COMBINATION THERAPY WITH AN ANTI-BCMA ANTIBODY AND A GAMMA SECRETASE INHIBITOR

Abstract

The present invention describes a method for treating cancer, such as multiple myeloma, involving the combination of an anti-BCMA agent (e.g., an anti-BCMA antibody) and a gamma-secretase inhibitor (e.g., nirogacestat). The invention also relates to dosages, treatment duration, and time intervals between the administration of the anti-BCMA antibody and the gamma-secretase inhibitor.

Description

COMBINATION THERAPY WITH AN ANTI-BCMA ANTIBODY AND A GAMMA INHIBITOR SECRETABA / nfrZLn / Lznz / E / Yii FIELD OF INVENTION The present invention relates to a combination therapy of a pharmaceutically active antigen-binding protein, for example, a monoclonal antibody, and a gamma-secretase inhibitor for use in the treatment of cancer. Particular dosage regimens and methods of administration are also included. BACKGROUND OF THE INVENTION Multiple myeloma (MM) is an incurable malignancy, accounting for 1% of all cancers and 10% of all hematologic malignancies. A variety of drugs and combination therapies have been evaluated and found effective in the treatment of multiple myeloma (National Comprehensive Cancer Network, 2016; Moreau, San Miguel et al., 2017). However, most, if not all, of these patients inevitably relapse (Richardson, Barlogie et al., 2003; Richardson, Barlogie et al., 2006; Jagannath, Barlogie et al., 2008). Drug combinations are emerging for previously treated MM patients, but these regimens may be limited by toxic effects (National Comprehensive Cancer Network, 2016). Agents with novel mechanisms of action are needed that can be combined with existing therapies without increasing severe toxicity. Low surface expression of B-cell maturation antigen (BCMA) on cancer cells, or low expression of soluble BCMA, can limit and impair the efficacy of therapeutic agents due to inadequate binding to BCMA present on the surface of tumor cells. The efficacy of these therapies has been limited by low levels of other target molecules on tumor cells (e.g., CD19, CD20), which are sought as targets by antibodies, antibody-drug conjugates, or chimeric antigen receptor T cells. This allows cancer cells expressing low levels of the target molecule to escape elimination. In the case of BCMA, the short extracellular portion of the molecule is cleaved from the cell surface by the action of gamma-secretase (γ-secretase), a membrane-bound enzyme involved in protein cleavage.This cleavage reduces the density of BCMA in cells such as myeloma cancer cells that express the molecule and results in elevated levels of soluble BCMA (sBCMA) in the serum of patients with certain autoimmune diseases (e.g., systemic lupus erythematosus) and cancer (e.g., multiple myeloma). Currently, there is still a need in the field of immunotherapy for alternative or improved compositions and methods to more efficiently treat autoimmune disease and cancer. BRIEF DESCRIPTION OF THE INVENTION In one aspect of the invention, a combination comprising an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor is provided. In another aspect of the invention, the combination comprises belantamab mafodotin and nirogacestat. In one aspect of the present invention, a combination comprising an anti-BCMA antigen-binding protein and a gamma secretase inhibitor is provided herein for use in cancer treatment. In another aspect of the present invention, a method for treating cancer in a subject in need is provided, comprising administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor. In another aspect of the present invention, a kit for use in cancer treatment is provided herein comprising: (i) an anti-BCMA antigen-binding protein; and (ii) instructions for use when combined with a gamma-secretase inhibitor. DESCRIPTION OF THE FIGURES Figure 1 demonstrates the viability of the L363 myeloma cell line when treated with different doses of a gamma-secretase inhibitor (nirogacestat) in combination with belantamab mafodotin or IgG-MMAF control. Figure 2 demonstrates that the ADCC activity of belantamab mafodotin in combination with nirogacestat was evaluated in the L363 myeloma cell line. Figure 3 shows ADC activity in cell lines expressing BCMA. Figure 4 demonstrates ADCC activity in cell lines expressing BCMA. Figure 5 shows the sBCMA levels after treatment with nirogacestat. Figure 6 shows the levels of BCMA on the cell surface after treatment with nirogacestat. / nfrZLn / Lznz / E / Yii DETAILED DESCRIPTION OF THE INVENTION In one aspect of the present invention, a combination comprising an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor is provided herein for use in the treatment of cancer or other B-cell-mediated diseases or disorders. B-cell disorders can be divided into defects in B-cell development / immunoglobulin production (immunodeficiencies) and excessive / uncontrolled proliferation (lymphomas, leukemias). As used herein, B-cell disorder refers to both types of diseases, and methods for treating B-cell disorders with an antigen-binding protein are provided. Examples of cancers, and in particular B-cell or plasma cell-mediated diseases or antibody-mediated diseases or disorders, include multiple myeloma (MM), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), non-secretory multiple myeloma, latent multiple myeloma, monoclonal gammopathy of undetermined importance (MGUS), solitary plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström macroglobulinemia, plasma cell leukemia, primary amyloidosis (AL), heavy chain disease, systemic lupus erythematosus (SLE), POEMS syndrome / osteosclerotic myeloma, cryoglobulinemia types I and II, light chain deposition disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura (ITP), acute glomerulonephritis, pemphigus and pemphigoid disorders, and acquired epidermolysis bullosa;or any non-Hodgkin lymphoma, B-cell leukemia (NHL), and Hodgkin lymphoma (HL).; In one particular modality, the disease or disorder is selected from the group consisting of multiple myeloma (MM), B-cell leukemia with non-Hodgkin lymphoma (NHL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). In one embodiment of the present invention, the disease is multiple myeloma or B-cell leukemia with non-Hodgkin lymphoma (NHL). In one embodiment of the present invention, the disease is multiple myeloma. / nfrZLn / Lznz / E / Yi In one embodiment of the invention, the cancer may be a hematopoietic (or hematologic, or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as liquid tumors. In one embodiment, the cancer is a B-cell-related cancer, and particularly a cancer expressing BOMA. In a further embodiment, the cancer is a leukemia, such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia. In another embodiment, the cancer is a lymphoma, such as non-Hodgkin lymphoma, Hodgkin lymphoma, and the like. In yet another embodiment, the cancer is a malignant plasma cell neoplasm, such as multiple myeloma, MGUS AL amyloidosis, and Waldenstrom macroglobulinemia. In one scenario, the cancer is multiple myeloma. In another scenario, the cancer is relapsed and / or refractory multiple myeloma. In yet another scenario, the patient with relapsed and / or treatment-resistant multiple myeloma has been previously treated with at least one, at least two, at least three, or at least four therapeutic agents for multiple myeloma. In another scenario, the patient may have had 0, 1, 2, 3, or 4 or more prior lines of treatment before being treated with the combinations described herein. In another scenario, the patient may have relapsed and / or refractory multiple myeloma and has had 0, 1, 2, 3, or 4 or more prior lines of treatment before being treated with the combinations described herein. In another scenario, the patient has been previously treated with at least 3 prior lines, which may include the following: an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and anti-CD38 therapy (e.g., daratumumab). The lines of therapy may be defined by the International Myeloma Workshop (IMWG) consensus panel [Rajkumar, 2011]. In one aspect of the invention as provided herein, the BOMA antigen-binding protein is administered at a specific dose or dose range. Throughout this document, mg / kg refers to milligrams of the therapeutic protein (e.g., antigen-binding protein) per kilogram of the patient's body weight. In one aspect of the invention as provided herein, the BCMA antigen-binding protein is administered at a dose of approximately 0.5–4.0 mg / kg or approximately 1.0–4.0 mg / kg. In one embodiment, the anti-BCMA antigen-binding protein is administered at a dose of approximately 0.5–2.0 mg / kg, approximately 0.5–1.0 mg / kg, approximately 1.0–3.0 mg / kg, or approximately 2.0–4.0 mg / kg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 0.5 to 2.0 mg / kg or approximately 2.0 to 3.5 mg / kg.In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 0.5 mg / kg, approximately 0.95 mg / kg, approximately 1 mg / kg, approximately 1.25 mg / kg, approximately 1.7 mg / kg, approximately 1.9 mg / kg, approximately 2.5 mg / kg, or approximately 3.4 mg / kg. In another modality, the therapeutically effective dose of BOMA antigen-binding protein is a fixed dose rather than expressed in mg / kg. Using a fixed dose could result in an exposure interval similar to that of dosing based on body weight. Fixed dosing can offer the advantage of reducing dosing errors, minimizing drug waste, shortening preparation time, and improving ease of administration. Therefore, in one modality, the fixed dose of BCMA antigen-binding protein is based on a reference body weight (median participant weight) of 70 kg or 80 kg. In one aspect of the invention as provided herein, the gamma-secretase inhibitor is administered at a dose of approximately 25-220 mg. In one embodiment, the gamma-secretase inhibitor is administered at a dose of approximately 50-150 mg. In one embodiment, the gamma-secretase inhibitor is administered at a dose of approximately 50 mg, approximately 100 mg, or approximately 150 mg. In one embodiment, the gamma-secretase inhibitor is administered at a dose of 50 mg, 100 mg, or 150 mg. In one embodiment, the gamma-secretase inhibitor is administered at a dose of 50 mg. In one embodiment, the gamma-secretase inhibitor is administered at a dose of 100 mg. In one embodiment, the gamma-secretase inhibitor is administered at a dose of 150 mg. In one modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 3.4 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 150 mg. In one modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 2.5 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 150 mg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 1.9 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 150 mg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 0.95 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 150 mg. In one modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 3.4 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 100 mg. / nfrZLn / Lznz / E / Yii In one modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 2.5 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 100 mg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 1.9 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 100 mg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 0.95 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 100 mg. In one modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 3.4 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 50 mg. In one modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 2.5 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 50 mg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 1.9 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 50 mg. In an additional modality, the anti-BCMA antigen-binding protein is administered at a dose of approximately 0.95 mg / kg, and the gamma-secretase inhibitor is administered at a dose of approximately 50 mg. In one regimen, the gamma-secretase inhibitor is administered twice daily (BID). In another regimen, the gamma-secretase inhibitor is administered daily. In yet another regimen, the gamma-secretase inhibitor can be administered on a “7-day dose / 14-day no dose” schedule, where the gamma-secretase inhibitor is administered twice daily (BID) on days 1–7 of a 21-day cycle and is not administered from day 8 through day 14. In one aspect of the invention, the gamma-secretase inhibitor can be administered simultaneously or sequentially to the anti-BCMA antigen-binding protein. In one embodiment, the gamma-secretase inhibitor is administered prior to the anti-BCMA antigen-binding protein. For example, in one aspect, the gamma-secretase inhibitor is administered at least 1 hour prior to the anti-BCMA antigen-binding protein. In one aspect of the invention, the anti-BCMA antigen-binding protein is dosed weekly. In a further aspect, the anti-BCMA antigen-binding protein is dosed once every 21 days (i.e., on day 1 of a 21-day cycle). / nfrZLn / Lznz / E / Yii In an additional modality, the dose of the anti-BCMA antigen-binding protein is adjusted to control the peak plasma concentration; for example, the dose is divided and administered one week apart. In one modality, the anti-BCMA antigen-binding protein is administered on Day 1 (half the full dose) and Day 8 (half the full dose) of a 21-day cycle. For example, if the full dose is 3.4 mg / kg, a split-dose regimen might comprise a 1.7 mg / kg dose on Day 1 and another 1.7 mg / kg dose on Day 8 of a 21-day cycle. In another modality, if the full dose is 2.5 mg / kg, a split-dose regimen might comprise a 1.25 mg / kg dose on Day 1 and another 1.25 mg / kg dose on Day 8 of a 21-day cycle. In another modality, if the full dose is 1.9 mg / kg, a “split dose” regimen may comprise a dose of 0.95 mg / kg on day 1 and another dose of 0.95 mg / kg on day 8 of a 21-day cycle. In one modality, approximately 0.95 mg / kg, approximately 1.9 mg / kg, approximately 2.5 mg / kg, or approximately 3.4 mg / kg of an anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one modality, 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of an anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one modality, 0.95 mg / kg of an anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one modality, 1.9 mg / kg of an anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In one modality, 2.5 mg / kg of an anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle. In a further embodiment, a loading dose of the anti-BCMA antigen-binding protein is administered on day 1 of a 21-day cycle, followed by a lower dose in subsequent cycles. Any of the dosages contemplated by the invention as provided herein may be administered in this manner. For example, dose 1 may comprise approximately 3.4 mg / kg of the anti-BCMA antigen-binding protein, and subsequent cycles may utilize a dose of approximately 2.4 mg / kg of the anti-BCMA antigen-binding protein. In one aspect of the invention as described herein, the anti-BCMA antigen-binding protein is an anti-BCMA antibody or fragment thereof, or a CAR-T cell, or an immunoconjugate. In one embodiment, the anti-BCMA antigen-binding protein is an anti-BCMA antibody. In a further embodiment, the anti-BCMA antigen-binding protein is a monoclonal antibody. In a further embodiment, the anti-BCMA antigen-binding protein is humanized. In one aspect of the invention as described herein, the anti-BCMA antigen-binding protein comprises CDR sequences having at least 90% or 95% or 99% sequence identity with CDRH1 according to SEQ ID NO:1; CDRH2 according to / nfrZLn / Lznz / E / Yii SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6. In one embodiment, the anti-BCMA antigen-binding protein comprises CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6. In one embodiment, the anti-BCMA antigen-binding protein comprises a heavy chain variable region (H) according to SEQ ID NO:7; and a light chain variable region (L) according to SEQ ID NO:8. In a further embodiment, the anti-BCMA antigen-binding protein comprises a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NO:10. In one aspect of the invention as described herein, the anti-BCMA antigen-binding protein is further conjugated. In one embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate comprising an antigen-binding protein according to the invention as described herein, which includes, but is not limited to, an antibody conjugated to one or more cytotoxic agents, such as a chemotherapeutic agent, a drug, a growth inhibitor, a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate). In a further embodiment, the anti-BCMA antigen-binding protein is conjugated to a toxin such as an auristatin, e.g., monomethyl-austatin E (MMAE) or monomethyl-austatin F (MMAF). In one embodiment, the anti-BCMA antigen-binding protein is conjugated to monomethyl-austatin F (MMAF). In one modality, the anti-BCMA antigen-binding protein is an immunoconjugate that has the following general structure: ABP-((Ligador)n-Ctx)m where ABP is an antigen-binding protein The linker is either absent or is a split or non-split linker Ctx is any cytotoxic agent described herein n is 0,1,2 or 3 and m is 1,2, 3, 4, 5, 6, 7, 8, 9 or 10. Example linkers include 6-maleimidocaproyl (MC), maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminoenyloxycaronyl (PAB), N-succinimidyl 4-(2-pyridylthio)pentanoate (SPP), N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-caroxylate (SMCC), and N-succinimidyl (4-iodo-acetyl)aminoenzoate (SIAB). / nfrZLn / Lznz / E / Yii In one embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF. In another embodiment, the anti-BCMA antigen-binding protein is an immunoconjugate containing a monoclonal antibody linked to MMAE or MMAF via an MC linker, as illustrated in the following structures: tntjZLn / Lznz / e / Yn In one modality, the anti-BCMA antigen-binding protein is the belantamab antibody. In another modality, the anti-BCMA antigen-binding protein is the belantamab mafodotin immunoconjugate. The antibody-drug conjugates (ADCs) of the present invention are potent anticancer agents designed to enable the targeted delivery of highly potent cytotoxic agents to tumor cells while sparing healthy tissue. Despite the use of tumor-specific antibodies, emerging clinical data with ADCs indicate that adverse events frequently occur before the ADCs have reached their optimal therapeutic dose. As such, although these ADCs are highly active in preclinical tumor models, their therapeutic window in the clinic is narrow, and dosing regimens appear hampered by dose-limiting toxicities that could not always be predicted based on preclinical model data. Therapies that could be combined to synergistically improve therapeutic efficacy without worsening the safety profile would be a major advance in the treatment of cancer patients, particularly with regard to the incidence and severity of treatment-emergent adverse events, such as ocular toxicity. Essentially, a combination with a drug that could improve the efficacy of doses leading to markedly higher overall response rates (ORRs) while having the best benefit-risk profile would lead to a paradigm shift in the management of patients treated with these antigen-binding proteins. The key to achieving the optimal benefit-risk profile depends on the dosage regimen of the therapies. In one aspect of the invention as described herein, the administration of the anti-BCMA antigen-binding protein, for example, after the gammasecretase inhibitor at a given time point and controlled dosing allows the plasma concentration to reach its peak and thus obtain the maximum effect of the addition of the anti-BCMA antigen-binding protein. In one aspect of the invention as described herein, the gammasecretase inhibitor is any of: nirogacestat (PF-03084014); LY3039478 (crenigacestat); CB-103; Tarenflurbil; Semagacestat; RG-4733; EVP-0962; Avagacestat; MK-0752; BMS-906024; or LY450139 (semagacestat). In one embodiment, the gamma-secretase inhibitor is nirogacestat, ((S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1-Himidazol-4-yl)pentanamide), (PF-03084014) which has a chemical structure of: / nfrZLn / Lznz / E / Yii In one aspect of the present invention, a combination comprising an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor is provided for use in preventing and / or reducing ocular toxicity in a patient with cancer, such as multiple myeloma. In one embodiment, ocular toxicity is prevented or reduced compared to a patient treated with the anti-BCMA antigen-binding protein alone (monotherapy). “Prevented” means that the patient does not develop any signs, diagnoses, or symptoms of ocular toxicity. “Reduced” refers to any reduction in the severity or degree of signs, diagnoses, or symptoms of ocular toxicity. “Ocular toxicity” refers to any unintended exposure of a therapeutic agent to eye tissue. Ocular toxicity may include: changes in the corneal epithelium, dry eyes, irritation, redness, blurred vision, photophobia, and / or changes in visual acuity. An eye exam can be performed by an ophthalmologist or optometrist. An eye exam may include one or more of the following: 1. Best corrected visual acuity, 2. Documentation of the manifest refraction and the method used to obtain the best corrected visual acuity, 3. Current lens prescription (if applicable), 4. Measurement of intraocular pressure, 5. Examination of the anterior segment (slit lamp), including fluorescein staining of the cornea and examination of the lens, 6. Fundoscopic examination with dilated pupil, and / or 7. An Ocular Surface Disease Index (OSDI) that is a visual function questionnaire that assesses the impact of possible eye change on vision, function, and health-related quality of life. Experts in the technique are familiar with and implement the methods described above. An ophthalmic examination may be performed before, during, and / or after treatment. In one aspect of the invention, a method is provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor according to the invention as described herein. One aspect of the invention provides a method for treating cancer in a subject in need thereof, comprising administering: i) a therapeutically effective dose of an anti-BCMA antigen-binding protein comprising CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6; and i) nirogacestat. One aspect of the invention provides a method for treating cancer in a subject in need thereof, comprising administering: i) a therapeutically effective dose of an anti-BCMA antigen-binding protein comprising a heavy chain variable region (HV) according to SEQ ID NO:7; and a light chain variable region (LV) according to SEQ ID NO:8; and i) nirogacestat. One aspect of the invention provides a method for treating cancer in a subject in need thereof, comprising administering: i) a therapeutically effective dose of an anti-BCMA antigen-binding protein comprising a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NO:10; and i) nirogacestat. / nfrZLn / Lznz / E / Yii In one aspect of the invention, a method is provided for treating cancer in a subject in need thereof, comprising administering belantamab mafodotin and nirogacestat. In one aspect of the invention, a method is provided for treating cancer in a subject in need thereof comprising administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of belantamab mafodotin and 50 mg, 100 mg or 150 mg of nirogacestat. In one aspect of the invention, a method is provided for treating cancer in a subject in need thereof comprising administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of belantamab mafodotin on day 1 of a 21-day cycle and 50 mg, 100 mg or 150 mg of nirogacestat twice daily (BID). In one aspect of the invention, a method is provided for treating cancer in a subject in need thereof comprising administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg, or 3.4 mg / kg of belantamab mafodotin, wherein half the dose is administered on day 1 and half the dose is administered on day 8 of a 21-day cycle; and 50 mg, 100 mg, or 150 mg of nirogacestat twice daily (BID) on days 1-7 of a 21-day cycle. In one aspect of the invention, a method is provided for treating multiple myeloma in a subject in need thereof comprising administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of belantamab mafodotin on day 1 of a 21-day cycle and 50 mg, 100 mg or 150 mg of nirogacestat twice daily (BID). In one aspect of the invention, a method is provided for treating multiple myeloma in a subject in need thereof, comprising administering 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg of belantamab mafodotin, wherein half the dose is administered on day 1 and half the dose is administered on day 8 of a 21-day cycle; and 50 mg, 100 mg or 150 mg of nirogacestat twice daily (BID) on days 1-7 of a 21-day cycle. In one aspect, a combination comprising an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor is provided according to the invention as described herein for use in cancer treatment. In one aspect, a combination is provided comprising a therapeutically effective dose of an anti-BCMA antigen-binding protein comprising CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6; and nirogacestat, for use in the treatment of cancer. In one aspect, a combination is provided comprising a therapeutically effective dose of an anti-BCMA antigen-binding protein comprising a heavy chain variable region (VH) according to SEQ ID NO:7; and a light chain variable region (VL) according to SEQ ID NO:8; and nirogacestat, for use in the treatment of cancer. In one aspect, a combination is provided comprising a therapeutically effective dose of an anti-BCMA antigen-binding protein comprising a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NQ:10; and nirogacestat, for use in the treatment of cancer. In one aspect, a combination comprising belantamab mafodotin and nirogacestat is provided for use in the treatment of cancer. In one aspect, a combination comprising belantamab mafodotin and nirogacestat is provided for use in the treatment of cancer, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg and nirogacestat is administered at 50 mg, 100 mg or 150 mg. In one aspect, a combination comprising belantamab mafodotin and nirogacestat is provided for use in the treatment of cancer, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg on day 1 of a 21-day cycle and nirogacestat is administered at 50 mg, 100 mg or 150 mg twice daily (BID). In one aspect, a combination comprising belantamab mafodotin and nirogacestat is provided for use in the treatment of cancer, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg and half the dose is administered on day 1 and half the dose is administered on day 8 of a 21-day cycle; and nirogacestat is administered at 50 mg, 100 mg or 150 mg twice daily (BID) on days 1-7 of a 21-day cycle. In one aspect, a combination comprising belantamab mafodotin and nirogacestat is provided for use in the treatment of multiple myeloma, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg and nirogacestat is administered at 50 mg, 100 mg or 150 mg. In one aspect, a combination comprising belantamab mafodotin and nirogacestat is provided for use in the treatment of multiple myeloma, wherein belantamab mafodotin is administered at 0.95 mg / kg, 1.9 mg / kg, 2.5 mg / kg or 3.4 mg / kg and half the dose is administered on day 1 and half the dose is administered on day 8 of a 21-day cycle; and nirogacestat is administered at 50 mg, 100 mg or 150 mg twice daily (BID) on days 1-7 of a 21-day cycle. In one aspect, a combination is provided for use in the preparation or manufacture of a drug for treating cancer, wherein the combination comprises an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor, according to the invention as described herein. / nfrZLn / Lznz / E / Yii In one aspect, a kit is provided for use in cancer treatment, comprising: (i) an anti-BCMA antigen-binding protein according to the invention as described herein; and (ii) instructions for use when combined with a gamma-secretase inhibitor according to the invention as described herein. In one aspect, a kit is provided for use in cancer treatment, comprising: (i) a gamma-secretase inhibitor according to the invention as described herein; and (ii) instructions for use when combined with an anti-BCMA antigen-binding protein according to the invention as described herein. In one aspect, a kit is provided for use in cancer treatment, comprising: (i) an anti-BCMA antigen-binding protein according to the invention as described herein; (i) a gamma-secretase inhibitor according to the invention as described herein; and, (iii) instructions for use. In one aspect of the invention, a method is provided for preventing ocular toxicity in a cancer patient, such as multiple myeloma, comprising administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor. In one aspect of the invention, a method is provided for reducing ocular toxicity in a cancer patient, such as multiple myeloma, comprising administering a therapeutically effective dose of an anti-BCMA antigen-binding protein and a gamma-secretase inhibitor. DEFINITIONS The term “combination” described herein refers to at least two therapeutic agents. As used herein, the term “therapeutic agent” means a substance that produces a desired effect in a tissue, system, animal, mammal, human, or other subject. In one modality, the combination may contain an additional therapeutic agent, such as, for example, an additional cancer therapeutic agent. In one modality, the additional cancer therapeutic agent is an immunomodulatory imide drug (IMiD) such as thalidomide, lenalidomide, pomalidomide, apremilast, or other thalidomide analogues. / nfrZLn / Lznz / E / Yii The administration of the combinations of the invention may be advantageous over the individual therapeutic agents in that the combinations may provide one or more of the following improved properties compared to the individual administration of a single therapeutic agent alone: ​​i) a greater anticancer effect than the most active individual agent, ii) synergistic or highly synergistic anticancer activity, iii) a dosing protocol that provides enhanced anticancer activity with a reduced side effect profile, iv) a reduction in the toxic effect profile, v) an increase in the therapeutic window, or vi) an increase in the bioavailability of one or both therapeutic agents. The combinations described herein may be in the form of a pharmaceutical composition. A “pharmaceutical composition” contains a combination described herein and one or more pharmaceutically acceptable carriers, diluents, or excipients. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not harmful to the recipient. In one modality, each therapeutic agent in a combination is individually formulated in its own pharmaceutical composition, and each of the pharmaceutical compositions is administered to treat cancer. In this modality, each of the pharmaceutical compositions may have the same or different carriers, diluents, or excipients. The anti-BCMA antigen-binding proteins in the combinations described herein are useful in the treatment or prevention of cancers. The anti-BCMA antigen-binding proteins described herein can bind to human BCMA, including, for example, human BCMA containing the amino acid sequence with GenBank accession number Q02223.2, or genes encoding for human BCMA that have at least 90 percent homology or at least 90 percent identity to it. The term antigen-binding protein, as used herein, refers to antibodies, antibody fragments, and other protein constructs capable of binding to human BCMA. The antigen-binding proteins of the present invention may comprise heavy-chain variable regions and light-chain variable regions of the invention that can be formatted into the structure of a natural antibody or functional fragment or equivalent thereof. Therefore, an antigen-binding protein of the invention may comprise the VH regions of the invention formatted into a full-length antibody, a (Fab')2 fragment, a Fab fragment, or equivalent thereof (such as scFV, bi-, tri-, or tetra-bodies, Tandabs, etc.), when paired with a suitable light chain. The antibody may be an IgG1, IgG2, IgG3, or IgG4; or IgM; IgA, IgE, or IgD; or a modified variant thereof.Therefore, the constant domain of the antibody heavy chain / nfrZLn / Lznz / E / Yii can be selected. The light chain constant domain can be either a kappa or lambda constant domain. Additionally, the antigen-binding protein can comprise modifications of all classes, for example, IgG dimers, Fe mutants that no longer bind to Fe receptors or mediate C1q binding. The antigen-binding protein can also be a chimeric antibody of the type described in WO86 / 01533, comprising an antigen-binding region and a non-immunoglobulin region. In another aspect, the antigen-binding protein is selected from the group consisting of dAb, Fab, Fab', F(abj2), Fv, diabody, tribody, tetrabody, minibody, and minibody. In one aspect of the present invention, the antigen-binding protein is a humanized or chimeric antibody. In a further aspect, the antibody is humanized. In one aspect, the antibody is a monoclonal antibody. Chimeric antigen receptors (CARs) have been developed as artificial T cell receptors to generate novel T cell specificities without the need for binding to antigen-MHC peptide complexes. These synthetic receptors contain a target-binding domain that is associated with one or more signaling domains via a flexible linker on a single fusion molecule. The target-binding domain is used to direct the T cell to specific targets on the surface of pathogenic cells, and the signaling domains contain molecular machinery for T cell activation and proliferation. The flexible linker, which spans the T cell membrane (i.e., forms a transmembrane domain), allows visualization of the CAR's target-binding domain on the cell membrane.CARs have successfully enabled T cells to be redirected against antigens expressed on the surface of tumor cells of various malignant neoplasms including lymphomas and solid tumors (Jenaet al. (2010) Blood, 116(7):1035-44). In one modality, the anti-BCMA antigen-binding protein is an antibody that has an enhanced effector function of antibody-dependent cell-mediated cytotoxicity (ADCC). The term Effector Function, as used herein, is intended to refer to one or more of antibody-dependent cell-mediated cytotoxicity (ADCC) responses, complement-dependent cytotoxicity (CDC)-mediated responses, Fe-mediated phagocytosis, and antibody recycling via the FcRn receptor. Gamma-secretase is a multi-subunit, integral membrane protease complex that cleaves single-pass transmembrane proteins within its transmembrane domain. The gamma-secretase complex plays a role in the processing of a variety of substrates, including Notch, CD44, cadherins, and ephrin B2, as well as the cleavage of amyloid precursor protein into beta-amyloid peptide, which is implicated in Alzheimer's disease. The gamma-secretase complex is also known to cleave B-cell maturation antigen (BCMA). Examples of gamma-secretase inhibitors (GSIs) include small molecules, peptidomimetic compounds, or gamma-secretase-specific binding proteins. A GSI can target any one or more of the proteins in the gamma-secretase complex, provided that the gamma-secretase cleavage activity is reduced compared to uninhibited gamma-secretase.In certain modalities, gamma-secretase activity is reduced by at least approximately 80%. Assays to measure gamma-secretase activity are known in the art (see, for example, Laurent et al., 2015). For example, the soluble BOMA level can be a surrogate measure of gamma-secretase activity. The gamma-secretase inhibitor nirogacestat is rapidly absorbed, with a median time to peak Cmax (Tmax) values ​​of 1 to 2.5 hours. Nirogacestat is slowly eliminated, with a terminal half-life ranging from 22.6 to 38.6 hours in cancer patients. Nirogacestat exposure generally increases proportionally to the dose between 20 and 330 mg BID (twice-daily dosing). After repeated BID administration, steady state is achieved by day 8, and the median accumulation ratio ranges from 1.18 to 2.84. “CDRs” are defined as the amino acid sequences of the complementarity-determining region of an antigen-binding protein. These are the hypervariable regions of the immunoglobulin heavy and light chains. There are three heavy-chain CDRs (or CDR regions) and three light-chain CDRs in the variable portion of an immunoglobulin. Therefore, CDR, as used herein, refers to all three heavy-chain CDRs, all three light-chain CDRs, all heavy- and light-chain CDRs, or at least two CDRs. The terms “VH” and “VL” are used herein to refer to the heavy-chain variable region and the light-chain variable region, respectively, of an antigen-binding protein. Throughout this specification, amino acid residues in variable domain sequences and full-length antibody sequences are numbered according to the Kabat numbering convention. Similarly, the terms “CDR,” “CDRL1,” “CDRL2,” “CDRL3,” “CDRH1,” “CDRH2,” and “CDRH3” used in the Examples follow the Kabat numbering convention (see Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, National Institutes of Health (1991)). Alternative numbering conventions exist for CDR sequences, for example, those established in Chothia et al. (1989) Nature 342: 877–883. Other numbering conventions for CDR sequences are also available to a skilled user, including the AbM (University of Bath) and Contact (University College London) methods. / nfrZLn / Lznz / E / Yii LIST OF SEQUENCES SEQ. ID. NO. 1 -CDRH1 NYWMH SEQ. ID. NO. 2: CDRH2 ATYRGHSDTYYNQKFKG SEQ. ID. NO. 3: CDRH3 GAIYDGYDVLDN SEQ. ID. NO. 4: CDRL1 SASQDISNYLN tntjZLn / Lznz / e / Yn SEQ. ID. NO. 5: CDRL2 YTSNLHS SEQ. ID. NO. 6: CDRL3 QQYRKLPWT SEQ. ID. NO. 7: Variable location of the cadena pesada QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTY YNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS SED. ID. NO. 8: Variable location of the cadena ligera DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR SEQ. ID. NO. 9: Región de cadena pesada QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTY YNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFL FPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK SEQ. ID. NO. 10: light chain region DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYAC EVTH QG LSS PVTKS FN RG EC EXAMPLES Justification of the combination Gamma-secretase is an integral membrane protein complex with protease activity against single-pass transmembrane proteins within its transmembrane domain (Wolfe, 2010). One of the substrates for gamma-secretase is BCMA, the target of belantamab mafodotin and belantamab. BCMA is unusual among gamma-secretase substrates because it does not require additional proteolytic steps either before or after gamma-secretase cleavage for the release of the extracellular domain of BCMA. This cleavage results in a soluble form of BCMA (“sBCMA”). Gamma-secretase is the sole enzyme responsible for the production of sBCMA, and inhibition of gamma-secretase reduces sBCMA and increases cell surface levels of BCMA in plasma cells, both in vitro and in vivo.In the context of multiple myeloma, sBCMA levels are elevated in patients with multiple myeloma and correlate with the percentage of plasma cells in the bone marrow (Sánchez, 2018). Furthermore, sBCMA has been linked to the immunodeficiency observed in patients with multiple myeloma. Gamma-secretase inhibition could potentially enhance the mechanisms of action of belantamab mafodotin and belantamab by increasing cell surface expression and improving the internalization of BCMA by multiple myeloma cells. Increased cell surface BCMA expression would increase the amount of belantamab mafodotin and belantamab bound to the cell surface, potentially enhancing the ADCC mechanism of belantamab mafodotin and belantamab through increased FcyR interaction and immune cell recruitment. Additionally, blocking BCMA clearance could potentially increase the internalization of bound belantamab mafodotin and belantamab, allowing for improved delivery of the cys-mcMMAF toxin to multiple myeloma cells. / nfrZLn / Lznz / E / Yii In preclinical experiments, using a panel of multiple myeloma and lymphoma cell lines with different levels of BCMA expression, a broad synergy was observed with the combined treatment of nirogacestat and belantamab mafodotin and belantamab, in assays designed to measure ADC and ADCC activity. Example 1 In the example shown in Figure 1, the L363 multiple myeloma cell line was pretreated with four different concentrations of nirogacestat (PF-03084014) for 24 hours, then treated with a dosage interval of belantamab mafodotin or controls for an additional 72 hours, and cell viability was measured. Belantamab, nirogacestat alone, isotype antibody conjugate (IgG-MMAF), or the combination of IgG-MMAF and nirogacestat had no effect on cell viability. However, a maximum 1000-fold change in EC50 was observed with the combination of nirogacestat and belantamab mafodotin compared to belantamab alone. Example 2 In the example shown in Figure 2, the ADCC activity of belantamab mafodotin in combination with nirogacestat was evaluated. L363 cells were pretreated with different concentrations of nirogacestat for 24 hours, exposed to belantamab, and FcyR docking was assessed using a modified Jurkat cell line. The EC50 for FcyR docking was increased 10-fold by the combination of nirogacestat and belantamab, compared to belantamab alone. Similar logarithmic changes were observed with the combination of nirogacestat and belantamab mafodotin in 19 additional multiple myeloma and lymphoma cell lines with evidence of belantamab mafodotin activity. Therefore, preclinical data support the mechanistic rationale for enhancing belantamab mafodotin activity through gamma-secretase inhibition. Although similar results were observed with other gamma-secretase inhibitors, nirogacestat appears to have a better safety profile than other gamma-secretase inhibitors that have been evaluated. This improved safety profile may allow for once-daily dosing of nirogacestat, in contrast to many other GSIs. Furthermore, once-daily dosing of nirogacestat may improve target coverage by continuously preventing BCMA cleavage due to more consistent drug exposure. Specifically, the incidence of dose-limiting diarrhea and elevated liver enzymes does not appear to be as high compared to other gamma-secretase inhibitors, such as RO4929097 or MK-0752 (Messersmith, 2015).Additionally, unlike other gamma-secretase inhibitors (e.g., semagacestat), there does not appear to be an increased incidence of secondary primary malignancies (SPMs) or treatment-emergent infections with nirogacestat (Messersmith, 2015) (Henley, 2014). Since gamma-secretase inhibitors are pharmacologically and functionally diverse (Ran, 2017), these contrasting findings among different gamma-secretase inhibitors could be related to differences in target-binding affinity and drug penetration into organ-specific stem cell compartments. Example 3 In this prophetic example, the synergistic activity of belantamab mafodotin and nirogacestat will be studied in the clinic: Group 1: Two doses of belantamab mafodotin (i.e., 1.9 mg / kg and 2.5 mg / kg) will be evaluated in up to five separate dosing cohorts in combination with up to three different doses of nirogacestat administered on a continuous BID schedule. The primary objective of Group 1 is to obtain confirmatory evidence that the belantamab mafodotin dose of 1.9 mg / kg when combined with 50 mg, 100 mg or 150 mg of nirogacestat BID has at least a similar Overall Response Rate (ORR”) to the belantamab mafodotin monotherapy dose used in the common control arm. The 2nd and 3rd dosing cohorts in Group 1 can only be initiated in parallel provided that the safety profile at the initial doses of belantamab mafodotin (1.9 mg / kg) and nirogacestat (100 mg BID) is determined to be acceptable. Where the overall safety profile of the initial doses (cohort 1) is determined to be unfavorable, nirogacestat will be reduced to 50 mg BID and the belantamab mafodotin dose will remain unchanged at 1.9 mg / kg (i.e., dose cohort -1). Further reductions in the dose intensity of nirogacestat to < 50 mg BID are not permitted, as the pharmacodynamic activity (i.e., γ-secretase inhibition) of the drug at these dose levels is believed to be low. If the 2.5 mg / kg dose of belantamab mafodotin is determined to have an unacceptable safety profile when administered as a single infusion, one option is to initiate a mezanine dose level of 2.5 mg / kg administered as two equally divided doses of 1.25 mg / kg on day 1 and day 8 of a Q3W program, as this dosing schedule would provide a -25% reduction in peak concentration while maintaining the same exposure (AUC) during a cycle compared to Q3W dosing, which could positively impact the benefit / risk of belantamab mafodotin. The maximum evaluable doses in Group 1 are 2.5 mg / kg of belantamab mafodotin and 150 mg BID of nirogacestat (cohort 4). Cohort 4 will be initiated only if the overall safety profile of cohort 3 (i.e., 2.5 mg / kg of belantamab mafodotin and 100 mg BID of nirogacestat) is determined to be acceptable. For the avoidance of doubt, the acronym BID refers to twice-daily dosing. / nfrZLn / Lznz / E / Yii Group 1 Dosage Levels The second and third dosage levels can be initiated simultaneously. Dose Level belantamab mafodotin IV Q3 weeks nirogacestat 4 2.5 mg / kg 150 mg 3 2.5 mg / kg 100 mg 2 1.9 mg / kg 150 mg 1 (initial dose) 1.9 mg / kg 100 mg -1 1.9 mg / kg 50 mg Group 2: This is an optional group that will only be initiated if the primary objective of Group 1 has been met (as described above), and if the overall benefit-risk profile of 1.9 mg / kg belantamab mafodotin in combination with 50 mg, 100 mg or 150 mg BID of nirogacestat is determined to be acceptable. The primary objective of Group 2 is to identify a single dose of belantamab mafodotin < 1.9 mg / kg that, when in combination with 50 mg, 100 mg, or 150 mg BID of nirogacestat, has a higher ORR than the belantamab mafodotin monotherapy dose in the common control arm. One or more separate dosing cohorts may be evaluated at belantamab mafodotin dose levels < 1.9 mg / kg in Group 2 in combination with a specific dose of nirogacestat. These lower dose levels of belantamab mafodotin will be selected for evaluation based on pharmacokinetics (PK), treatment-emergent adverse events (TEAEs), and ORR findings. Group 3: This is an optional group that will only be initiated if 3.4 mg / kg is the monotherapy dose of belantamab mafodotin in the common control arm, and the safety / tolerability of 2.5 mg / kg of belantamab mafodotin administered as a single infusion on day 1, or as two equally divided doses on day 1 and day 8, is favorable. The primary objective of Group 3 is to demonstrate that the 3.4 mg / kg dose of belantamab mafodotin, when administered as two equally divided doses of 1.7 mg / kg on Day 1 and Day 8 (to attenuate the risk of potentially Cmax-driven toxicities), when in combination with a specific dose of nirogacestat, has a higher ORR than the common control arm, but with an overall safety profile that is not markedly worse than 3.4 mg / kg of belantamab mafodotin monotherapy within the platform trial. If potentially overlapping grade 3 toxicities related to nirogacestat occur more than 7 days after the start of treatment, it may be possible to administer nirogacestat on a 7-day dose / 14-day no-dose twice-daily dosing schedule, especially since pharmacodynamically active plasma levels of nirogacestat are reached rapidly, usually < 48 hours after the start of treatment, and steady-state plasma levels of nirogacestat are reached by day 8 on a twice-daily dosing schedule. Example 4 For this secondary, prophetic study, a lower starting dose of belantamab mafodotin of 0.95 mg / kg was selected. Clinical activity of belantamab mafodotin monotherapy at a dose <1.9 mg / kg is expected to be low based on the Bayesian logistic regression model (BLRM) of FTIH trial data, although a small number of participants were treated at doses lower than 1.9 mg / kg (e.g., n=3 at 0.48 mg / kg, n=4 at 0.96 mg / kg). While the starting dose of 0.95 mg / kg is expected to have only limited efficacy on its own, nirogacestat is expected to potentiate the effect of belantamab mafodotin. This lower starting dose is expected to have an improved safety profile compared to the higher doses used in belantamab mafodotin monotherapy trials; for example, corneal toxicity events are likely to be associated with a lower rate of grade 2 events compared to higher doses of 2.5 mg / kg and 3.4 mg / kg, which are associated with higher levels of predicted hematological response. Three cohorts will be administered 0.95 mg / kg of belantamab mafodotin, but with different doses of nirogacestat: • 0.95 mg / kg of belantamab mafodotin in combination with 50 mg BID of nirogacestat • 0.95 mg / kg of belantamab mafodotin in combination with 100 mg BID of nirogacestat • 0.95 mg / kg of belantamab mafodotin in combination with 150 mg BID of nirogacestat. Nirogacestat will be administered intermittently, for example, on a 7-day on / 14-day off schedule, or continuously. Clinical trial results will provide the data to support the optimal dosing regimen required for maximum risk-benefit. / nfrZLn / Lznz / E / Yii Example 5: ADC Activity To determine whether belantamab mafodotin exhibits synergistic combination with GSIs in an antibody-dependent cytotoxicity assay, multiple myeloma and lymphoma cell lines expressing BCMA were analyzed in a 3-day cell proliferation assay. After loading cells into 384-well plates, nirogacestat was dosed at fixed concentrations of 2.5 µM, 0.25 µM, 0.025 µM, and 0.0025 µM. The plates were incubated overnight and then dosed with a 10-point dose titration of belantamab mafodotin from 9.9 µg / ml to 0.00025 µg / ml for each fixed concentration of nirogacestat. After 3 days of incubation, cell viability was assessed using a Promega Cell-titer Glo and analyzed using GraphPad software. Representative data are shown in Figure 3. The results show a 3-fold change in potency with belantamab mafodotin in combination with nirogacestat. Example 6: ADCC Activity The ADCC activity of belantamab, the MMAF-unconjugated form of belantamab mafodotin, was evaluated in combination with nirogacestat using the Promega Jurkat ADCC assay. BCMA-expressing multiple myeloma and cancerous lymphoma cell lines were plateped in a 1536-well format at a 10:1 ratio (Jurkat effector cells: cancer cells). Immediately thereafter, the cells were dosed with nirogacestat at fixed concentrations of 2.5 µM, 0.25 µM, 0.025 µM, and 0.0025 µM. Belantamab was then titrated through each fixed concentration from 9.9 µg / ml to 0.00025 µg / ml. The plates were incubated for 24 hours and evaluated for ADCC activity after the addition of Promega Bio-glo. Data were analyzed using Graphpad software. Representative data for ADCC activity are shown in Figure 4. Example 7: sBCMA levels Soluble BCMA was detected in the supernatant of 3-day-old cell cultures from BCMA-expressing cell lines after treatment with nirogacestat at fixed concentrations of 2.5 μM, 0.25 μM, 0.025 μM, and 0.0025 μM using the R&D Human sBCMA ELISA Kit. A dose-dependent loss of sBCMA was detected after nirogacestat treatment (Figure 5). / nfrZLn / Lznz / E / Yii Example 8: Detection of BCMA levels on cell surface Cell surface levels of BCMA were examined by flow cytometry after a 3-day treatment with nirogacestat at fixed concentrations of 2.5 μM, 0.25 μM, 0.025 μM, and 0.0025 μM in BCMA-expressing cell lines. BCMA levels were compared to isotype controls. A dose-dependent increase in cell surface BCMA was detected. Representative data for cell surface BCMA levels are shown in Figure 6.

Claims

NOVELTY OF THE INVENTION Having described the present invention as above, the following claims are considered novel and are therefore claimed as property: CLAIMS 1. A method for treating cancer comprising administering: i) a therapeutically effective dose of an anti-BCMA antibody comprising CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6; and i) nirogacestat.

2. The method of claim 1, wherein the anti-BCMA antibody comprises a heavy chain variable region (HV) according to SEQ ID NO:7; and a light chain variable region (LV) according to SEQ ID NO:

8.

3. The method of claim 1, wherein the anti-BCMA antibody comprises a heavy chain (H) according to SEQ ID NO:9 and a light chain (L) according to SEQ ID NO:

10.

4. A method for treating cancer comprising administering belantamab mafodotin and nirogacestat.

5. The method of claim 4, wherein belantamab mafodotin is administered at 0.95 mg / kg.

6. The method of claim 4, wherein belantamab mafodotin is administered at 1.9 mg / kg.

7. The method of claim 4, wherein belantamab mafodotin is administered at 2.5 mg / kg.

8. The method of claim 4, wherein belantamab mafodotin is administered at 3.4 mg / kg. / nfrZLn / Lznz / E / Yii 9. The method of claim 4, wherein nirogacestat is administered at 50 mg.

10. The method of claim 4, wherein nirogacestat is administered at 100 mg.

11. The method of claim 4, wherein nirogacestat is administered at 150 mg.

12. The method of claims 4-11, wherein belantamab mafodotin is administered on day 1 of a 21-day cycle and nirogacestat is administered twice daily (BID).

13. The method of claims 4-11, wherein half of the belantamab mafodotin dose is administered on day 1 and the other half of the belantamab mafodotin dose is administered on day 8 of a 21-day cycle; and nirogacestat is administered twice daily (BID) on days 1-7 of a 21-day cycle.

14. The method of claim 13, wherein a first dose of 1.7 mg / kg of belantamab mafodotin is administered on day 1 and a second dose of 1.7 mg / kg of belantamab mafodotin is administered on day 8.

15. The method of claim 13, wherein a first dose of 1.25 mg / kg of belantamab mafodotin is administered on day 1 and a second dose of 1.25 mg / kg of belantamab mafodotin is administered on day 8.

16. The method of claim 13, wherein a first dose of 0.95 mg / kg of belantamab mafodotin is administered on day 1 and a second dose of 0.95 mg / kg of belantamab mafodotin is administered on day 8.

17. The method of any preceding claim, wherein the cancer is multiple myeloma.

18. The method of any preceding claim, wherein the cancer is relapsed and / or refractory multiple myeloma.

19. The method of claim 17, wherein the patient has received at least one prior line of cancer treatment.

20. The method of claim 17, wherein the patient has received at least 3 prior lines of cancer treatment including an immunomodulatory drug (IMiD), a proteasome inhibitor (Pl) and anti-CD38 treatment.

21. A combination comprising i) a therapeutically effective dose of an anti-BCMA antibody comprising CDRH1 according to SEQ ID NO:1; CDRH2 according to SEQ ID NO:2; CDRH3 according to SEQ ID NO:3; CDRL1 according to SEQ ID NO:4; CDRL2 according to SEQ ID NO:5; and CDRL3 according to SEQ ID NO:6; and, II) nirogacestat for use in the treatment of cancer.

22. A combination comprising belantamab mafodotin and nirogacestat for use in the treatment of cancer.

23. A combination comprising belantamab mafodotin and nirogacestat for use in the manufacture of a drug for the treatment of cancer.

24. A kit comprising: (i) belantamab mafodotin; and (ii) instructions for use when combined with nirogacestat.

25. A kit comprising: (i) nirogacestat; and (ii) instructions for use when combined with belantamab mafodotin.

26. A method for preventing or reducing ocular toxicity associated with a patient treated with a cancer therapeutic product comprising administering a therapeutically effective amount of belantamab mafodotin and nirogacestat.

27. The method of claim 26, wherein ocular toxicity is reduced or prevented compared to a patient treated with belantamab mafodotin alone.

28. The method of claim 26 or 27, wherein ocular toxicity is at least one of the following: changes in the corneal epithelium, dry eyes, irritation, redness, blurred vision, photophobia, or changes in visual acuity. / nfrZLn / Lznz / E / Yi 29. The method of claims 26-28, wherein ocular toxicity is measured by at least one of the following methods: best corrected visual acuity, documentation of manifest refraction and the method used to obtain best corrected visual acuity, current lens prescription (if applicable), intraocular pressure measurement, anterior segment examination (slit lamp) including fluorescein staining of the cornea and examination of the lens, dilated pupil fundoscopic examination, or an ocular surface disease index (OSDI).