, after at least two prior lines of treatment, after at least three prior lines of treatment, after at least four prior lines of treatment, after one to four prior lines of treatment, after two to four prior lines of treatment, after one to two prior lines of treatment, after two to three prior lines of treatment, after three to four prior lines of treatment, after one prior line of treatment, after two prior lines of treatment, after three prior lines of treatment, or after four prior lines of treatment for the disease or disorder. In one embodiment, belantamab is administered as a first-line treatment for cancer. In one embodiment, belantamab is administered after one or more prior lines of treatment for cancer. In one embodiment, belantamab is administered after at least one prior line of treatment for the cancer, after at least two prior lines of treatment for the cancer, after at least three prior lines of treatment for the cancer, after at least four prior lines of treatment for the cancer, after one to four prior lines of treatment for the cancer, after two to four prior lines of treatment for the cancer, after one to two prior lines of treatment for the cancer, after two to three prior lines of treatment for the cancer, after three to four prior lines of treatment for the cancer, after one prior line of treatment for the cancer, after two prior lines of treatment for the cancer, after three prior lines of treatment for the cancer, or after four prior lines of treatment for the cancer. In one embodiment, the patient has not been treated with a prior treatment for the disease or disorder. In one embodiment, the patient has been treated with at least one prior treatment for the disease or disorder.In one embodiment, the patient has been treated with at least one prior line of therapy, at least two prior lines of therapy, at least three prior lines of therapy, at least four prior lines of therapy, one to four prior lines of therapy, two to four prior lines of therapy, one to two prior lines of therapy, two to three prior lines of therapy, three to four prior lines of therapy, one prior line of therapy, two prior lines of therapy, three prior lines of therapy, or four prior lines of therapy for the disease or disorder.

[0121] In one embodiment, the patient has relapsed or refractory multiple myeloma and has previously received at least four prior therapies to treat the multiple myeloma.

[0122] In one embodiment, the prior cancer treatment line is selected from an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulator, or a combination thereof. For example, a patient who has had 0, 1, 2, 3, or 4 or more prior treatment lines before being treated as described herein may have previously been treated with an immunomodulator (e.g., an immunomodulatory imid drug (ImiD)), a proteasome inhibitor (PI), an anti-CD38 treatment, or a combination thereof. In one embodiment, the prior cancer treatment line includes an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulator.

[0123] Examples of anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g., DARZALEX®, DARZALEX FASPRO®). In one embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0124] Examples of proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib. In one embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In one embodiment, the proteasome inhibitor is bortezomib.

[0125] Examples of immunomodulatory imide drugs (ImiDs) useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In one embodiment, the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide.

[0126] In one embodiment, belantamab is administered as monotherapy. In one embodiment, belantamab is administered in combination with at least one additional treatment. In one embodiment, belantamab is administered in combination with at least one additional cancer treatment. In one embodiment, belantamab is administered on day 1 of a treatment cycle. In one embodiment, belantamab is administered on day 1 of a 28-day treatment cycle. In one embodiment, belantamab is administered on days 1 and 15 of a 28-day treatment cycle. In one embodiment, belantamab is administered on day 1 of a 21-day treatment cycle.

[0127] In one embodiment, the additional cancer treatment is selected from an anti-CD38 monoclonal antibody, a gamma secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0128] Examples of anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g., DARZALEX®, DARZALEX FASPRO®). In one embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0129] Examples of gamma secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

[0130] Examples of proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib. In one embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In one embodiment, the proteasome inhibitor is bortezomib.

[0131] Examples of immunomodulatory imide drugs (ImiDs) useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In one embodiment, the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide. In one embodiment, the immunomodulatory agent is pomalidomide.

[0132] Examples of anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembrolizimab and dostarlimab. In one embodiment, the anti-PD-1 monoclonal antibody is selected from pembrolizimab or dostarlimab.

[0133] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0134] In one embodiment, the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In one embodiment, the additional cancer treatment is lenalidomide and dexamethasone. In one embodiment, the additional cancer treatment is pomalidomide and dexamethasone. In one embodiment, the additional cancer treatment is bortezomib and dexamethasone. In one embodiment, the additional cancer treatment is pomalidomide, bortezomib, and dexamethasone. In one embodiment, the additional cancer treatment is lenalidomide, bortezomib, and dexamethasone.

[0135] In one embodiment, the additional cancer treatment is a standard of care treatment.

[0136] In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time, hi one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle.

[0137] In one embodiment, the additional cancer treatment is dexamethasone. In one embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once a week. In one embodiment, if the patient is under 75 years of age, the additional cancer treatment is dexamethasone at a dose of 40 mg once a week. In one embodiment, if the patient is at least 75 years of age, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In one embodiment, if the patient has a BMI of at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg once a week. In one embodiment, if the patient has a BMI of less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle.

[0138] In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle, and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle. In one embodiment, if the patient is under 75 years of age or has a BMI of at least 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28 day cycle, and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28 day cycle. In one embodiment, if the patient is at least 75 years old or has a BMI less than 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28-day cycle, and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28-day cycle.

[0139] Induction dose period In some instances, a patient receives an initial therapy or combination of therapies, referred to as an induction dose, before the administration of a subsequent therapy or combination of therapies. An "induction period" refers to a period of time during which a particular initial therapy or combination of therapies is administered before the administration of a subsequent therapy or combination of therapies.

[0140] In some embodiments, the method further comprises administering an induction dose of belantamab mafodotin prior to initiating administration of belantamab. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg to about 3.4 mg / kg once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg to about 1.9 mg / kg once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, or about 3.4 mg / kg once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.4 mg / kg once during the induction period. In one embodiment, the induction dose of belantamab mafodotin is about 1.9 mg / kg administered once during the induction period.

[0141] In one embodiment, the run-in period is 4 weeks ± 3 days, and belantamab mafodotin is administered on day 1 of the run-in period.

[0142] In one embodiment, the dose of belantamab mafodotin is administered parenterally, i.e., subcutaneously (sc or SC), intrathecally, intraperitoneally, intramuscularly (im or IM), or intravenously (iv or IV), including by intravenous infusion. In one embodiment, the dose of belantamab mafodotin is administered intravenously. In one embodiment, the dose of belantamab mafodotin is administered via intravenous infusion.

[0143] In one embodiment, belantamab mafodotin is administered as monotherapy during the induction period. In one embodiment, belantamab mafodotin is administered in combination with at least one additional treatment during the induction period. In one embodiment, belantamab mafodotin is administered in combination with at least one additional cancer treatment during the induction period.

[0144] In one embodiment, the additional cancer treatment for administration during the induction period is selected from an anti-CD38 monoclonal antibody, a gamma secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0145] Examples of anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g., DARZALEX®, DARZALEX FASPRO®). In one embodiment, the anti-CD38 monoclonal antibody for administration during the run-in period is selected from daratumumab or isatuximab.

[0146] Examples of gamma secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

[0147] Examples of proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib. In one embodiment, the proteasome inhibitor for administration during the induction period is selected from bortezomib, carfilzomib, or ixazomib. In one embodiment, the proteasome inhibitor for administration during the induction period is bortezomib.

[0148] Examples of immunomodulatory imide drugs (ImiDs) useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In one embodiment, the immunomodulatory agent for administration during the induction period is selected from thalidomide, lenalidomide, or pomalidomide. In one embodiment, the immunomodulatory agent for administration during the induction period is lenalidomide or pomalidomide. In one embodiment, the immunomodulatory agent for administration during the induction period is lenalidomide. In one embodiment, the immunomodulatory agent for administration during the induction period is pomalidomide.

[0149] Examples of anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembrolizimab and dostarlimab. In one embodiment, the anti-PD-1 monoclonal antibody is selected from pembrolizimab or dostarlimab.

[0150] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0151] In one embodiment, the additional cancer treatment for administration during the induction period is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In one embodiment, the additional cancer treatment for administration during the induction period is lenalidomide and dexamethasone. In one embodiment, the additional cancer treatment for administration during the induction period is pomalidomide and dexamethasone. In one embodiment, the additional cancer treatment for administration during the induction period is lenalidomide and dexamethasone. In one embodiment, the additional cancer treatment for administration during the induction period is bortezomib and dexamethasone. In one embodiment, the additional cancer treatment for administration during the induction period is pomalidomide, bortezomib, and dexamethasone. In one embodiment, the additional cancer treatment for administration during the induction period is lenalidomide, bortezomib, and dexamethasone.

[0152] In one embodiment, the additional cancer treatment for administration during the induction period is a standard of care treatment.

[0153] In one embodiment, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In one embodiment, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28-day lead-in period.

[0154] In one embodiment, the additional cancer treatment for administration during the induction period is dexamethasone. In one embodiment, the additional cancer treatment for administration during the induction period is a 20 mg to 40 mg dose of dexamethasone once a week. In one embodiment, if the patient is under 75 years of age, the additional cancer treatment for administration during the induction period is a 40 mg dose of dexamethasone once a week. In one embodiment, if the patient is at least 75 years of age, the additional cancer treatment for administration during the induction period is a 20 mg dose of dexamethasone once a week. In one embodiment, if the patient has a BMI of at least 18.5, the additional cancer treatment for administration during the induction period is a 40 mg dose of dexamethasone once a week. In one embodiment, if the patient has a BMI of less than 18.5, the additional cancer treatment for administration during the induction period is a 20 mg dose of dexamethasone once a week. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of the 28-day induction period.

[0155] In one embodiment, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of the 28-day lead-in period, and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of the 28-day lead-in period. In one embodiment, if the patient is under 75 years of age or has a BMI of at least 18.5, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of the 28-day lead-in period, and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of the 28-day lead-in period. In one embodiment, if the patient is at least 75 years old or has a BMI less than 18.5, the additional cancer treatment for administration during the lead-in period is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of the 28-day lead-in period, and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of the 28-day lead-in period.

[0156] In one embodiment, the method comprises administering an induction dose of belantamab mafodotin during a lead-in period, followed by administration of belantamab during a subsequent treatment period. In one embodiment, the method comprises administering a single induction dose of belantamab mafodotin at a dose of about 1.4 mg / kg to about 3.4 mg / kg during the lead-in period, followed by administration of a dose of about 300 mg to about 2000 mg of belantamab during a subsequent treatment period. In one embodiment, the method comprises administering a single induction dose of belantamab mafodotin at a dose of about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg during the lead-in period, followed by administration of a dose of about 300 mg, about 900 mg, or about 2000 mg of belantamab during a subsequent treatment period.

[0157] In some embodiments, the method further includes wearing an eye patch contact lens during the induction period and / or subsequent treatment period. An eye patch contact lens is a soft, flexible, plastic therapeutic contact lens that allows oxygen to penetrate to the cornea and is worn in one or both eyes for a period of time to protect the cornea and / or treat ocular toxicity, e.g., ocular toxicity resulting from treatment with a therapeutic agent such as belantamab mafodotin. In some embodiments, the eye patch contact lens is composed of N-carboxyvinyl ester (NCVE), N-vinylpyrrolidone (NVE), poly[dimethylsiloxyl]di[silylbutanol]bis[vinylcarbamate] (PBVC), and / or tris-(trimethylsiloxysilyl)propylvinylcarbamate (TPVC). In some embodiments, the eye patch contact lens is composed of NCVE, NVE, PBVC, and TPVC. In some embodiments, the patch contact lens is composed of NCVE, NVE, PBVC, and TPVC and has a water content of 30% to 40%, e.g., 30%, 32%, 34%, 36%, 38%, or 40%. In some embodiments, the patch contact lens is composed of NCVE, NVE, PBVC, and TPVC and has a water content of about 36%. In some embodiments, the patch contact lens is made from balafilcon A, a copolymer of silicone vinyl carbamate, N-vinylpyrrolidone, a siloxane crosslinker, and a vinylalanine wetting monomer, which has a water content of 36% by weight when immersed in a solution, e.g., saline.

[0158] Discontinuation of belantamab In one embodiment, the method further comprises discontinuing administration of belantamab, followed by administration of belantamab mafodotin. In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg once every 3 weeks ± 3 days. In one embodiment, administration of belantamab is discontinued after the patient demonstrates progressive disease.

[0159] In one embodiment, the method further comprises administering belantamab mafodotin, followed by discontinuing administration of belantamab. In one embodiment, belantamab mafodotin is administered at a dose of 2.5 mg / kg once every 3 weeks ± 3 days. In one embodiment, administration of belantamab is discontinued after the patient demonstrates progressive disease.

[0160] Treatment methods using belantamab mafodotin In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, the method comprising administering belantamab mafodotin to the patient.

[0161] In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg to about 3.4 mg / kg. In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg to about 1.9 mg / kg. In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, or about 3.4 mg / kg. In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg. In one embodiment, belantamab mafodotin is administered at a dose of about 1.9 mg / kg. In one embodiment, belantamab is administered once every 8 weeks ± 3 days.

[0162] In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg to about 3.4 mg / kg once every 8 weeks ± 3 days. In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every 8 weeks ± 3 days. In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.5 mg / kg, about 3.0 mg / kg, or about 3.4 mg / kg once every 8 weeks ± 3 days. In one embodiment, belantamab mafodotin is administered at a dose of about 1.4 mg / kg once every 8 weeks ± 3 days. In one embodiment, belantamab mafodotin is administered at a dose of about 1.9 mg / kg once every 8 weeks ± 3 days.

[0163] In some embodiments, the method further comprises wearing an eye patch contact lens.

[0164] Co-administration of BCMA antagonists Described herein are methods for treating diseases or disorders in patients that benefit from the inhibition or blocking of B-cell maturation antigen (BCMA). Also described are uses of BCMA inhibitory or blocking therapy in treating diseases or disorders in patients. Additionally, described herein are kits that include BCMA inhibitory or blocking therapy and instructions for use.

[0165] In one aspect, the present disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist. The term "BCMA antagonist" refers to a molecule that specifically binds to B-cell maturation antigen (BCMA) and inhibits the binding of BAFF and / or APRIL to the BCMA receptor. Examples of BCMA antagonists include, but are not limited to, anti-BCMA antibodies or antigen-binding fragments thereof, anti-BCMA antibody-drug conjugates, bispecific anti-BCMA antibodies or antigen-binding fragments thereof, and BCMA-targeted chimeric antigen receptor T (CAR T) cell therapies.

[0166] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. The first BCMA antagonist is different from the second BCMA antagonist. In one embodiment, the first and second BCMA antagonists are both anti-BCMA antibodies or fragments thereof, both anti-BCMA antibody-drug conjugates, both bispecific anti-BCMA antibodies or fragments thereof, or both BCMA-targeted chimeric antigen receptor T (CAR T) cell therapies. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof, and the second BCMA antagonist is a different anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a different anti-BCMA antibody-drug conjugate. In one embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof and the second BCMA antagonist is a different bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy and the second BCMA antagonist is a different BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0167] In one embodiment, the bispecific anti-BCMA antibody or antigen-binding fragment thereof comprises an anti-BCMA antibody or antigen-binding fragment thereof and an anti-CD38 antibody or antigen-binding fragment thereof. In one embodiment, the bispecific anti-BCMA antibody or antigen-binding fragment thereof specifically binds to both BCMA and CD3.

[0168] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of idecbutagen bileucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0169] In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is belantamab.

[0170] In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0171] In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0172] In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is idecactagen bicleucel. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is siltacabtagene autolucel. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is teclistamab. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is REGN5458. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is SEA-BCMA. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is ABBV-383. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is erlantamab. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is pavutumab. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is alnuctamab. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is MEDI2228. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is CC99712.

[0173] In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is idecactagen bicleucel. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is siltacabtagene autolucel. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is teclistamab. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is REGN5458. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is SEA-BCMA. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is ABBV-383. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is erlantamab. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is pavutumab. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is alnuctamab. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is MEDI2228. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is CC99712.

[0174] In one embodiment, the combination further comprises a third BCMA antagonist. In one embodiment, the third BCMA antagonist is selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. The third BCMA antagonist is different from the first and second BCMA antagonists. In one embodiment, the third BCMA antagonist is selected from the group consisting of idecbutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0175] In one embodiment, the combination comprises belantamab mafodotin, belantamab, and an anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and an anti-BCMA antibody-drug conjugate. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and a bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0176] In one embodiment, the combination comprises belantamab mafodotin, belantamab, and idecabutagen bicleucel. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and siltacabtagene autolucel. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and teclistamab. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and REGN5458. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and SEA-BCMA. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and ABBV-383. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and erlantamab. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and pavlutumab. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and alnuctamab. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and MEDI2228. In one embodiment, the combination comprises belantamab mafodotin, belantamab, and CC99712.

[0177] In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab. In one embodiment, the first and second BCMA antagonists, and, if present, a third BCMA antagonist, are administered simultaneously, such as on the same day of a treatment cycle. In one embodiment, the first and second BCMA antagonists, and, if present, a third BCMA antagonist, are administered on the same day of a treatment cycle. In one embodiment, the first and second BCMA antagonists, and, if present, a third BCMA antagonist, are administered during the same treatment cycle on different days of the treatment cycle.

[0178] In one embodiment, the first and second BCMA antagonists, and, if present, the third BCMA antagonist, are administered at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every 1 week ± 3 days, from once every 1 week ± 3 days to once every 8 weeks ± 3 days, from once every 1 week ± 3 days to once every 6 weeks ± 3 days, from once every 1 week ± 3 days to once every 4 weeks ± Administered independently once every 3 days, once every 1 week ± 3 days to once every 3 weeks ± 3 days, once every 1 week ± 3 days to once every 2 weeks ± 3 days, once every 2 weeks ± 3 days to once every 3 weeks ± 3 days, once every 3 weeks ± 3 days to once every 4 weeks ± 3 days, once every 4 weeks ± 3 days to once every 5 weeks ± 3 days, once every 5 weeks ± 3 days to once every 6 weeks ± 3 days, once every 6 weeks ± 3 days to once every 7 weeks ± 3 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days.

[0179] In one embodiment, the first and second BCMA antagonists, and, if present, the third BCMA antagonist, are administered in combination with the wearing of an eye patch contact lens.

[0180] In one embodiment, the first and second BCMA antagonists, and, if present, the third BCMA antagonist, are administered in combination with at least one additional therapy. In one embodiment, the additional cancer therapy is selected from an anti-CD38 monoclonal antibody, a gamma secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0181] Examples of anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g., DARZALEX®, DARZALEX FASPRO®). In one embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0182] Examples of gamma secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

[0183] Examples of proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib. In one embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In one embodiment, the proteasome inhibitor is bortezomib.

[0184] Examples of immunomodulatory imide drugs (ImiDs) useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In one embodiment, the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide.

[0185] Examples of anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembrolizimab and dostarlimab. In one embodiment, the anti-PD-1 monoclonal antibody is selected from pembrolizimab or dostarlimab.

[0186] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0187] In one embodiment, the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In one embodiment, the additional cancer treatment is lenalidomide and dexamethasone. In one embodiment, the additional cancer treatment is pomalidomide and dexamethasone. In one embodiment, the additional cancer treatment is bortezomib and dexamethasone. In one embodiment, the additional cancer treatment is pomalidomide, bortezomib, and dexamethasone. In one embodiment, the additional cancer treatment is lenalidomide, bortezomib, and dexamethasone.

[0188] In one embodiment, the additional cancer treatment is a standard of care treatment.

[0189] In one embodiment, the first and second BCMA antagonists, and, if present, the third BCMA antagonist, are administered on day 1 of a treatment cycle. In one embodiment, the first and second BCMA antagonists, and, if present, the third BCMA antagonist, are administered on day 1 of a 28-day treatment cycle. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily on days 1 to 21 of a 28-day cycle. In one embodiment, the additional cancer treatment is dexamethasone. In one embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly. In one embodiment, if the patient is under 75 years of age, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly. In one embodiment, if the patient is at least 75 years old, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In one embodiment, if the patient has a BMI of at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg once a week. In one embodiment, if the patient has a BMI of less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1 to 21 of a 28-day cycle, and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, if the patient is under 75 years of age or has a BMI of at least 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28-day cycle, and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28-day cycle.In one embodiment, if the patient is at least 75 years old or has a BMI less than 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28-day cycle, and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28-day cycle.

[0190] In one aspect, the disclosure provides a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist. In one embodiment, the kit further comprises a third BCMA antagonist. In one embodiment, the instructions further describe use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with the second and third BCMA antagonists.

[0191] In one aspect, the first, second, and third BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. In one embodiment, the first, second, and third BCMA antagonists are independently selected from the group consisting of idecbutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0192] In one aspect, the disclosure provides a kit comprising: (i) belantamab mafodotin; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with belantamab.

[0193] In one aspect, the disclosure provides a kit comprising: (i) belantamab; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with belantamab mafodotin.

[0194] Sequential use of BCMA antagonists Described herein are methods for treating diseases or disorders in patients that benefit from the inhibition or blocking of B-cell maturation antigen (BCMA). Also described are uses of BCMA inhibitory or blocking therapy in treating diseases or disorders in patients. Additionally, described herein are kits that include BCMA inhibitory or blocking therapy and instructions for use.

[0195] In one aspect, the disclosure provides a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with a first BCMA antagonist, comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0196] In one aspect, the present disclosure provides a method for reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and the second BCMA antagonist is not the same as the first BCMA antagonist. "Corneal toxicity" or "adverse corneal reaction" refers to changes in the cornea, including corneal epithelial defects such as keratopathy (e.g., mild superficial keratopathy, moderate superficial keratopathy, severe superficial keratopathy) and corneal ulcers. In some embodiments, corneal toxicity or adverse corneal reaction refers to keratopathy, and the severity or grade of such adverse corneal reaction can be determined using the Keratopathy Visual Acuity (KVA) scale for treatment-related corneal toxicity according to Table 2. In some embodiments, the patient has a Grade 1 adverse corneal reaction. In some embodiments, the patient has a Grade 2 adverse corneal reaction. In some embodiments, the patient has a Grade 3 adverse corneal reaction. In some embodiments, the patient has a Grade 4 adverse corneal reaction. In some embodiments, reducing ocular toxicity refers to reducing the severity of the adverse corneal reaction or the grade of treatment-related corneal toxicity, as determined according to the KVA scale.

[0197] [Table 2]

[0198] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. The first BCMA antagonist is different from the second BCMA antagonist. In one embodiment, the first and second BCMA antagonists are both anti-BCMA antibodies or fragments thereof, both anti-BCMA antibody-drug conjugates, both bispecific anti-BCMA antibodies or fragments thereof, or both BCMA-targeted chimeric antigen receptor T (CAR T) cell therapies. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof, and the second BCMA antagonist is a different anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a different anti-BCMA antibody-drug conjugate. In one embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof and the second BCMA antagonist is a different bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy and the second BCMA antagonist is a different BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0199] In one embodiment, the bispecific anti-BCMA antibody or antigen-binding fragment thereof comprises an anti-BCMA antibody or antigen-binding fragment thereof and an anti-CD38 antibody or antigen-binding fragment thereof. In one embodiment, the bispecific anti-BCMA antibody or antigen-binding fragment thereof comprises an anti-BCMA antibody or antigen-binding fragment thereof and an anti-CD3 antibody or antigen-binding fragment thereof.

[0200] In one embodiment, the first and second BCMA antagonists are independently selected from the group consisting of idecbutagen bileucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0201] In one embodiment, the first BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is belantamab. In one embodiment, the second BCMA antagonist is belantamab mafodotin. In one embodiment, the second BCMA antagonist is belantamab.

[0202] In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy and the second BCMA antagonist is belantamab mafodotin.

[0203] In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is an anti-BCMA antibody-drug conjugate. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy and the second BCMA antagonist is belantamab.

[0204] In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is idecactagen bicleucel. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is siltacabtagene autolucel. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is teclistamab. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is REGN5458. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is SEA-BCMA. In one embodiment, the first BCMA antagonist is idecbutagen bileucel, and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is siltacabtagene autreucel, and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is teclistamab, and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is REGN5458, and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is SEA-BCMA, and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is ABBV-383 and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is erlantamab and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is pavutumab and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is alnuctamab and the second BCMA antagonist is belantamab mafodotin.In one embodiment, the first BCMA antagonist is MEDI2228 and the second BCMA antagonist is belantamab mafodotin. In one embodiment, the first BCMA antagonist is CC99712 and the second BCMA antagonist is belantamab mafodotin.

[0205] In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is idecbutagen bileucel. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is siltacabtagene autolucel. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is teclistamab. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is REGN5458. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is SEA-BCMA. In one embodiment, the first BCMA antagonist is idecbutagen bileucel and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is siltacabtagene autreucel, and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is teclistamab, and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is REGN5458, and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is SEA-BCMA, and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is ABBV-383, and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is erlantamab, and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is pavlutumab and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is alnuctamab and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is MEDI2228 and the second BCMA antagonist is belantamab.In one embodiment, the first BCMA antagonist is CC99712 and the second BCMA antagonist is belantamab.

[0206] In one embodiment, the method further comprises administering to the patient a therapeutically effective amount of a third BCMA antagonist in combination with the second BCMA antagonist, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second and third BCMA antagonists, and wherein the third BCMA antagonist is not the same as the first and second BCMA antagonists.

[0207] In one embodiment, the first BCMA antagonist is an anti-BCMA antibody or antigen-binding fragment thereof, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is a bispecific anti-BCMA antibody or antigen-binding fragment thereof, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab.

[0208] In one embodiment, the first BCMA antagonist is idecbutagen bileucel, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is siltacabtagene autreucel, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is teclistamab, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is REGN5458, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is SEA-BCMA, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is ABBV-383, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is erlantamab, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is pavutumab, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is alnuctamab, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is MEDI2228, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab.In one embodiment, the first BCMA antagonist is CC99712, the second BCMA antagonist is belantamab mafodotin, and the third BCMA antagonist is belantamab.

[0209] In one embodiment, the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In one embodiment, the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody. In one embodiment, the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab. In one embodiment, the first BCMA antagonist is belantamab and the second BCMA antagonist is belantamab mafodotin.

[0210] In one embodiment, the second BCMA antagonist, and if present, the third BCMA antagonist, is administered at least once every 8 weeks ± 3 days, at least once every 6 weeks ± 3 days, at least once every 4 weeks ± 3 days, at least once every 3 weeks ± 3 days, at least once every 2 weeks ± 3 days, at least once every 1 week ± 3 days, from once every 1 week ± 3 days to once every 8 weeks ± 3 days, from once every 1 week ± 3 days to once every 6 weeks ± 3 days, from once every 1 week ± 3 days to once every 4 weeks ± 3 days once every 1 week ± 3 days to once every 3 weeks ± 3 days, once every 1 week ± 3 days to once every 2 weeks ± 3 days, once every 2 weeks ± 3 days to once every 3 weeks ± 3 days, once every 3 weeks ± 3 days to once every 4 weeks ± 3 days, once every 4 weeks ± 3 days to once every 5 weeks ± 3 days, once every 5 weeks ± 3 days to once every 6 weeks ± 3 days, once every 6 weeks ± 3 days to once every 7 weeks ± 3 days, and / or once every 7 weeks ± 3 days to once every 8 weeks ± 3 days.

[0211] In one embodiment, the second BCMA antagonist and, if present, the third BCMA antagonist are administered in combination with the wear of an eye patch contact lens.

[0212] In one embodiment, the second BCMA antagonist, and, if present, the third BCMA antagonist, are administered in combination with at least one additional therapy. In one embodiment, the additional cancer therapy is selected from an anti-CD38 monoclonal antibody, a gamma secretase inhibitor, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0213] Examples of anti-CD38 antibodies useful in the methods described herein include, but are not limited to, isatuximab or isatuximab-irfc (e.g., SARCLISA®) and daratumumab (e.g., DARZALEX®, DARZALEX FASPRO®). In one embodiment, the anti-CD38 monoclonal antibody is selected from daratumumab or isatuximab.

[0214] Examples of gamma secretase inhibitors useful in the methods described herein include, but are not limited to, nirogacestat (PF-0308014), crenigacestat (LY3039478), CB-103, tarenflurbil, semagacestat (LY450139), RG-4733, EVP-0962, avagacestat, MK-0752, and BMS-906024, and derivatives and polymorphs thereof.

[0215] Examples of proteasome inhibitors useful in the methods described herein include, but are not limited to, bortezomib (e.g., VELCADE®), ixazomib (e.g., NINLARO®), carfilzomib (e.g., KYPROLIS®), oprozomib, and delanzomib. In one embodiment, the proteasome inhibitor is selected from bortezomib, carfilzomib, or ixazomib. In one embodiment, the proteasome inhibitor is bortezomib.

[0216] Examples of immunomodulatory imide drugs (ImiDs) useful in the methods described herein include, but are not limited to, thalidomide (e.g., THALOMID®), lenalidomide (e.g., REVLIMID®), and pomalidomide (e.g., POMALYST®). In one embodiment, the immunomodulatory agent is selected from thalidomide, lenalidomide, or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide or pomalidomide. In one embodiment, the immunomodulatory agent is lenalidomide.

[0217] Examples of anti-PD-1 monoclonal antibodies useful in the methods described herein include, but are not limited to, pembrolizimab and dostarlimab. In one embodiment, the anti-PD-1 monoclonal antibody is selected from pembrolizimab or dostarlimab.

[0218] Other additional cancer treatments include corticosteroids. Examples of corticosteroids include, but are not limited to, dexamethasone (e.g., DECADRON®, DEXASONE®, DIODEX®, HEXADROL®, MAXIDEX®), prednisone (e.g., DELTASONE®), and methylprednisolone (e.g., MEDROL®).

[0219] In one embodiment, the additional cancer treatment is selected from lenalidomide, pomalidomide, dexamethasone, or a combination thereof. In one embodiment, the additional cancer treatment is lenalidomide and dexamethasone. In one embodiment, the additional cancer treatment is pomalidomide and dexamethasone. In one embodiment, the additional cancer treatment is bortezomib and dexamethasone. In one embodiment, the additional cancer treatment is pomalidomide, bortezomib, and dexamethasone. In one embodiment, the additional cancer treatment is lenalidomide, bortezomib, and dexamethasone.

[0220] In one embodiment, the additional cancer treatment is a standard of care treatment.

[0221] In one embodiment, the second BCMA antagonist and, if present, the third BCMA antagonist are administered on day 1 of a treatment cycle. In one embodiment, the second BCMA antagonist and, if present, the third BCMA antagonist are administered on day 1 of a 28-day treatment cycle. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily on days 1 to 21 of a 28-day cycle. In one embodiment, the additional cancer treatment is dexamethasone. In one embodiment, the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly. In one embodiment, if the patient is under 75 years of age, the additional cancer treatment is dexamethasone at a dose of 40 mg once weekly. In one embodiment, if the patient is at least 75 years old, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In one embodiment, if the patient has a BMI of at least 18.5, the additional cancer treatment is dexamethasone at a dose of 40 mg once a week. In one embodiment, if the patient has a BMI of less than 18.5, the additional cancer treatment is dexamethasone at a dose of 20 mg once a week. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1 to 21 of a 28-day cycle, and dexamethasone at a dose of 20 mg to 40 mg administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, if the patient is under 75 years of age or has a BMI of at least 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28-day cycle, and dexamethasone at a dose of 40 mg administered on days 1, 8, 15, and 22 of a 28-day cycle.In one embodiment, if the patient is at least 75 years old or has a BMI less than 18.5, the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg administered once daily on days 1-21 of a 28-day cycle, and dexamethasone at a dose of 20 mg administered on days 1, 8, 15, and 22 of a 28-day cycle.

[0222] In one embodiment, the first BCMA antagonist is discontinued after the patient manifests progressive disease.

[0223] Combining an antibody-drug conjugate with the corresponding unconjugated antibody In some instances, an immunoconjugate or antibody-drug conjugate is used in combination with its corresponding unconjugated antibody. When used in connection with an immunoconjugate or antibody-drug conjugate (ADC), the corresponding unconjugated antibody refers to the antibody portion of the immunoconjugate or ADC that lacks the cytotoxic payload and, optionally, any portion of the linker of the immunoconjugate or ADC. In one aspect, the present disclosure provides a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising an antibody-drug conjugate and the corresponding unconjugated antibody.

[0224] In one aspect, the disclosure provides a method of reducing the toxicity of an antibody-drug conjugate, comprising administering to a patient in need thereof a therapeutically effective amount of a combination comprising the antibody-drug conjugate and a corresponding unconjugated antibody.

[0225] In one aspect, the disclosure provides a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, comprising administering a therapeutically effective amount of a corresponding unconjugated antibody to the patient, wherein the patient had discontinued administration of the antibody-drug conjugate prior to initiating administration of the corresponding unconjugated antibody.

[0226] In one aspect, the disclosure provides a method of reducing toxicity in a patient previously treated with an antibody-drug conjugate, comprising administering to the patient a therapeutically effective amount of a corresponding unconjugated antibody, wherein the patient had discontinued administration of the antibody-drug conjugate before initiating administration of the corresponding unconjugated antibody.

[0227] In one embodiment, the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, fam-trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, roncatuximab tesirin, tisotumab vedotin, moxetumomab pasudotox, MEDI2228, or CC99712.

[0228] Diseases and Disorders Described herein are methods of treating a disease or disorder in a patient that would benefit from inhibition or blockade of B-cell maturation antigen (BCMA). Also described are uses of BCMA inhibitory or blocking therapy in treating a disease or disorder in a patient.

[0229] In one embodiment, the disease or disorder is a plasma cell disorder or a B cell disorder. B cell disorders can be divided into defects in B cell development / immunoglobulin production (immunodeficiency) and excessive / uncontrolled proliferation (lymphoma, leukemia). As used herein, B cell disorder refers to both types of disease, and methods for treating B cell disorders are provided. In some embodiments, the cancer can be a B cell cancer (e.g., leukemia and lymphoma).

[0230] Examples of diseases or disorders that can be treated according to the methods described herein include multiple myeloma (MM), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-secretory multiple myeloma, smoldering multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), solitary plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom's macroglobulinemia, and leukemia. Diseases or disorders include, but are not limited to, plasma cell leukemia, primary amyloidosis (AL), heavy chain disease, systemic lupus erythematosus (SLE), POEMS syndrome / osteosclerotic myeloma, type I and type II cryoglobulinemia, light chain deposition disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura (ITP), acute glomerulonephritis, pemphigus and pemphigoid disorders, and epidermolysis bullosa acquisita; or any non-Hodgkin's lymphoma B-cell leukemia (NHL) and Hodgkin's lymphoma (HL). In some cases, the disease or disorder may be selected from the group consisting of multiple myeloma (MM), non-Hodgkin's lymphoma B-cell leukemia (NHL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). In one embodiment, the disease may be multiple myeloma or non-Hodgkin's lymphoma B-cell leukemia (NHL). In one embodiment, the disease can be multiple myeloma.

[0231] In one embodiment, the disease or disorder is a BCMA-expressing cancer. In one embodiment, the disease or disorder is multiple myeloma (MM). In one embodiment, the MM is relapsed and / or refractory MM, newly diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly diagnosed MM. In one embodiment, the disease or disorder is multiple myeloma that has been previously treated with at least one, at least two, at least three, or at least four therapeutic agents to treat multiple myeloma. In one embodiment, the disease or disorder is relapsed and / or refractory multiple myeloma that has been previously treated with at least one, at least two, at least three, or at least four therapeutic agents to treat multiple myeloma. In another embodiment, the disease or disorder is relapsed and / or refractory multiple myeloma that has been previously treated with at least three prior lines of therapy, which may include the following: an immunomodulatory drug (ImiD), a proteasome inhibitor (PI), and an anti-CD38 therapy (e.g., daratumumab), or a combination thereof. The line of therapy may be defined by the International Myeloma Workshop (IMWG) consensus panel. In some embodiments, patients who have had a previous line of therapy may have recurrent, recurrent, and / or refractory cancer. In some cases, the cancer may be a primary cancer. In some cases, the cancer may be a metastatic cancer. In some cases, the cancer may be a chemotherapy-resistant cancer.

[0232] In one embodiment, the disease or disorder is an autoimmune disease or disorder, hi one embodiment, the disease or disorder is systemic lupus erythematosus (SLE), idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, type 1 diabetes, multiple sclerosis, or psoriasis.

[0233] Antibody sequence The term "belantamab" refers to a BCMA blocking antibody ("anti-BCMA antibody") or a functional fragment or functional variant thereof that specifically binds to B-cell maturation antigen (BCMA) and inhibits binding of BAFF and / or APRIL to the BCMA receptor, comprising an immunoglobulin heavy chain variable domain (VH) comprising a complementarity determining region (CDR) H1 comprising the amino acid sequence of SEQ ID NO:5; a CDRH2 comprising the amino acid sequence of SEQ ID NO:6; a CDRH3 comprising the amino acid sequence of SEQ ID NO:7; and an immunoglobulin light chain variable domain (VL) comprising a CDRL1 comprising the amino acid sequence of SEQ ID NO:8; a CDRL2 comprising the amino acid sequence of SEQ ID NO:9; and a CDRL3 comprising the amino acid sequence of SEQ ID NO:10. Exemplary antibody heavy and light chain variable region sequences are provided in Table 3 below. In certain embodiments, the VH comprises the amino acid sequence of SEQ ID NO:3. In certain embodiments, the VL comprises the amino acid sequence of SEQ ID NO:4. In certain embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:1. In certain embodiments, the light chain comprises the amino acid sequence of SEQ ID NO:2. In certain other embodiments, belantamab comprises a VH comprising the amino acid sequence of SEQ ID NO: 3 and a VL comprising the amino acid sequence of SEQ ID NO: 4. In other embodiments, belantamab comprises the heavy and light chain sequences of SEQ ID NO: 1 and SEQ ID NO: 2, respectively.

[0234] The terms "belantamab mafodotin" and "belamaf" are used interchangeably and refer to an immunoconjugate comprising belantamab conjugated to monomethyl auristatin F (MMAF) via a 6-maleimidocaproyl (MC) linker.

[0235] The term "biosimilar" refers to a biopharmaceutical or biological product that is highly similar to a reference biological product (e.g., belantamab or belantamab mafodotin), despite minor differences in clinically inactive ingredients, and in that there are no clinically meaningful differences between the biological product and the reference product in terms of product safety, purity, and potency (Section 351(i) of the Public Health Service Act (42 U.S.C. 262(i))).

[0236] Thus, the term "biosimilar" refers to a biological product that is highly similar to a reference product (e.g., belantamab or belantamab mafodotin) approved by a regulatory authority (e.g., the Federal Drug Administration (FDA) or the European Medicines Agency (EMA)) based on (a) analytical testing that demonstrates that the biological product is highly similar to the reference product, despite minor differences in clinically inactive components; (b) animal testing (including evaluation of toxicity); and / or (c) data from one or more clinical trials (including evaluation of immunogenicity and pharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency (e.g., no clinically meaningful differences between the biological product and the reference product in terms of product safety, purity, and potency) for one or more appropriate conditions for the use(s) for which the reference product has been approved and intended to be used and for which approval is sought. In certain embodiments, a biosimilar product is an interchangeable product as determined by a regulatory authority (e.g., the FDA).

[0237] It will generally be understood that a biosimilar of belantamab mafodotin will contain post-translational modifications essential to the function and efficacy of belantamab mafodotin (as disclosed in International Patent Application Publication No. 2021 / 024133). However, in certain embodiments, a biosimilar (e.g., a biosimilar of belantamab or belantamab mafodotin) may contain one or more molecular differences, such as post-translational modifications, including but not limited to, glycosylation, oxidation, deamidation, and / or cleavage, that differ from the post-translational modifications of the reference drug (e.g., belantamab or belantamab mafodotin), provided that these differences do not result in a material change in the safety and / or efficacy of the drug. In certain embodiments, a biosimilar (e.g., a biosimilar of belantamab or belantamab mafodotin) may have the same or a different glycosylation pattern as the reference drug (e.g., belantamab or belantamab mafodotin). In particular, but not by way of limitation, a biosimilar (e.g., a biosimilar of belantamab or belantamab mafodotin) may have a different glycosylation pattern, for example, if the difference addresses or is intended to address a safety concern associated with the reference drug (e.g., belantamab or belantamab mafodotin). In addition, a biosimilar (e.g., a biosimilar of belantamab or belantamab mafodotin) may deviate from the reference drug (e.g., belantamab or belantamab mafodotin) in, for example, its strength, dosage form, formulation, excipients, and / or presentation, provided that the safety and efficacy of the drug are not compromised. In other embodiments, a biosimilar (e.g., a biosimilar of belantamab or belantamab mafodotin) may contain differences, e.g., in the pharmacokinetic (PK) profile and / or pharmacodynamic (PD) profile, compared to the reference drug (e.g., belantamab or belantamab mafodotin), but is still sufficiently similar to the reference drug to be approved or considered suitable for approval.In certain embodiments, a biosimilar (e.g., a biosimilar of belantamab or belantamab mafodotin) may exhibit different binding characteristics compared to the reference drug product (e.g., belantamab or belantamab mafodotin), in which case the different binding characteristics are not considered by regulatory agencies such as the FDA and / or EMA to be a barrier to approval as a similar biological product. The term "biosimilar" is also used interchangeably by regulatory authorities in other countries and regions.

[0238] It is understood that a drug's International Nonproprietary Name (INN) (e.g., belantamab or belantamab mafodotin) is interpreted to include generic, bioequivalent, and / or biosimilar versions of that drug, including, but not limited to, any drug that has received abbreviated regulatory approval by reference to a prior regulatory approval for that drug. In addition, a drug's INN optionally includes, but is not limited to, glycosylation variants of belantamab or belantamab mafodotin, and biosimilars thereof.

[0239] [Table 3]

[0240] Embodiment Embodiment 1 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a dose of about 300 mg to about 2000 mg of belantamab.

[0241] Embodiment 2 is the method of embodiment 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.

[0242] Embodiment 3 is the method of embodiment 1 or 2, wherein the doses are administered at regular intervals over a period of time.

[0243] Embodiment 4 is the method of embodiment 1 or 2, wherein the dose is administered from once every 1 week ± 3 days to once every 4 weeks ± 3 days.

[0244] Embodiment 5 is the method of embodiment 1 or 2, wherein the dose is administered once every 2 weeks ± 3 days.

[0245] Embodiment 6 is the method of embodiment 1 or 2, wherein the dose is administered once every 3 weeks ± 3 days.

[0246] Embodiment 7 is the method of embodiment 1 or 2, wherein the dose is administered once every 4 weeks ± 3 days.

[0247] Embodiment 8 is the method of embodiment 1 or 2, wherein the doses are administered on days 1 and 15 of a 28-day cycle.

[0248] Embodiment 9 is the method of embodiment 1 or 2, wherein the dose is administered on day 1 of a 21-day cycle.

[0249] Embodiment 10 is the method of any one of the above embodiments, wherein the patient has been treated with at least one prior line of treatment for the cancer.

[0250] Embodiment 11 is the method of any one of the above embodiments, wherein the patient has been treated with one, two, three, or four prior lines of therapy for the cancer.

[0251] Embodiment 12 is the method of embodiment 11, wherein the prior cancer treatment lines include an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

[0252] Embodiment 13 is the method of any one of the above embodiments, wherein belantamab is administered via intravenous infusion or subcutaneous injection.

[0253] Embodiment 14 is the method of any one of the above embodiments, wherein the patient is further receiving at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0254] Embodiment 15 is the method of embodiment 14, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0255] Embodiment 16 is the method of embodiment 15, wherein the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time.

[0256] Embodiment 17 is the method of Embodiment 16, wherein the patient is receiving lenalidomide on days 1-21 of a 28-day cycle.

[0257] Embodiment 18 is the method of any one of Embodiments 14-17, wherein the further cancer treatment is dexamethasone.

[0258] Embodiment 19 is the method of embodiment 18, wherein the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly.

[0259] Embodiment 20 is the method of embodiment 19, wherein the patient is receiving dexamethasone on days 1, 8, 15, and 22 of a 28-day cycle.

[0260] Embodiment 21 is the method of Embodiment 19, wherein (i) the patient is under 75 years of age and is receiving dexamethasone at a dose of 40 mg once a week; or (ii) the patient is at least 75 years of age and is receiving dexamethasone at a dose of 20 mg once a week.

[0261] Embodiment 22 is the method of embodiment 19, wherein (i) the patient has a BMI of at least 18.5 and is receiving a 40 mg dose of dexamethasone once a week; or (ii) the patient has a BMI of less than 18.5 and is receiving a 20 mg dose of dexamethasone once a week.

[0262] Embodiment 23 is the method of any one of the above embodiments, further comprising discontinuing administration of belantamab, followed by administration of belantamab mafodotin.

[0263] Embodiment 24 is the method of any one of Embodiments 1-22, further comprising administering belantamab mafodotin, followed by discontinuing administration of belantamab.

[0264] Embodiment 25 is the method of Embodiment 23 or 24, wherein belantamab mafodotin is administered at a dose of 2.5 mg / kg once every 3 weeks ± 3 days.

[0265] Embodiment 26 is the method of any one of the preceding embodiments, further comprising administering an induction dose of belantamab mafodotin prior to initiating administration of belantamab, wherein the induction dose of belantamab mafodotin is about 1.4 mg / kg to about 3.4 mg / kg administered once during the induction period.

[0266] Embodiment 27 is the method of Embodiment 26, wherein the induction dose of belantamab mafodotin is about 1.4 mg / kg to about 1.9 mg / kg administered once during the induction period.

[0267] Embodiment 28 is the method of Embodiment 26, wherein the induction dose of belantamab mafodotin is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg once during the induction period.

[0268] Embodiment 29 is the method of Embodiment 26, wherein the induction dose of belantamab mafodotin is about 1.4 mg / kg administered once during the induction period.

[0269] Embodiment 30 is the method of any one of Embodiments 26-29, wherein the lead-in period is 4 weeks ± 3 days, and belantamab mafodotin is administered on day 1 of the lead-in period.

[0270] Embodiment 31 is the method of any one of Embodiments 26 to 30, further comprising administering to the patient during the induction period at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0271] Embodiment 32 is the method of embodiment 31, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0272] Embodiment 33 is the method of embodiment 32, wherein the additional cancer treatment is lenalidomide at a dose of 10 mg to 25 mg once daily for a period of time.

[0273] Embodiment 34 is the method of embodiment 33, wherein lenalidomide is administered to the patient on days 1-21 of the lead-in period.

[0274] Embodiment 35 is the method of any one of Embodiments 32-34, wherein the further cancer treatment is dexamethasone.

[0275] Embodiment 36 is the method of embodiment 35, wherein the additional cancer treatment is dexamethasone at a dose of 20 mg to 40 mg once weekly.

[0276] Embodiment 37 is the method of embodiment 36, wherein dexamethasone is administered to the patient on days 1, 8, 15, and 22 of the run-in period.

[0277] Embodiment 38 is the method of embodiment 36, wherein (i) the patient is under 75 years of age and the dexamethasone is administered to the patient at a dose of 40 mg once weekly; or (ii) the patient is at least 75 years of age and the dexamethasone is administered to the patient at a dose of 20 mg once weekly.

[0278] Embodiment 39 is the method of embodiment 36, wherein (i) the patient has a BMI of at least 18.5 and dexamethasone is administered to the patient at a dose of 40 mg once a week; or (ii) the patient has a BMI of less than 18.5 and dexamethasone is administered to the patient at a dose of 20 mg once a week.

[0279] Embodiment 40 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient belantamab mafodotin at a dose of about 1.4 mg / kg to about 3.4 mg / kg once every 8 weeks ± 3 days, e.g., at a dose of about 1.4 mg / kg to about 1.9 mg / kg once every 8 weeks ± 3 days. It is a method.

[0280] Embodiment 41 is the method of embodiment 40, wherein the dose is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg once every 8 weeks ± 3 days.

[0281] Embodiment 42 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

[0282] Embodiment 43 is the method of embodiment 42, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0283] Embodiment 44 is the method of embodiment 42 or 43, wherein the first and second BCMA antagonists are independently selected from the group consisting of idecbutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0284] Embodiment 45 is the method of any one of Embodiments 42 to 44, wherein the first BCMA antagonist is belantamab mafodotin.

[0285] Embodiment 46 is the method of any one of Embodiments 42-44, wherein the first BCMA antagonist is belantamab.

[0286] Embodiment 47 is the method of embodiment 42, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

[0287] Embodiment 48 is the method of embodiment 47, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.

[0288] Embodiment 49 is the method of embodiment 48, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.

[0289] Embodiment 50 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising belantamab mafodotin and belantamab.

[0290] Embodiment 51 is the method of any one of Embodiments 42 to 50, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0291] Embodiment 52 is the method of embodiment 51, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

[0292] Embodiment 53 is a kit comprising: (i) a first B-cell maturation antigen (BCMA) antagonist; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with a second BCMA antagonist.

[0293] Embodiment 54 is a kit comprising: (i) belantamab mafodotin; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) when combined with belantamab.

[0294] Embodiment 55 is a kit comprising: (i) belantamab; and (ii) instructions for use in treating a disease or disorder responsive to inhibiting or blocking BCMA when combined with belantamab mafodotin.

[0295] Embodiment 56 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient who has previously been treated with a first BCMA antagonist, comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0296] Embodiment 57 is the method of embodiment 56, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0297] Embodiment 58 is the method of embodiment 56 or 57, wherein the first and second BCMA antagonists are independently selected from the group consisting of idecbutagen bicleucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0298] Embodiment 59 is the method of any one of embodiments 56-58, wherein the first BCMA antagonist is belantamab mafodotin.

[0299] Embodiment 60 is the method of any one of embodiments 56 to 58, wherein the first BCMA antagonist is belantamab.

[0300] Embodiment 61 is the method of any one of embodiments 56 to 58, wherein the second BCMA antagonist is belantamab mafodotin.

[0301] Embodiment 62 is the method of any one of embodiments 56 to 58, wherein the second BCMA antagonist is belantamab.

[0302] Embodiment 63 is the method of embodiment 56, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

[0303] Embodiment 64 is the method of embodiment 63, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.

[0304] Embodiment 65 is the method of embodiment 63, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.

[0305] Embodiment 66 is the method of embodiment 56, wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

[0306] Embodiment 67 is the method of embodiment 66, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.

[0307] Embodiment 68 is the method of embodiment 66, wherein the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.

[0308] Embodiment 69 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab mafodotin, comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient had discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

[0309] Embodiment 70 is a method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with belantamab, comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient had discontinued administration of belantamab prior to initiating administration of belantamab mafodotin.

[0310] Embodiment 71 is the method of any one of Embodiments 56 to 70, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0311] Embodiment 72 is the method of embodiment 71, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or combinations thereof, such as lenalidomide and dexamethasone.

[0312] Embodiment 73 is a method of reducing corneal toxicity in a patient previously treated with a first B-cell maturation antigen (BCMA) antagonist, comprising administering to the patient a therapeutically effective amount of a second BCMA antagonist, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and wherein the second BCMA antagonist is not the same as the first BCMA antagonist.

[0313] Embodiment 74 is the method of embodiment 73, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

[0314] Embodiment 75 is the method of embodiment 73 or 74, wherein the first and second BCMA antagonists are independently selected from the group consisting of idecbutagen bileucel, siltacabtagene autolucel, teclistamab, REGN5458, belantamab mafodotin, belantamab, SEA-BCMA, ABBV-383, erlantamab, pavlutumab, alnuctamab, MEDI2228, and CC99712.

[0315] Embodiment 76 is the method of any one of embodiments 73 to 75, wherein the first BCMA antagonist is belantamab mafodotin.

[0316] Embodiment 77 is the method of any one of embodiments 73 to 75, wherein the first BCMA antagonist is belantamab.

[0317] Embodiment 78 is the method of any one of embodiments 73 to 75, wherein the second BCMA antagonist is belantamab mafodotin.

[0318] Embodiment 79 is the method of any one of embodiments 73 to 75, wherein the second BCMA antagonist is belantamab.

[0319] Embodiment 80 is the method of embodiment 73, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

[0320] Embodiment 81 is the method of embodiment 80, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.

[0321] Embodiment 82 is the method of embodiment 80, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab.

[0322] Embodiment 83 is the method of embodiment 73, wherein the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

[0323] Embodiment 84 is the method of embodiment 83, wherein the anti-BCMA antibody-drug conjugate is selected from the group consisting of belantamab mafodotin, MEDI2228, and CC99712.

[0324] Embodiment 85 is the method of embodiment 83, wherein the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.

[0325] Embodiment 86 is a method of reducing corneal toxicity in a patient previously treated with belantamab mafodotin, comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient has discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

[0326] Embodiment 87 is a method of reducing corneal toxicity in a patient previously treated with belantamab, comprising administering a therapeutically effective amount of belantamab mafodotin to the patient, wherein the patient has discontinued administration of belantamab prior to initiating administration of belantamab mafodotin.

[0327] Embodiment 88 is the method of any one of Embodiments 73 to 87, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

[0328] Embodiment 89 is the method of embodiment 88, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or combinations thereof, such as lenalidomide and dexamethasone.

[0329] Embodiment 90 is a method of treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

[0330] Embodiment 91 is a method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, comprising administering to the patient a therapeutically effective amount of the corresponding unconjugated antibody, wherein the patient has discontinued administration of the antibody-drug conjugate before initiating administration of the corresponding unconjugated antibody.

[0331] Embodiment 92 is the method of embodiment 90 or 91, wherein the antibody-drug conjugate is selected from gemtuzumab ozogamicin, brentuximab vedotin, ado-trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, fam-trastuzumab deruxtecan, govitecan, belantamab mafodotin, roncatuximab tesirin, tisotumab vedotin, moxetumomab pasudotox, MEDI2228, or CC99712.

[0332] Embodiment 93 is the method of any one of Embodiments 1 to 52 or 56 to 92, or the kit of any one of Embodiments 53 to 55, wherein the disease or disorder is a plasma cell disorder or a B cell disorder.

[0333] Embodiment 94 is the method of any one of embodiments 1 to 52 or 56 to 92, or the kit of any one of embodiments 53 to 55, wherein the disease or disorder is a BCMA-expressing cancer.

[0334] Embodiment 95 is the method of any one of Embodiments 1 to 52 or 56 to 92, or the kit of any one of Embodiments 53 to 55, wherein the disease or disorder is multiple myeloma (MM).

[0335] Embodiment 96 is the method of embodiment 95, wherein the MM is relapsed and / or refractory MM, newly diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly diagnosed MM.

[0336] Embodiment 97 is the kit of embodiment 95, wherein the MM is relapsed and / or refractory MM, newly diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly diagnosed MM.

[0337] Embodiment 98 is a method of treating cancer in a patient, wherein the patient has a Grade 1 corneal adverse reaction attributable to administration of belantamab mafadotin, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering a therapeutically effective amount of belantamab to the patient for a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period.

[0338] Embodiment 99 is a method of treating cancer in a patient, wherein the patient has a Grade 2 or higher corneal adverse reaction attributable to administration of belantamab mafadotin, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering a therapeutically effective amount of belantamab II to the patient for a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period. [Example]

[0339] The following examples are offered to illustrate, but not to limit, the claimed disclosure.

[0340] [Example 1] In vivo efficacy of belantamab in treating the subcutaneous NCI-H929 human multiple myeloma model in NOD / SCID mice. A study was conducted to evaluate the in vivo therapeutic efficacy of belantamab (GSK2857914) and belantamab mafodotin (GSK2857916) in treating the subcutaneous NCI-H929 human multiple myeloma model in NOD / SCID mice. Groups of 10 mice were dosed by intraperitoneal administration at the amounts and at the frequencies and durations shown in Table 4.

[0341] [Table 4]

[0342] method: NCI-H929 tumor cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 0.05 mM β-ME at 37°C under 5% CO2 in air. Exponentially growing cells were harvested and counted for tumor inoculation. Each mouse received 5 × 10 NCI-H929 tumor cells in 0.1 ml of PBS mixed with Matrigel (1:1) for tumor development. 6 The average tumor size was 121 mm. 3 Randomization began when the 20% CI of the 20-30% CI reached 0.85-10.85. Eighty mice were enrolled in the study. All animals were randomly assigned to eight study groups. Randomization was performed based on a randomized block design with the "matching distribution" method (Study Director™ software, version 3.1.399.19). The date of randomization was designated as day 0. Treatment began on the day of randomization (day 0) per the study design.

[0343] After tumor cell inoculation, animals were checked daily for morbidity and mortality. During routine monitoring, animals were checked for the effects of tumor growth and treatment on behavior such as mobility, food and water consumption, weight gain / loss (body weight was measured twice weekly after randomization), loss of eye / hair mattness, and any other abnormalities. Mortality and observed clinical signs were recorded in detail for each individual animal. Tumor volume was measured twice weekly after randomization using calipers in two dimensions, and the volume was calculated in mm using the formula: V = (L × W × W) × 0.52. 3 where V is tumor volume, L is tumor length (the longest dimension of the tumor), and W is tumor width (the longest dimension of the tumor perpendicular to L). Dosing and tumor and body weight measurements were performed in a clean bench. Body weight and tumor volume were measured using StudyDirector™ software (version 3.1.399.19).

[0344] Statistical analysis:To compare tumor volumes between different groups on prespecified days, a Bartlett test was first used to check the assumption of homogeneity of variance across all groups. If the p-value of the Bartlett test was ≥0.05, a one-way ANOVA was performed to test for overall equality of means across all groups. If the p-value of the one-way ANOVA was <0.05, further post-hoc testing was performed by performing Tukey's HSD (strict significance difference) test for all pairwise comparisons and a Dunnett's test for comparing each treatment group with the vehicle group. If the p-value of the Bartlett test was <0.05, a Kruskal-Wallis test was performed to test for overall equality of medians between all groups. If the p-value of the Kruskal-Wallis test was <0.05, further post-hoc testing was performed by performing Conover's nonparametric test for all pairwise comparisons or for comparing each treatment group with the vehicle group, both with a one-step p-value adjustment.

[0345] In addition, pairwise comparisons without correction for multiple comparisons were performed, and nominal / uncorrected p-values ​​were reported directly from Welch's t-test or Mann-Whitney U-test. Specifically, a Bartlett test was first used to check the assumption of homogeneity of variances for a pair of groups. If the p-value of the Bartlett test was ≥ 0.05, a Welch's t-test was performed; otherwise, a Mann-Whitney U-test was performed to obtain nominal p-values.

[0346] All statistical analyses were performed in the Ra language and environment for statistical computing and graphics (version 3.3.1). Unless otherwise specified, all tests were two-sided, and a p-value <0.05 was considered statistically significant.

[0347] Survival time was analyzed by the Kaplan-Meier method. The target event was the death of the animal. Survival time was defined as the time from the date of randomization until the tumor volume reached 2500 mm 3The median survival time (MST), corresponding 95% confidence interval, and life expectancy (ILS) were calculated for each group. Kaplan-Meier curves were generated for each group, and the log-rank test was used to compare survival curves between groups. All data were analyzed using SPSS 18.0. P<0.05 was considered statistically significant.

[0348] result: Tumor volume analysis showed that 4 mg / kg GSK2857916 and 8 mg / kg GSK2857914, either as single agents or in combination with different dosing schedules (G2–G8), demonstrated significant antitumor efficacy in the NCI-H929 xenograft model compared to vehicle (G1). Additionally, GSK2857916 in combination with GSK2857914 (G4 and G6) demonstrated significantly improved antitumor efficacy compared to GSK2857916 alone (G2). Tumor volume increase curves between randomization and end of study are shown in Figure 1. Tumor growth inhibition (TGI) from data collected on day 24 is provided in Table 5.

[0349] [Table 5]

[0350] Survival analysis showed that 4 mg / kg GSK2857916 and 8 mg / kg GSK2857914, either as single agents or in combination with different dosing schedules (G2–G8), significantly extended the lifespan of mice in the NCI-H929 xenograft model compared to vehicle (G1). In addition, GSK2857916 in combination with GSK2857914 (G4 and G6) was able to further extend the lifespan of mice compared to GSK2857916 alone (G2). Kaplan-Meier survival curves for all treatment groups according to study day are shown in Figure 2. The median survival times of mice in each group are provided in Table 6.

[0351] [Table 6]

[0352] [Example 2] A phase 1 / 2 study evaluating the safety and efficacy of belantamab in multiple myeloma (MM). The trial will be conducted to evaluate the safety and efficacy of belantamab in participants with relapsed or refractory multiple myeloma (RRMM).

[0353] Study design Part 1: Dose Escalation Phase in RRMM Part 1 is a Phase 1, open-label study evaluating the safety, tolerability, and clinical activity of escalating doses of single-agent belantamab in participants with RRMM who have received at least three prior lines of therapy to determine the recommended Part 2 dose. Belantamab will be administered twice per cycle, starting at 300 mg IV on days 1 and 15 of 28-day cycles. Dose escalation will be guided by a modified toxicity probability interval to 900 mg and then to a maximum dose of 2000 mg according to the dose escalation plan and as directed by the dose escalation committee. Further intermediate doses will be explored if suggested by the dose escalation committee and agreed upon by the medical monitor and investigator. Progression from one dose level to another and the recommended Part 2 dose are based on the totality of available data from Part 1 of belantamab treatment; the dose escalation committee will consider, among other things, the safety and tolerability of each dose level, available PK and PD data, and preliminary efficacy, and will consequently recommend two dose levels for further characterization in Part 2.

[0354] Participants will be dosed until progressive disease (PD), after which they will have the option to receive treatment with single-agent belantamab mafodotin at 2.5 mg / kg Q3W (Part 1B). Participants who elect to be treated with belantamab mafodotin following their first PD will continue with an end-of-treatment (EOT) visit, after which they will begin belantamab mafodotin treatment and will then continue to be monitored for safety, tolerability, and disease response throughout their belantamab mafodotin treatment course until their next PD. After their second PD, participants will undergo a second EOT belantamab mafodotin visit (if feasible) and will be monitored for safety until at least 70 days after their last belantamab mafodotin dose. Participants who discontinue belantamab mafodotin treatment after their first PD will cease treatment and continue with EOT visits and follow-up safety monitoring.

[0355] Duration of belantamab treatment is until first PD (optionally followed by belantamab mafodotin treatment until second PD), unacceptable toxicity, or other treatment termination criteria. For example, treatment duration may be up to approximately 8 months.

[0356] From cycle 3 onwards, visit frequency will be every 2 weeks. More frequent visits are planned in cycles 1 and 2.

[0357] Part 2: Combinatorial evaluation in RRMM. Part 2 is a two-arm, safety, run-in, randomized, open-label study evaluating the safety, tolerability, and clinical activity of one cycle of belantamab mafodotin-xRd (belantamab mafodotin, treatment x, lenalidomide, and dexamethasone) followed by continued treatment with belantamab-xRd (belantamab, treatment x, lenalidomide, and dexamethasone) in participants with relapsed MM who have received at least one prior line of therapy (2L+). In some instances, treatment x includes a combination of an anti-CD38 antibody, such as daratumumab or isatuximab, and a gamma secretase inhibitor, such as nirogacetat. In some instances, treatment x includes a proteasome inhibitor, such as bortezomib.

[0358] Combination treatment xRd includes lenalidomide (R) and dexamethasone (d). The choice of treatment x is based on data from the ongoing belantamab mafodotin trial and is either a standard or emerging treatment for MM.

[0359] Belantamab dosing will be based on the full set of available Part 1 data. Two different dose levels of belantamab (Arm A and Arm B) will be administered every 4 weeks. More frequent dosing will be used if justified by Part 1 data based on safety, tolerability, PK / PD modeling, or other data. Up to approximately 20 participants evaluable for safety and tolerability will receive one cycle (28 days) of belantamab mafodotin-xRd and then be randomized equally to Arm A and Arm B. A single dose of 1.4 mg / kg belantamab mafodotin will be administered in combination with treatment x, 25 mg or 10 mg lenalidomide once daily (days 1-21 of the cycle), and 40 mg dexamethasone once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥ 75 years or BMI < 18.5).

[0360] Belantamab-xRd dosing will continue until progressive disease (PD).

[0361] Part 2 of this study will evaluate overall safety and tolerability as well as corneal adverse events in 10 participants / arms after three cycles of treatment. Participants will be considered evaluable for safety and tolerability if they have completed at least three cycles of treatment, including one cycle of belantamab mafodotin-xRd followed by two cycles of belantamab-xRd. Participants who do not meet the evaluable definition may be replaced if they discontinue treatment for reasons other than treatment-related adverse events, death, or PD. The totality of data from Parts 1 and 2 will be used to determine the recommended Phase 2 dose of belantamab to be used in Part 3.

[0362] Participants who terminate treatment in Part 2 of the study for reasons other than PD will continue to be followed for progression-free survival and overall survival.

[0363] Treatment will continue until PD, unacceptable toxicity, or any other treatment termination criteria. For example, treatment may last up to approximately 15 months.

[0364] Visit frequency will be every 4 weeks starting with Cycle 3, unless data from Part 1 and the ongoing belantamab mafodotin trial suggest more frequent dosing with belantamab-xRd. More visits are planned during Cycles 1 and 2.

[0365] Part 3: Combination evaluation in newly diagnosed transplant-ineligible multiple myeloma (TI-NDMM). Part 3 is a four-arm, randomized, open-label, phase 2 study evaluating the safety and efficacy of one cycle of belantamab mafodotin-xRd followed by continued belantamab-xRd in participants with TI-NDMM. The cycle length is 4 weeks. Two different doses of belantamab (Arm A and Arm B) are administered every 4 weeks. The belantamab dose level will be selected based on the totality of available data from Parts 1 and 2 and may differ from that administered in Part 2; the selection process by the dose escalation committee will consider the overall safety and tolerability of the combination, available PK / PD data, and evidence regarding the efficacy of different dose levels. Treatment with belantamab-xRd will continue until PD. The doses of belantamab mafodotin and xRd are the same in Arm A and Arm B: a single dose of 1.4 mg / kg belantamab mafodotin is administered in combination with treatment x, 25 mg or 10 mg lenalidomide once daily (days 1-21 of the cycle), and 40 mg dexamethasone once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥ 75 years or BMI < 18.5).

[0366] Part 3 will also test the following outcomes: 1) treatment with continuous dosing of belantamab mafodotin-xRd (Arm C), and 2) treatment with continuous dosing of belantamab mafodotin-xRd in the absence of an initial dose of belantamab mafodotin-xRd (Arm D).

[0367] In Arm C, belantamab mafodotin is administered at a dose of 1.4 mg / kg once every two 28-day cycles (Q8W) in combination with treatment x, 25 mg or 10 mg lenalidomide once daily (days 1-21 of the cycle), and 40 mg dexamethasone once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥ 75 years or BMI < 18.5).

[0368] In arm D, belantamab is administered once per 28-day cycle in combination with treatment x, lenalidomide 25 mg or 10 mg once daily (days 1–21 of the cycle), and dexamethasone 40 mg once daily (days 1, 8, 15, and 22 of the cycle) (or 20 mg if age ≥ 75 years or BMI < 18.5).

[0369] Approximately 80 participants will be randomized 1:1:1:1 to either Arm A, Arm B, Arm C, or Arm D, with the aim of obtaining data on 20 evaluable participants per arm. Participants will be considered evaluable if they have completed at least four cycles of treatment, including one cycle of belantamab mafodotin-xRd followed by three cycles of belantamab-xRd. Participants not meeting the definition of evaluable may be replaced if they discontinue treatment for reasons other than treatment-related adverse events, death, or disease progression.

[0370] The dose of xRd will be the same in all four arms of the study, but the dose and dosing frequency of belantamab mafodotin and belantamab may differ in arms C and D compared with those in arms A and B, respectively.

[0371] The study will end 18 months after a subject's last initial dose. At that time, data collection will stop for all recruited participants who are no longer receiving study treatment, and the study database will be closed. If disease has not progressed at the end of the study, participants who continue to benefit from the investigator-suggested treatment will be transferred to a post-analysis extension study and continue receiving treatment. Under these circumstances, the maximum treatment duration for participants in Part 3 until the data cutoff date for this study will be approximately 24 months.

[0372] Unless data from parts 1 and 2 and from the ongoing belantamab mafodotin trial suggest more frequent dosing with belantamab-xRd, visit frequency will be every 4 weeks, starting with cycle 3. More visits are planned over the course of cycles 1 and 2.

[0373] A summary of study treatments is provided in Table 7.

[0374] [Table 7]

[0375] A summary of treatment doses and dosing frequencies is provided in Table 8. Standard of care (SoC) treatments or emerging MM treatments will also be administered as provided in Table 8.

[0376] [Table 8] JPEG2025540200000011.jpg77168

[0377] Dosage adjustment: Belantamab mafodotin In Arm C of Part 3, continued belantamab mafodotin will be administered at 1.4 mg / kg Q8W and based on new data from ongoing belantamab mafodotin studies, the dose level may be escalated to 1.9 mg / kg Q8W unless data support more frequent dosing. The initial dose will be consistent with Parts A and B, but here the ongoing dose will be selected based on consideration of data from other studies and clinical experience with belantamab mafodotin.

[0378] Medication Adjustments: Lenalidomide and Dexamethasone Lenalidomide will be administered as 25 mg PO daily on days 1 through 21 of each 28-day cycle in participants with a CLcr ≥ 60 mL / min (Cockcroft-Gault). The lenalidomide dose will be reduced by 10 mg / day daily on days 1 through 21 in participants with a CLcr 30-60 mL / min. Lenalidomide will be administered at a fixed dose level, with no adjustments required for body weight or BSA. On days of lenalidomide and belantamab / belantamab mafodotin coadministration, lenalidomide should be administered as close as possible to the end of the 1- to 2-hour washout period after the belantamab / belantamab mafodotin dose. On PK days, lenalidomide should be administered within 6 hours of the end of the washout period after the belantamab / belantamab mafodotin dose. Dexamethasone 40 mg PO weekly on days 1, 8, 15, and 22 of each cycle (or age ≥ 75 years or BMI < 18.5 kg / m 2 In this case, 20 mg will be given.

[0379] Eligibility Criteria Inclusion Criteria: Participants were eligible for inclusion in the study only if all of the following criteria were met:

[0380] 1. Participants are at least 18 years of age or of legal age of consent in the jurisdiction in which the study is conducted.

[0381] 2. Participants have a histologically or cytologically confirmed diagnosis of MM as defined by the International Myeloma Working Group (IMWG).

[0382] Part 1: Participants had received at least three prior lines of anti-myeloma therapy, including immunomodulatory agents, proteasome inhibitors, and anti-CD38 mAbs (unless contraindicated or unavailable), as defined by the International Myeloma Workshop Consensus Panel.

[0383] Part 2: Participants who met all of the following: (1) had undergone autologous stem cell transplantation (ASCT) or were deemed transplant-ineligible; (2) had been previously treated with at least one prior line of MM therapy; (3) had documented disease progression during or after their most recent course of therapy.

[0384] Part 3: Participants who meet both of the following criteria: (1) NDMM with a documented need for treatment according to IMWG criteria; and (2) are not considered candidates for high-dose chemotherapy with ASCT because of: (a) age ≥ 65 years; or (b) age 18–65 years with the presence of comorbid conditions that may have an adverse effect on the tolerability of high-dose chemotherapy with ASCT or who refuse high-dose chemotherapy with ASCT as initial treatment.

[0385] 3. Participants with a history of ASCT are eligible to participate in the study, provided the following eligibility criteria are met: (a) transplant was >100 days prior to screening; and (b) no active infection.

[0386] 4. Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) 0-2.

[0387] 5. Measurable disease defined as at least one of the following: (a) serum M-protein concentration ≥ 0.5 g / dL (≥ 5 g / L); (b) urinary M-protein excretion ≥ 200 mg / 24 hours (≥ 0.2 g / 24 hours); or (c) serum free light chain (FLC) assay: involved FLC level ≥ 10 mg / dL (≥ 100 mg / L) and abnormal serum FLC ratio (< 0.26 or > 1.65).

[0388] 6. Have appropriate organ system function as provided in Table 9:

[0389] [Table 9]

[0390] 7. All prior therapy-related toxicities (as defined by NCI-CTCAE, v5.0, 2017) must be Grade ≤1 at screening, except for alopecia (any grade), neuropathy (grade ≤2), or endocrinopathy (any grade) managed with replacement therapy.

[0391] 8. Participants currently receiving physiological doses of oral steroids (<10 mg / day), inhaled steroids, or ophthalmic steroids are acceptable for the study.

[0392] Exclusion criteria: Participants will be excluded from the study if any of the following criteria apply:

[0393] Medical Condition: 1. Diagnosis of primary AL amyloidosis, active POEMS syndrome, or primary plasma cell leukemia.

[0394] 2. Any serious and / or unstable pre-existing medical condition, psychiatric condition or other condition (including laboratory abnormalities) that may interfere with the participant's safety, consent or compliance with study procedures.

[0395] 3. Participant presents with signs of meningeal or central nervous system involvement of MM.

[0396] 4. Current corneal epithelial lesions, excluding non-fused SPK.

[0397] 5. Current unstable liver or biliary tract disease as assessed by the investigator, defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) is acceptable if the participant meets other enrollment criteria.

[0398] 6. The presence of malignancies other than the disease under study will be excluded, with the exception of any other malignancies in which the participant has been disease-free for more than 2 years and any other malignancies that, in the opinion of the PI and GSK Medical Director, do not affect the assessment of the effect of the study's treatment on the current targeted malignancy (MM). Note: Participants with curatively treated non-melanoma skin cancer will not be excluded.

[0399] 7. Evidence of cardiovascular risk, including any of the following: (a) evidence of current clinically significant untreated arrhythmia, including, but not limited to, clinically significant ECG abnormalities such as second-degree (Mobiz type II) or third-degree AV block; (b) QTcF interval >450 msec (QT interval corrected for heart rate according to the Fridericia formula), and / or hypokalemia, and / or family history of long QT syndrome (for Part 1); (c) history of MI, acute coronary syndrome (including unstable angina), coronary angioplasty, stent placement, or bypass graft surgery, all within 3 months of screening; (d) class III or IV heart failure as defined by the NYHA functional classification system; (e) uncontrolled hypertension.

[0400] 8. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to any drug chemically related to belantamab / belantamab mafodotin or any of the components of the study treatment. History of severe hypersensitivity to other mAbs.

[0401] 9. Active infection requiring antibiotic, antiviral or antifungal treatment.

[0402] 10. Known HIV infection unless the participant can meet all of the following criteria: (a) at least 4 weeks of established ART, HIV viral load <400 copies / mL; (b) CD4+ T cell (CD4+) count ≥350 cells / uL; (c) no history of AIDS-defining opportunistic infection within the past 12 months.

[0403] 11. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess or gastrointestinal obstruction.

[0404] 12. Presence of HBsAg or HBcAb at screening. Note: The presence of HBsAb, indicative of prior vaccination, will not exclude participants.

[0405] 13. A positive hepatitis C antibody test result or a positive hepatitis C RNA test result at screening or within 3 months prior to the first dose of study treatment, unless the participant can meet the following criteria: (a) a negative RNA test; (b) successful antiviral treatment (usually 8 weeks in duration) followed by a negative HCV RNA test after completion of antiviral treatment and a washout period of at least 4 weeks.

[0406] 14. Presence of an active renal condition (infection, need for dialysis, or any other condition that may affect the participant's safety). Participants with isolated proteinuria due to MM are eligible, provided that they meet the criteria given in the Adequate Organ System Function table (Table 9).

[0407] Prior / concomitant therapy: 15. Parts 1 and 2: Refractory to belantamab mafodotin (confirmed PD per IMWG criteria during belantamab mafodotin therapy or within 60 days of completing such therapy). Prior belantamab mafodotin is permitted if discontinued due to toxicity that subsequently resolves. Note: Prior treatment with other anti-BCMA-directed agents is permitted.

[0408] 16. Parts 2 and 3: Discontinuation of prior treatment with lenalidomide due to intolerable AEs.

[0409] 17. Parts 1 and 2: Refractory to prior standard antimyeloma therapy, including lenalidomide, is permitted for other mAbs within 30 days or systemic antimyeloma therapy within 14 days of the first dose of study drug.

[0410] 18. Prior radiation therapy within 2 weeks prior to initiation of study therapy. Participants must have recovered from all radiation-related toxicities, not required corticosteroids, and not had radiation pneumonitis. A 1-week washout is permitted for palliative radiation for non-CNS disease (radiation therapy ≤ 2 weeks).

[0411] 19. Part 3 only: Upfront systemic therapy for MM.

[0412] Note: A rescue course of steroids (defined as dexamethasone ≤ 40 mg or its equivalent per day for up to 4 days (i.e., 160 mg total)) is permitted.

[0413] Note: Local palliative radiation is permitted prior to enrollment, provided it occurs at least 2 weeks before the first dose of study intervention, the participant has recovered from radiation-related toxicity, and the participant has not required corticosteroids for radiation-induced AEs.

[0414] 20. Plasmapheresis within 7 days prior to the first dose of study drug.

[0415] 21. Prior allogeneic transplantation is not permitted.

[0416] 22. Participant has received prior CAR-T therapy with chemotherapy-induced lymphodepletion within 3 months prior to screening.

[0417] 23. Any major surgery (other than bone stabilization surgery) within 2 weeks prior to the first dose, or individuals who have not fully recovered from surgery.

[0418] 24. Prior treatment with a mAb within 30 days prior to receiving the first dose of study drug, or treatment with an investigational agent or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives prior to receiving the first dose of study drug, whichever is longer.

[0419] Other exclusions: 25. Subjects who have received a transfusion of blood products (including platelets or red blood cells), or colony-stimulating factors (including G-CSF, GMCSF, and recombinant erythropoietin) or any thrombopoietin receptor agonist within 2 weeks prior to the first dose of study drug.

[0420] 26. Participants must not have received a live / live-attenuated vaccine within 30 days prior to the first dose of study treatment, while receiving belantamab for at least 70 days following the final study treatment. Examples of live vaccines include, but are not limited to, measles, mumps, rubella, varicella / shingles (chickenpox), yellow fever, rabies, BCG, and typhoid vaccines. Injectable seasonal influenza and COVID-19 vaccines are neither live nor attenuated virus vaccines, and both are acceptable; however, intranasal influenza vaccines (e.g., FluMist) are live-attenuated vaccines and are not acceptable.

[0421] 27. Known, current drug or alcohol abuse.

[0422] Meals and Dietary Restrictions (Parts 2 and 3 only) Refrain from consuming red wine, Seville oranges, grapefruit or grapefruit juice, pomelo, exotic citrus fruits, grapefruit hybrids, or fruit juice starting one day before each dose of bela / belamaf and one day before a study visit independent of belantamab / belantamab mafodotin dosing, until the end of the day of belantamab / belantamab mafodotin dosing or the end of the study visit.

[0423] Drinking water is not permitted until 2 hours after oral medication administration, but drinking water is permitted ad libitum at all other times.

[0424] Lenalidomide capsules should be swallowed whole with water; capsules should not be opened, split, or chewed.

[0425] Lenalidomide should be taken by mouth at approximately the same time each day.

[0426] Lenalidomide capsules contain lactose. The risk-benefit relationship should be evaluated in participants with lactose intolerance.

[0427] Caffeine, alcohol and tobacco (for parts 1, 2 and 3) Participants will refrain from consuming caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours prior to clinical visits on days scheduled for routine PK and pharmacodynamic sample collection throughout the study.

[0428] Participants will abstain from alcohol for 24 hours prior to clinical visits on days scheduled for routine PK and pharmacodynamic sample collection throughout the study period.

[0429] Participants who use tobacco products will be instructed that they will not be allowed to use nicotine-containing products (including nicotine patches and other delivery devices such as vaporizers) while they are in the clinical unit.

[0430] Dose modifications (dose reductions and dose delays) Dose modifications may be made for individual participants based on their safety findings. After Cycle 1, participants may reduce or postpone their belantamab or belantamab mafodotin dose due to toxicity, including corneal events / toxicity.

[0431] If a dose is delayed, participants must wait until the next scheduled dose to resume treatment. In individual cases, if, in the investigator's judgment, waiting for a full cycle to resume treatment after a delay (skipped dose) related to resolved toxicity would be harmful to the participant's health, the investigator should contact the medical monitor to discuss early resumption. Early resumption may only be considered for participants who have recovered from toxicity up to Grade 1. Dosing of belantamab mafodotin in Parts 2 and 3 cannot occur more frequently than every 28 days (+3-day window). In such cases, efficacy and safety assessments should remain every 4 weeks in line with the initial efficacy and safety assessments for the study, which may result in two separate visits (one for dosing and one for disease assessment). Only participants in Part 1B who elect to receive belantamab mafodotin after PD during belantamab therapy in Part 1 will receive belantamab mafodotin every 3 weeks (+3-day window) and undergo efficacy and safety assessments every 3 weeks, as approved by the EMA and FDA. Dose-related assessments will be entered into the electronic case report form (eCRF) under the next scheduled cycle.

[0432] Dose deferrals will be permitted in cases of medical / surgical events or for logistical reasons unrelated to study therapy (e.g., elective surgery, unrelated medical events, participant vacation, and / or holidays, but not a participant decision to defer treatment). The reason for any dose deferral must be documented in the participant's eCRF and medical record and discussed with the medical monitor.

[0433] The maximum dose delay permitted for belantamab or belantamab mafodotin in the absence of evidence of PD or significant investigational product-related toxicity is 16 weeks unless otherwise agreed in writing by the medical monitor.

[0434] In Part 1, the decision to proceed to the next dose level of belantamab (either escalation or deceleration) will be made by the DEC based on safety, tolerability, and preliminary PK data obtained in participants at the preceding dose level.

[0435] [Example 3] Analysis of the effect of varying the drug-to-antibody ratio (DAR) of GSK2857916 on its antitumor activity in vivo. The effect of drug-to-antibody ratio (DAR) on the in vitro and in vivo activity of GSK2857916 was evaluated. Results demonstrate that variation in DAR had no significant effect on in vivo antitumor activity, and that activity was dose-dependent rather than DAR-dependent.

[0436] Experimental procedure Severe combined immunodeficiency (SCID) female mice were 9 weeks old and weighed 15.6–23.8 grams on study day 1. The H929 human plasmacytoma cell line was obtained from the American Type Culture Collection (ATCC). Cells were maintained as exponentially growing suspension cultures in RPMI 1640 medium supplemented with 20% fetal bovine serum, 2 mM glutamine, 50 μM mercaptoethanol, penicillin G sodium 100 units / mL, streptomycin sulfate 100 μg / mL, and gentamicin 25 μg / mL. Tumor cells were cultured in tissue culture flasks in a humidified incubator at 37°C in an atmosphere of 5% CO2 and 95% air.

[0437] H929 cells used for transplantation were harvested during logarithmic growth and resuspended in 50% Matrigel (BD Biosciences) in cold PBS. 1 × 10 cells were transplanted into each mouse. 7 Tumor cells (0.1 ml cell suspension) were injected subcutaneously in the right flank. Twenty days after tumor implantation, which was designated as day 1 of the study, mice bearing established H929 tumors were sorted into four groups (n = 10 / group). Individual tumor volumes ranged from 126 to 288 mm for all groups. 3 The mean tumor volume of the group ranged from 195 to 198 mm 3Dosing was initiated according to the treatment regimen summarized in Table 10, with dosing volumes adjusted to suit individual animal body weights.

[0438] Results and Discussion The results of this study are shown in Figure 3. The results demonstrate that 2 mg / kg GSK2857916 DAR4.1 resulted in significant tumor growth delay but did not result in early tumor regression. Although the same dose of toxin would be expected to be delivered under each condition, 4 mg / kg GSK2857916 DAR2.1 was significantly more potent than 2 mg / kg GSK2857916 DAR4.1. Furthermore, although more toxin would be expected to be delivered under the latter condition, 4 mg / kg GSK2857916 DAR2.1 was more potent than 2 mg / kg GSK2857916 DAR5.7. These results suggest that antibody dose, rather than the DAR of the molecule, is a more important determinant of antitumor activity.

[0439] In summary, varying the DAR from 2.1 to 5.7 had no effect on the antitumor activity of 2 mg / kg GSK2857916. Rather, the administered ADC dose was the primary determinant of antitumor activity, as 4 mg / kg GSK2857916 DAR2.1 was significantly more active than 2 mg / kg GSK2857916 DAR4.1, even though the same amount of toxin was administered in both cases. Thus, this analysis demonstrates that, at a given drug concentration, the effect of varying the DAR on in vivo antitumor activity is not significant.

[0440] [Table 10]

[0441] [Example 4] Evaluation of soluble BCMA (sBCMA) levels in patients with relapsed / refractory multiple myeloma (RRMM) treated with belantamab mafodotin Soluble BCMA (sBCMA) levels were analyzed as an exploratory endpoint in patients enrolled in a Phase III, open-label, randomized trial (DREAMM-3 trial; NCT04162210) evaluating the safety and efficacy of single-agent belantamab mafodotin compared with the pomalidomide-dexamethasone combination in participants with RRMM. Overall, these results suggest that unconjugated belantamab administered in combination with belantamab mafodotin may affect sBCMA levels and therefore improve the efficacy of belantamab mafodotin treatment.

[0442] Experimental procedure Study participants with RRMM were randomized 2:1 to receive either single-agent belantamab mafodotin or the combination of pomalidomide and dexamethasone (pom / dex). Belantamab mafodotin was administered by intravenous (IV) infusion at a dose of 2.5 mg / kg on day 1 of a 21-day cycle, i.e., once every three weeks (Q3W). Pomalidomide was administered daily on days 1–21 of a 28-day cycle, and dexamethasone was administered weekly (i.e., on days 1, 8, 15, and 22 of each 28-day cycle). Participants in both study arms received treatment until disease progression, death, unacceptable toxicity, consent withdrawal, loss to follow-up, or study end, whichever occurred first.

[0443] Serum samples were obtained from patients in both study arms at the following time points for belantamab mafodotin infusion: pre-dose, end of infusion, 2 hours post-infusion, 24 hours post-infusion, 4 days post-infusion, and 8-15 days post-infusion. sBCMA levels in cell supernatants were measured using a validated electrochemiluminescence immunoassay.

[0444] Results and Discussion sBCMA levels are affected by treatment with belantamab mafodotin.Analysis of sBCMA levels in patients treated with belantamab mafodotin versus pom / dex demonstrated differences in sBCMA levels between the two treatment arms, with sBCMA levels being particularly affected by belantamab mafodotin treatment compared with pom / dex treatment. As shown in Figure 4, patients in the highest quartile of baseline sBCMA levels (i.e., before belantamab mafodotin administration) (Q4) had the lowest progression-free survival (PFS) in both treatment arms, indicating a poorer response to treatment. Responses for patients in the highest quartile of baseline sBCMA levels (Q3 and Q4) in the pom / dex arm were virtually identical between the two quartiles (PFS of approximately 4–5 months). However, in the belantamab mafodotin arm, response among patients in the highest quartiles of baseline sBCMA levels (Q3 and Q4) was differentiated between the two quartiles, with observed PFS of approximately 7 months and approximately 15 months for patients in Q4 and Q3, respectively. These data indicate that response to belantamab mafodotin treatment is directly influenced by baseline sBCMA levels, whereas no such effect is observed with pom / dex treatment.

[0445] Belantamab mafodotin binds to sBCMA in patient samples.sBCMA levels were measured at the end of belantamab mafodotin infusion (EOI) in participants in the belantamab mafodotin treatment arm. Patient samples were obtained within 30 minutes following the end of belantamab mafodotin infusion, and sBCMA levels in the samples were measured. Based on the sBCMA levels detected at EOI, it was determined that belantamab mafodotin substantially bound all peripheral sBCMA at the 2.5 mg / kg dose level. See Figure 5, which shows the level of sBCMA reduction from pre-dose belantamab mafodotin to EOI for Cycle 1, Day 1 of belantamab mafodotin treatment, where the x-axis represents pre-dose sBCMA levels and the y-axis represents the difference in sBCMA levels from pre-infusion to EOI. The level of sBCMA reduction at EOI was consistent across cycles (data not shown). In the data presented, the ELISA detected approximately 89% of the bound sBCMA, which is likely the detection limit of the assay, as there is no evidence that the amount of sBCMA exceeded the amount of test drug.

[0446] Although sBCMA undergoes immediate binding following infusion of belantamab mafodotin, sBCMA levels rebound after 24 hours.sBCMA levels were detected to be increased in participants treated with belantamab mafodotin 24 hours after the end of infusion (EOI). While a linear decline in sBCMA levels was observed, an exponential increase in sBCMA levels was observed after 24 hours, suggesting that the rebound in sBCMA was nonlinear with respect to baseline sBCMA levels and resulted in a different pattern from the decline in sBCMA levels (Figure 6). However, the sBCMA levels observed 24 hours after EOI were not solely due to dissociation of sBCMA from belantamab mafodotin, as the half-life of sBCMA is approximately 24 hours, suggesting that the majority of the increase in sBCMA levels was due to fresh shedding from tumor cells. Furthermore, when evaluating sBCMA levels in patients grouped by response to belantamab mafodotin treatment, patients with progressive disease (PD) had the highest baseline sBCMA levels, but there was a large overlap observed in baseline sBCMA levels between responders and non-responders (Figure 7A). The rebound of sBCMA levels after belantamab mafodotin infusion was also greatest for the progressive disease group, but there was a difference observed between responders (including patients with complete response (CR), very good partial response (VGPR), and partial response (PR)) and non-responders (including patients with stable disease (SD) or progressive disease (PD)), and this difference was magnified compared to baseline levels (Figure 7B). This suggests that the presence of sBCMA in the periphery and the rate / level of sBCMA rebound after belantamab mafodotin infusion may have a direct impact on the efficacy of belantamab mafodotin treatment.

[0447] Taken together, these data suggest that removing or binding free sBCMA may be an advantageous strategy to improve the efficacy of belantamab mafodotin.

[0448] [Example 5] In vivo efficacy of belantamab and belantamab mafodotin in the treatment of human multiple myeloma xenograft models in NOG mice A study was conducted to evaluate the in vivo therapeutic efficacy of belantamab (GSK2857914), belantamab mafodotin (GSK2857916), and nirogacestat as single agents and in combination in the treatment of the MM.1S-Luc human multiple myeloma xenograft model in NOG mice.

[0449] Experimental procedure Cell culture. MM.1S-Luc cancer cells were maintained in vitro in RPMI 1640 medium supplemented with 10% fetal bovine serum and 1% sodium pyruvate + 1% L-glutamine + 1% penicillin-streptomycin at 37°C in a 5% CO atmosphere. Exponentially growing cells were harvested and quantified using a cell counter before tumor inoculation.

[0450] Tumor inoculation. Each mouse received 1 x 10 MM.1S-Luc tumor cells (1 x 10 ) in 0.1 mL of PBS for tumor development. 7 Mice were inoculated intravenously via the tail vein with tumor cells. 7 days after tumor cell inoculation, the mice were imaged and randomly assigned to one of seven study groups.

[0451] Treatment administration. Groups of ten (10) mice were dosed by intraperitoneal (ip) administration at the amounts and at the frequencies and durations indicated in Table 11.

[0452] [Table 11]

[0453] Tumor monitoring. Tumor growth was imaged twice weekly by bioluminescence imaging. 15 minutes prior to imaging, mice were subcutaneously injected with 150 mg / kg of D-luciferin (PerkinElmer, Cat. No. 122799). Mice were imaged using a PerkinElmer IVIS Lumina Series III in vivo imaging system.

[0454] result The mean tumor volume curves for the vehicle and treatment groups between randomization and the end of the study are shown in Figure 8, and tumor growth inhibition (TGI) from data collected on day 11 is shown in Table 12. Kaplan-Meier survival curves for all treatment groups according to study are shown in Figure 9, and median survival and Kaplan-Meier statistical analysis are presented in Table 13. These results demonstrate that GSK2857916 as a single agent (Group 2), GSK2857916 in combination with GSK2857914 (Groups 3 and 4), and GSK2857916 in combination with nirogacestat (Group 5) resulted in significant antitumor efficacy in the MM1S-LUC model, with statistically significant differences (p<0.01) compared to the vehicle control group at day 11, with TGI values ​​of 98.87%, 99.19%, 97.88%, and 99.19%, respectively. GSK2857916 in combination with GSK2857914 (Groups 3 and 4) demonstrated the greatest antitumor efficacy over the course of the study across all treatment groups. Furthermore, GSK2857916 in combination with GSK2857914 (Groups 3 and 4) and GSK2857916 in combination with nirogacestat (Group 5) significantly prolonged animal survival (median survival, 54.5, 58.00, and 53.50 days, respectively) compared with the vehicle control group (median survival, 25.00 days).

[0455] [Table 12]

[0456] [Table 13]

[0457] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties, e.g., molecular weight, reaction conditions, and the like, used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0458] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the present disclosure are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. Any numerical values, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0459] As used in the context of the present disclosure as described (particularly in the context of the claims that follow), the terms "a," "an," "the," and similar referents should be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referencing each separate value falling within that range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the disclosure and does not impose limitations on the scope of the disclosure unless specifically claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0460] Groupings of alternative elements or embodiments of the disclosure disclosed herein are not to be construed as limiting. The members of each group may be referred to and claimed individually or in any combination with other members of the group or with other elements found herein. It is anticipated that one or more members of a group may be included in or deleted from the group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification includes the modified group and thus satisfies the written description of the entire Markush group as used in the appended claims.

[0461] Certain embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Of course, variations on these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate reasonable use of such variations by those skilled in the art, and the inventors intend that the present disclosure may be practiced otherwise than as specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure unless otherwise indicated herein or clearly contradicted by context.

[0462] Specific embodiments disclosed herein may be further limited in the claims using the phrases "consisting of" or "consisting essentially of." The transitional phrase "consisting of," when used in a claim, excludes any element, step, or ingredient not specified in the claim, whether as filed or added by amendment. The transitional phrase "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics. Embodiments of the present disclosure so claimed are implicitly or explicitly described and enabled herein.

[0463] It should be understood that the embodiments of the present disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that may be employed are within the scope of the present disclosure. Thus, by way of example, and not of limitation, alternative configurations of the present disclosure may be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that exactly as shown and described.

[0464] Although the present disclosure has been described and illustrated herein by reference to various specific materials, procedures, and examples, it is understood that the disclosure is not limited to the particular combination of materials and procedures selected for that purpose. As one skilled in the art will recognize, many variations in such details can be implied. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the present disclosure being indicated by the following claims. All publications, patents, and patent applications referenced in this application are incorporated herein by reference in their entirety.

Claims

1. 1. A method of treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to said patient a dose of belantamab between about 300 mg and about 2000 mg.

2. 10. The method of claim 1, wherein the dose is about 300 mg, about 900 mg, or about 2000 mg.

3. 3. The method of claim 1 or 2, wherein the patient has been treated with one, two, three, or four lines of therapy for the prior cancer, the lines of therapy for the prior cancer including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

4. 4. The method of any one of claims 1 to 3, wherein the patient is further receiving at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

5. 5. The method of claim 4, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

6. 6. The method of any one of claims 1-5, further comprising administering an induction dose of belantamab mafodotin prior to initiating administration of belantamab, wherein the induction dose of belantamab mafodotin is from about 1.4 mg / kg to about 3.4 mg / kg once during an induction period.

7. 7. The method of claim 6, wherein the induction dose of belantamab mafodotin is about 1.4 mg / kg, about 1.9 mg / kg, about 2.5 mg / kg, or about 3.4 mg / kg once during an induction period.

8. 8. The method of claim 6 or 7, wherein the lead-in period is 4 weeks ± 3 days, and belantamab mafodotin is administered on day 1 of the lead-in period.

9. 9. The method of any one of claims 6 to 8, further comprising administering to the patient during the run-in period at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

10. 10. The method of claim 9, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

11. A method for treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising a first BCMA antagonist and a second BCMA antagonist.

12. 12. The method of claim 11, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

13. 12. The method of claim 11, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is a corresponding unconjugated anti-BCMA antibody.

14. A method for treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient, comprising administering to the patient a therapeutically effective amount of a combination comprising belantamab mafodotin and belantamab.

15. 15. The method of any one of claims 11-14, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

16. 16. The method of claim 15, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

17. A method for treating a disease or disorder responsive to inhibiting or blocking B-cell maturation antigen (BCMA) in a patient previously treated with a first BCMA antagonist, comprising administering a therapeutically effective amount of a second BCMA antagonist to the patient, wherein the patient has discontinued administration of the first BCMA antagonist before initiating administration of the second BCMA antagonist, and the second BCMA antagonist is not the same as the first BCMA antagonist.

18. 18. The method of claim 17, wherein the first and second BCMA antagonists are independently selected from the group consisting of an anti-BCMA antibody or antigen-binding fragment thereof, an anti-BCMA antibody-drug conjugate, a bispecific anti-BCMA antibody or antigen-binding fragment thereof, and a BCMA-targeted chimeric antigen receptor T (CAR T) cell therapy.

19. 18. The method of claim 17, wherein the first BCMA antagonist is an anti-BCMA antibody-drug conjugate and the second BCMA antagonist is the corresponding unconjugated anti-BCMA antibody; or the second BCMA antagonist is an anti-BCMA antibody-drug conjugate and the first BCMA antagonist is the corresponding unconjugated anti-BCMA antibody.

20. 20. The method of claim 19, wherein the first BCMA antagonist is belantamab mafodotin and the second BCMA antagonist is belantamab; or the second BCMA antagonist is belantamab mafodotin and the first BCMA antagonist is belantamab.

21. A method for reducing corneal toxicity in a patient previously treated with belantamab mafodotin, comprising administering a therapeutically effective amount of belantamab to the patient, wherein the patient has discontinued administration of belantamab mafodotin prior to initiating administration of belantamab.

22. 22. The method of any one of claims 17-21, further comprising administering to the patient at least one additional cancer treatment, such as an anti-CD38 monoclonal antibody, a proteasome inhibitor, an immunomodulatory agent, or an anti-PD-1 monoclonal antibody.

23. 23. The method of claim 22, wherein the additional cancer treatment is selected from lenalidomide, dexamethasone, daratumumab, isatuximab, pomalidomide, bortezomib, or a combination thereof, such as lenalidomide and dexamethasone.

24. A method of treating a disease or disorder in a patient, comprising administering a therapeutically effective amount of a combination comprising an antibody-drug conjugate and a corresponding unconjugated antibody.

25. 1. A method of treating a disease or disorder in a patient previously treated with an antibody-drug conjugate, comprising administering to the patient a therapeutically effective amount of a corresponding unconjugated antibody, wherein the patient has discontinued administration of the antibody-drug conjugate prior to initiating administration of the corresponding unconjugated antibody.

26. The method of any one of claims 1 to 25, wherein the disease or disorder is a plasma cell disorder or a B cell disorder.

27. The method of any one of claims 1 to 25, wherein the disease or disorder is a BCMA-expressing cancer.

28. The method of any one of claims 1 to 25, wherein the disease or disorder is multiple myeloma (MM).

29. 29. The method of claim 28, wherein the MM is relapsed and / or refractory MM, newly diagnosed MM, transplant-ineligible MM, or transplant-ineligible newly diagnosed MM.

30. 1. A method of treating cancer in a patient, wherein the patient has a Grade 2 or greater corneal adverse reaction attributable to administration of belantamab mafadotin, the method comprising temporarily discontinuing administration of belantamab mafadotin; administering a therapeutically effective amount of the belantamab to the patient for a lead-in period; and resuming administration of belantamab mafadotin after the lead-in period.

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