Combination therapy with nirogacestat and BCMA-directed therapy and uses thereof

Abstract

To provide a combination therapy with nirogacestat and BCMA-directed therapy and uses thereof.SOLUTION: The present disclosure provides methods of treating cancer or light chain amyloidosis in a subject in need thereof, comprising administering to the subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy and the uses thereof. In one aspect, Form A of nirogacestat dihydrobromide is administered to the subject before, concurrently with, or after administering the BCMA-directed therapy.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present disclosure provides a method of treating cancer (e.g., multiple myeloma) or light chain amyloidosis in a subject in need thereof, the method comprising administering to the subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy. [Background technology]

[0002] background B-cell maturation antigen (BCMA) is a substrate for gamma secretase (Laurent et al., Nat Commun. 2015 Jun 11, 6:7333). Gamma secretase is a multisubunit protease complex that cleaves single-pass transmembrane proteins at residues within their transmembrane domains. BCMA expression is associated with several cancers, including hematological cancers such as multiple myeloma. There is a need for improved strategies to target diseases such as cancer or light chain amyloidosis, and for methods to improve existing therapeutics that target BCMA. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Laurent et al., Nat Commun.2015 Jun 11,6:7333 Summary of the Invention

[0004] Summary of the Invention In one aspect, the present disclosure relates to a method of treating cancer in a subject in need thereof, comprising administering to the subject a combination therapy comprising an effective amount of nirogacestat dihydrobromide Form A and a BCMA-directed therapy. In one aspect, the present disclosure relates to the use of a combination therapy comprising an effective amount of nirogacestat dihydrobromide Form A and a BCMA-directed therapy in the treatment of cancer in a subject in need thereof.

[0005] In one aspect, the cancer is characterized by insufficient expression of BCMA.

[0006] In another embodiment, the cancer is characterized by a detectable level of soluble BCMA in a serum sample from the subject.

[0007] In another embodiment, the cancer is a blood cancer. In one embodiment, the blood cancer is multiple myeloma. In one embodiment, the cancer is selected from the group consisting of Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML).

[0008] In another aspect, the present disclosure relates to a method of treating light chain amyloidosis, comprising administering to a subject in need thereof a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In another aspect, the present disclosure relates to the use of a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy in the treatment of light chain amyloidosis in a subject in need thereof.

[0009] In one aspect, Form A of nirogacestat dihydrobromide reduces shedding of BCMA from the surface of BCMA-positive cells in a subject.

[0010] In another embodiment, Form A of nirogacestat dihydrobromide reduces the level of soluble BCMA in a subject.

[0011] In another embodiment, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive cancer cells in a subject.

[0012] In another embodiment, form A of nirogacestat dihydrobromide increases the BCMA density of membrane-bound BCMA on the surface of BCMA-positive cancer cells in a subject.

[0013] In another embodiment, Form A of nirogacestat dihydrobromide enhances the activity of a BCMA-directed therapy in a subject.

[0014] In another embodiment, Form A of nirogacestat dihydrobromide allows a lower dose of a BCMA-directed therapy to be administered to a subject compared to the amount of the BCMA-directed therapy administered alone, while maintaining an equivalent level of efficacy (e.g., one or more treatment endpoints discussed below (e.g., CR, nCR, sCR, MRD)). In some embodiments, Form A of nirogacestat dihydrobromide allows a lower or the same dose of a BCMA-directed therapy to be administered to a subject compared to the amount of the BCMA-directed therapy administered alone, while achieving a high level of efficacy (e.g., one or more treatment endpoints discussed below (e.g., CR, nCR, sCR, MRD)).

[0015] In one embodiment, a subject is administered nirogacestat Form A at a dose of about 20 mg to about 220 mg. In another embodiment, a subject is administered nirogacestat Form A at a dose of about 20 mg to about 220 mg once or twice daily. In another embodiment, a subject is administered nirogacestat Form A at a dose of about 20 mg to about 220 mg once or twice daily for at least one week.

[0016] In one embodiment, Form A of nirogacestat dihydrobromide is administered to a subject prior to, concurrently with, or after administering a BCMA-directed therapy to the subject.

[0017] In one embodiment, the subject is administered the combination therapy as a first line therapy.

[0018] In one embodiment, the subject having cancer or light chain amyloidosis who is being treated with Form A of nirogacestat dihydrobromide and a BCMA-directed therapy has previously been treated for the cancer or light chain amyloidosis. In some embodiments, the subject having cancer or light chain amyloidosis who is being treated with Form A of nirogacestat dihydrobromide and a BCMA-directed therapy has previously been treated for the cancer or light chain amyloidosis with one or more of a proteasome inhibitor, immunomodulatory therapy, immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), stem cell transplant, chemotherapy, targeted therapy (e.g., an XPO1 inhibitor), or a BCMA-directed therapy that is not in combination with nirogacestat.

[0019] In one embodiment, the subject is administered Form A of nirogacestat dihydrobromide orally and the BCMA-directed therapy is administered intravenously or subcutaneously. In one embodiment, the BCMA-directed therapy comprises one or more of allogeneic chimeric antigen receptor T-cell therapy, autologous chimeric antigen receptor T-cell therapy, immunotherapy (e.g., monoclonal antibody therapy), antibody-drug conjugate therapy, or bispecific antibody therapy with dual specificity against BCMA and an immune-related target (e.g., CD3). In another embodiment, the BCMA-directed therapy comprises at least allogeneic chimeric antigen receptor T-cell therapy. In another embodiment, the BCMA-directed therapy comprises at least autologous chimeric antigen receptor T-cell therapy. In another embodiment, the BCMA-directed therapy comprises at least immunotherapy (e.g., monoclonal antibody therapy). In another embodiment, the BCMA-directed therapy comprises at least antibody-drug conjugate therapy. In another embodiment, the BCMA-directed therapy comprises at least bispecific antibody therapy with dual specificity against BCMA and an immune-related target (e.g., CD3).

[0020] In one embodiment, Form A of nirogacestat dihydrobromide is administered in tablet form.

[0021] In one embodiment, the subject is a human. [Brief explanation of the drawings]

[0022] [Figure 1] FIG. 1 is the powder X-ray diffraction pattern ("XRPD") corresponding to crystalline Form A.

[0023] [Figure 2] FIG. 2 is a thermogravimetric analysis thermogram ("TGA") corresponding to Form A crystals.

[0024] [Figure 3] FIG. 3 is a differential scanning calorimetry thermogram ("DSC") corresponding to Form A crystals. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description of the Invention I. Overview B-cell maturation antigen (BCMA) is expressed on the surface of plasma cells and regulates their survival. In multiple myeloma, BCMA is widely expressed on malignant cells but rarely on normal tissues. BCMA can be released from the cell surface as soluble BCMA (sBCMA), which can be detected in the serum of patients with several different types of B-cell malignancies. Serum BCMA levels can correlate with disease activity and overall survival in these patients.

[0026] Gamma secretase is involved in cleaving membrane-bound BCMA and shedding its extracellular domain into serum as soluble BCMA. BCMA shedding can pose challenges for BCMA-targeted therapeutics. Some of the challenges include: First, BCMA shedding can reduce surface BCMA expression on cancer cells, thereby reducing target binding sites for BCMA-targeted therapeutics. Second, BCMA shedding can generate a soluble BCMA sink that binds to BCMA-targeted therapeutics and prevents these agents from binding to membrane-bound BCMA expressed on cancer cells. Third, soluble BCMA molecules can also capture circulating BCMA ligands, such as B-cell activating factor (BAFF) and proliferation-inducing ligand (APRIL), preventing them from stimulating BCMA expressed on the surface of B cells and plasma cells, thereby resulting in a defective humoral immune response in patients.

[0027] The use of gamma secretase inhibitors to prevent BCMA shedding can enhance the efficacy of BCMA-directed therapies that target pathological B cells that express BCMA. The present disclosure provides a method of treating cancer or light chain amyloidosis in a subject in need thereof, comprising administering to the subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In one embodiment, the cancer is characterized by insufficient expression of BCMA.

[0028] In another embodiment, the cancer is characterized by detectable levels of sBCMA.

[0029] In another embodiment, the cancer is a blood cancer. In one embodiment, the blood cancer is multiple myeloma. In one embodiment, the cancer is selected from the group consisting of Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML).

[0030] In one aspect, the present disclosure provides a method of treating light chain amyloidosis in a subject in need thereof, comprising administering to the subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. II. Definition

[0031] To facilitate understanding of the disclosure set forth herein, several terms and phrases are defined below.

[0032] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0033] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The terms "a" (or "an"), and "one or more" and "at least one" may be used interchangeably herein. In certain embodiments, the term "a" or "an" means "single." In other embodiments, the term "a" or "an" includes "two or more" or "plurality."

[0034] Furthermore, "and / or," as used herein, should be interpreted as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" used in phrases such as "A, B, and / or C" is intended to encompass each of the following embodiments: "A, B, and C," "A, B, or C," "A or C," "A or B," "B or C," "A and C," "A and B," "B and C," "A (alone)," "B (alone)," and "C (alone)."

[0035] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein, e.g., in reference to a mammalian subject, such as a human subject.

[0036] The terms "treating" or "treatment" or "treat" or "alleviating" or "alleviating" and the like refer to a therapeutic measure that cures, slows, reduces symptoms, and / or halts the progression of a diagnosed pathological condition or disorder. Thus, those in need of treatment include those already diagnosed with the disorder or suspected of having the disorder. In certain embodiments, a subject has been successfully "treated" for cancer, e.g., multiple myeloma, according to the methods of the present invention if the patient exhibits one or more of the following: a reduction in the number of cancer cells or the complete absence of cancer cells; a reduction in one or more symptoms associated with the particular cancer; a decrease in morbidity and mortality; an improvement in quality of life; an increase in progression-free survival (PFS); disease-free survival (DFS); overall survival (OS); metastasis-free survival (MFS); complete response (CR); near complete response (nCR); stringent complete response (sCR); minor response (MR); minimal residual disease (MRD); partial response (PR); very good partial response (VGPR); stable disease (SD); a decrease in progressive disease (PD); an increase in time to progression (TTP); or any combination thereof. In some embodiments, the International Myeloma Working Group (IMWG) Unified Response Criteria for Multiple Myeloma criteria can be used to determine whether an effective amount of Form A of nirogacestat dihydrobromide in combination with a BCMA-directed therapy meets any of these particular endpoints (e.g., CR, nCR, sCR, MRD).

[0037] A CR for subjects with multiple myeloma can be negative immunofixation in serum and urine, and disappearance of any soft tissue plasmacytoma and less than 5% plasma cells in the bone marrow.

[0038] An sCR for a subject with multiple myeloma can be a CR plus a normal serum-free light chain (FLC) ratio and the absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence.

[0039] VGPR in subjects with multiple myeloma can be serum and urinary M-protein detectable by immunofixation but not by electrophoresis, or a greater than 90% decrease in serum M-protein plus urinary M-protein levels of less than 100 mg / 24 hours.

[0040] A PD for subjects with multiple myeloma can be a greater than 25% increase from the lowest response value of any one or more of the following: Serum M components and / or (absolute increase must be >0.5 g / dL), Urinary M components and / or (absolute increase must be greater than 200 mg / 24 hours), For patients without measurable serum and urinary M-protein levels only, the difference between involved and uninvolved FLC levels. The absolute increase must be greater than 10 mg / dL. · percentage of bone marrow plasma cells (absolute percentage must be greater than 10%), - the development of a new bone lesion or soft tissue plasmacytoma, or a clear increase in the size of an existing bone lesion or soft tissue plasmacytoma, Development of hypercalcemia (corrected serum calcium >11.5 mg / dL or 2.65 mmol / L) attributable solely to a plasma cell proliferative disorder.

[0041] For subjects with multiple myeloma, PR can be a greater than 50% reduction in serum M protein and a greater than 90% reduction in urinary M protein after 24 hours or a reduction to less than 200 mg / 24 hours.If serum and urinary M protein are not measurable, a greater than 50% reduction in the difference between involved and uninvolved FLC levels may be required instead of the M protein standard.If serum and urinary M protein are not measurable and serum-free photoassay is also not measurable, a greater than 50% reduction in plasma cells may be required instead of M protein if the baseline bone marrow plasma cell rate is greater than 30%.In addition, a greater than 50% reduction in the size of soft tissue plasmacytomas may also be required if present at baseline.

[0042] SD in subjects with multiple myeloma may not meet the criteria for CR, VGPR, PR, or PD.

[0043] A subject with multiple myeloma who tests MRD negative has less than one myeloma cell per million bone marrow cells.

[0044] The term "administering," "administering," or "administration" refers to delivering one or more compounds or compositions to a subject parenterally, enterally, or topically. Examples of parenteral administration include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Examples of enteral administration include, but are not limited to, oral, inhalation, intranasal, sublingual, and rectal administration. Examples of topical administration include, but are not limited to, transdermal and vaginal administration.

[0045] The term "effective amount" refers to an amount of a compound, preparation, substance, or composition described herein that is effective to achieve a particular biological result.

[0046] The term "therapeutically effective amount" includes an amount of a compound that, when administered, is sufficient to prevent or alleviate to some extent one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to that amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or clinician.

[0047] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott (incorporated herein by reference). Williams & Wilkins: Philadelphia, PA, 2005, Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004.

[0048] The term "insufficient expression of BCMA" as used throughout this disclosure refers to a lower than maximal expression level of BCMA or equivalent receptor density of BCMA on cancer cells, as demonstrated by the fact that administration of a gamma secretase inhibitor, e.g., nirogacestat dihydrobromide, can increase the expression level of BCMA or equivalent receptor density on cancer cells of a subject.

[0049] The term "first-line therapy," as used throughout this disclosure, refers to a treatment regimen generally accepted or recommended by a medical institution or regulatory agency, e.g., the U.S. Food and Drug Administration or the European Medicines Agency, for the initial treatment of a subject's cancer or light chain amyloidosis. Subjects with cancer or light chain amyloidosis may have previously experienced and / or are currently being treated for one or more unrelated diseases or disorders (e.g., anxiety).

[0050] Whenever an embodiment is described herein using the phrase "comprising," it is understood that other similar embodiments that are described using the phrase "consisting of" and / or "consisting essentially of" are also included. III. Form A of nirogacestat dihydrobromide

[0051] The present disclosure relates to combination therapies comprising Form A of nirogacestat dihydrobromide (dihydrobromide salt of (S)-2-(((S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide of Formula (I). [ka]

[0052] Form A of nirogacestat dihydrobromide is characterized by an XRPD pattern with peaks at 8.8±0.2 degrees, 9.8±0.2 degrees, and 23.3±0.2 degrees two-theta.

[0053] In one embodiment, crystalline form A of nirogacestat dihydrobromide is anhydrous. In another embodiment, crystalline form A of nirogacestat dihydrobromide has a melting point of about 254°C.

[0054] In another embodiment, Form A of nirogacestat dihydrobromide is characterized by an XRPD pattern having peaks at 8.8±0.2, 9.8±0.2, and 23.3±0.2 degrees two-theta, as measured with Cu Kα radiation. In another embodiment, Form A of nirogacestat dihydrobromide is characterized by an XRPD pattern having peaks at 8.8±0.2, 9.8±0.2, 23.3±0.2, 25.4±0.2, 28.0±0.2, and 29.3±0.2 degrees two-theta, as measured with Cu Kα radiation. In another embodiment, Form A of nirogacestat dihydrobromide is characterized by an XRPD pattern having peaks at 8.8±0.2 degrees, 9.8±0.2 degrees, 20.0±0.2 degrees, 23.3±0.2 degrees, 25.4±0.2 degrees, 28.0±0.2 degrees, 29.3±0.2 degrees, and 32.5±0.2 degrees two-theta, as measured with Cu Kα radiation.

[0055] In another embodiment, Form A of nirogacestat dihydrobromide is characterized by an XRPD pattern substantially as shown in Figure 1. In another embodiment, Form A of nirogacestat dihydrobromide is characterized by a TGA profile substantially as shown in Figure 2. In another embodiment, Form A is characterized by a DSC profile substantially as shown in Figure 3.

[0056] Form A of nirogacestat dihydrobromide can be administered to a subject via oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, and infusion), rectal, intranasal, topical, or transdermal (e.g., via the use of a patch) routes. In one embodiment, Form A of nirogacestat dihydrobromide can be administered to a subject via oral, parenteral (e.g., subcutaneous, intravenous, intramuscular, intrasternal, and infusion), rectal, intranasal, topical, or transdermal (e.g., via the use of a patch) routes. In one embodiment, Form A of nirogacestat dihydrobromide is administered orally. In one embodiment, Form A of nirogacestat dihydrobromide is provided in tablet form.

[0057] In one embodiment, the pharmaceutical composition comprises Form A of nirogacestat dihydrobromide. In one embodiment, the pharmaceutical composition is an oral tablet comprising Form A of nirogacestat dihydrobromide and a pharmaceutically acceptable carrier. In one embodiment, the tablet contains about 10 mg to about 400 mg of Form A of nirogacestat dihydrobromide. In one embodiment, the tablet contains about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg , about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of Form A of nirogacestat dihydrobromide. In one embodiment, the tablet contains about 10 mg of Form A of nirogacestat dihydrobromide. In one embodiment, the tablet contains about 20 mg of Form A of nirogacestat dihydrobromide. In one embodiment, the tablet contains about 50 mg of Form A of nirogacestat dihydrobromide. In one embodiment, the tablet contains about 100 mg of Form A of nirogacestat dihydrobromide. In one embodiment, the tablet contains about 150 mg of nirogacestat dihydrobromide Form A. In one embodiment, the tablet contains about 200 mg of nirogacestat dihydrobromide Form A. In one embodiment, the tablet contains about 220 mg of nirogacestat dihydrobromide Form A.

[0058] For oral administration, known carriers can be included in the pharmaceutical composition. For example, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate, and glycine can be used with various disintegrating agents such as starch (preferably corn, potato, or tapioca starch), methylcellulose, alginic acid, and certain complex silicates, and can be included in tablets with granulating binders such as polyvinylpyrrolidone, sucrose, gelatin, and acacia. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc are often useful for tableting purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules. Preferred materials in this regard include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof, as well as various sweeteners or flavoring agents, dyes or pigments, and, if necessary, emulsifying and / or suspending agents.

[0059] For parenteral administration, solutions containing nirogacestat can be prepared in either sesame or peanut oil, aqueous propylene glycol, or sterile water or saline. Aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. These aqueous solutions are suitable for intravenous injection. Oily solutions are suitable for intraarticular, intramuscular, and subcutaneous injection. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. IV B-cell maturation antigen (BCMA)-directed therapy

[0060] In some embodiments, the BCMA-directed therapy includes, but is not limited to, one or more of allogeneic chimeric antigen receptor T-cell therapy, autologous chimeric antigen receptor T-cell therapy, immunotherapy (e.g., monoclonal antibody therapy), antibody-drug conjugate therapy, or bispecific antibody therapy with dual specificity for BCMA and an immune-related target (e.g., CD3). In some embodiments, the BCMA-directed therapy may include at least allogeneic chimeric antigen receptor T-cell therapy. In some embodiments, the BCMA-directed therapy may include at least autologous chimeric antigen receptor T-cell therapy. In some embodiments, the BCMA-directed therapy may include at least immunotherapy (e.g., monoclonal antibody therapy). In some embodiments, the BCMA-directed therapy may include at least an antibody-drug conjugate. In some embodiments, the BCMA-directed therapy may include at least a bispecific antibody therapy with dual specificity for BCMA and an immune-related target (CD3). In some embodiments, the BCMA-directed therapy includes any combination of the therapies listed above.

[0061] In some embodiments, the BCMA-directed therapy can be formulated for intravenous or subcutaneous administration in a liquid dosage form. V. Treatment Method

[0062] In one embodiment, an effective amount of Form A of nirogacestat dihydrobromide in combination with a BCMA-directed therapy is administered to treat cancer in a subject. In some embodiments, the cancer is a hematological cancer. In one embodiment, the hematological cancer is multiple myeloma. In some embodiments, the cancer is selected from the group consisting of Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML).

[0063] In some embodiments, a subject with cancer (e.g., multiple myeloma) exhibits a complete response after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In some embodiments, a subject with cancer (e.g., multiple myeloma) exhibits a near-complete response after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In some embodiments, a subject with cancer (e.g., multiple myeloma) exhibits a stringent complete response after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In some embodiments, a subject with cancer (e.g., multiple myeloma) exhibits a minor response after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In some embodiments, a subject with cancer (e.g., multiple myeloma) exhibits a partial response after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In some embodiments, subjects with cancer (e.g., multiple myeloma) show very good partial responses after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy. In some embodiments, subjects with cancer (e.g., multiple myeloma) show stable disease after administration of an effective amount of Form A of nirogacestat dihydrobromide and a BCMA-directed therapy.

[0064] In one embodiment, an effective amount of Form A of nirogacestat dihydrobromide in combination with a BCMA-directed therapy is administered to treat light chain amyloidosis in a subject.

[0065] In one embodiment, Form A of nirogacestat dihydrobromide is administered to a subject with cancer (e.g., multiple myeloma) or light chain amyloidosis prior to, concurrently with, or after administering a BCMA-directed therapy to the subject.

[0066] In one embodiment, a subject with cancer (e.g., multiple myeloma) or light chain amyloidosis is administered the above-described combination therapy as a first-line therapy. In such an embodiment, the subject with cancer (e.g., multiple myeloma) or light chain amyloidosis may have previously experienced and / or currently been treated for one or more unrelated diseases or disorders (e.g., anxiety).

[0067] In some embodiments, a combination of an effective amount of Form A of nirogacestat and a BCMA-directed therapy can be used in combination with one or more other known cancer treatments. In some embodiments, the other known cancer treatments include, but are not limited to, radiation therapy, chemotherapy, stem cell transplantation, immunotherapy (e.g., monoclonal antibodies, e.g., monoclonal antibodies against CD38), proteasome inhibitors, immunomodulatory therapy, hormone therapy, photodynamic therapy, targeted therapy (e.g., XPO1 inhibitors), or a combination thereof. In some embodiments, the other known cancer treatments can be immunomodulatory therapy, proteasome inhibitors, immunotherapy (e.g., monoclonal antibodies, e.g., monoclonal antibodies against CD38), or a combination thereof. In some embodiments, the other known cancer treatments can be a combination of immunomodulatory therapy, proteasome inhibitors, and immunotherapy (e.g., monoclonal antibodies, e.g., monoclonal antibodies against CD38).

[0068] In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis. In some embodiments, the subject with cancer (e.g., multiple myeloma) or light chain amyloidosis who is being treated with Form A of nirogacestat dihydrobromide and a BCMA-directed therapy has previously been treated for the cancer or light chain amyloidosis with one or more of a proteasome inhibitor, immunomodulatory therapy, immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), stem cell transplant, chemotherapy, targeted therapy (e.g., an XPO1 inhibitor), a BCMA-directed therapy not in combination with nirogacestat, and combinations thereof. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering a proteasome inhibitor to the subject. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering an immunomodulatory therapy to the subject. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38) to the subject. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation to the subject. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering chemotherapy to the subject. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering a targeted therapy (e.g., an XPO1 inhibitor) to the subject.In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor and an immunomodulatory therapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor and an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering a proteasome inhibitor to the subject in combination with chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering a proteasome inhibitor to the subject in combination with chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering a proteasome inhibitor to the subject in combination with targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having been previously treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor and a BCMA-directed therapy that is not in combination with nirogacestat.In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy and an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation to the subject and administration of an immunomodulatory therapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy and chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy and a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administration of immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38) to the subject. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38) and chemotherapy.In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38) and a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38) and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a stem cell transplant and administration of chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation to the subject and administration of a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation to the subject and administration of a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of chemotherapy and a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having been previously treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of chemotherapy and a BCMA-directed therapy that is not in combination with nirogacestat.In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a targeted therapy (e.g., an XPO1 inhibitor) and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunomodulatory therapy, and an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administering to the subject a combination of a proteasome inhibitor and an immunomodulatory therapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunomodulatory therapy, and chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunomodulatory therapy, and a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunomodulatory therapy, and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administration of a combination of a proteasome inhibitor and immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38).In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), and chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), and targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has previously been treated for cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy and an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy, an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), and chemotherapy. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy, an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), and a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of an immunomodulatory therapy, an immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having been previously treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administering to the subject a combination of immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38) and a BCMA-directed therapy that is not in combination with nirogacestat.In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), chemotherapy, and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of immunotherapy (e.g., a monoclonal antibody, e.g., a monoclonal antibody against CD38), a targeted therapy (e.g., an XPO1 inhibitor), and a BCMA-directed therapy that is not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administering to the subject a combination of chemotherapy and a targeted therapy (e.g., an XPO1 inhibitor). In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administering to the subject a combination of chemotherapy and a BCMA-directed therapy not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having previously been treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising stem cell transplantation and administering to the subject a combination of targeted therapy (e.g., an XPO1 inhibitor) and a BCMA-directed therapy not in combination with nirogacestat. In one embodiment, the subject has cancer or light chain amyloidosis after having been previously treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of chemotherapy, a targeted therapy (e.g., an XPO1 inhibitor), and a BCMA-directed therapy that is not in combination with nirogacestat.In one embodiment, the subject has cancer or light chain amyloidosis after having been previously treated for the cancer (e.g., multiple myeloma) or light chain amyloidosis by a method comprising administering to the subject a combination of a proteasome inhibitor, an immunomodulatory therapy, an immunotherapy (e.g., a monoclonal antibody such as a monoclonal antibody against CD38), and a BCMA-directed therapy that is not in combination with nirogacestat.

[0069] In one embodiment, Form A of nirogacestat dihydrobromide prevents cleavage of membrane-bound BCMA, thereby reducing shedding of BCMA from the surface of BCMA-positive cells in a subject. In some embodiments, Form A of nirogacestat dihydrobromide reduces shedding of BCMA from the surface of BCMA-positive cells in a subject by about 5% to about 100% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces shedding of BCMA from the surface of BCMA-positive cells in a subject by about 10% to about 100% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces shedding of BCMA from the surface of BCMA-positive cells in a subject by about 15% to about 95% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 20% to about 90% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 25% to about 85% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 30% to about 80% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 35% to about 75% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 40% to about 70% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 45% to about 65% compared to not administering Form A of nirogacestat.In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 50% to about 60% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces BCMA shedding from the surface of BCMA-positive cells in a subject by about 50% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces shedding of BCMA from the surface of BCMA-positive cells in a subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to not administering Form A of nirogacestat dihydrobromide. In some embodiments, Form A of nirogacestat dihydrobromide reduces shedding of BCMA from the surface of BCMA-positive cells in a subject by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to not administering Form A of nirogacestat dihydrobromide.

[0070] In another embodiment, Form A of nirogacestat dihydrobromide prevents cleavage of membrane-bound BCMA, thereby reducing the level of sBCMA in a subject. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 5% to about 100% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 10% to about 100% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 15% to about 95% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 20% to about 90% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 25% to about 85% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 30% to about 80% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 35% to about 75% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 40% to about 70% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 45% to about 65% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 50% to about 60% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 50% compared to not administering Form A of nirogacestat.In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% compared to not administering Form A of nirogacestat. In some embodiments, Form A of nirogacestat dihydrobromide reduces the level of sBCMA in a subject by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% compared to not administering Form A of nirogacestat.

[0071] In one embodiment, soluble B cell maturation antigen (sBCMA) is measured from cell supernatants using an immunoassay (e.g., ELISA), HPLC-MS or MS. In one embodiment, soluble B cell maturation antigen (sBCMA) is measured from a subject's serum sample using an immunoassay (e.g., ELISA), HPLC-MS or MS.

[0072] In one embodiment, serum and supernatant samples from a subject can be analyzed by BCMA enzyme-linked immunosorbent assay (ELISA) to determine the subject's soluble BCMA level. In one embodiment, serum or supernatant samples can be diluted or concentrated, and BCMA ELISA assays can be performed according to the manufacturer's protocol. ELISA plates can be analyzed using a plate reader.

[0073] In another embodiment, serum and supernatant samples from a subject can be analyzed by high performance liquid chromatography coupled to a mass spectrometer (HPLC-MS) to determine the level of soluble BCMA in the subject. In one embodiment, serum and supernatant samples from a subject can be analyzed by mass spectrometry (MS) to determine the level of soluble BCMA in the subject.

[0074] In another embodiment, subjects administered Form A of nirogacestat dihydrobromide exhibit a greater number of BCMA-positive multiple myeloma cells after administration (post-administration) compared to the number of BCMA-positive multiple myeloma cells before administration (baseline), i.e., the percentage of BCMA-positive multiple myeloma cells after administration is greater compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 5% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 25% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 30% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 35% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 40% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 45% to about 99% compared to baseline, hi some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 50% to about 99% compared to baseline.In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 60% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 65% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 70% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 75% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 80% to about 99% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 90% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 90% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 30% to about 90% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 40% to about 90% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 50% to about 90% compared to baseline, hi some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 60% to about 90% compared to baseline.In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 70% to about 90% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 80% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 80% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 30% to about 80% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 40% to about 80% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 50% to about 80% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 60% to about 80% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 70% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 70% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 30% to about 70% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 40% to about 70% compared to baseline, hi some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 50% to about 70% compared to baseline.In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 60% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 60% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 30% to about 60% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 40% to about 60% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 50% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 50% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 30% to about 50% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 40% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 20% to about 40% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 10% to about 30% compared to baseline. In some embodiments, Form A of nirogacestat dihydrobromide increases the percentage of BCMA-positive multiple myeloma cells after administration by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99%.

[0075] In one embodiment, the percentage of BCMA-positive multiple myeloma cells is measured by gating negative or positive using flow cytometry. In one embodiment, multiple myeloma cells are extracted from a subject. In one embodiment, multiple myeloma cells are extracted from a subject by bone marrow aspiration.

[0076] In one embodiment, flow cytometric evaluation of bone marrow aspirate material can be performed directly on the aspirate without pretreatment or after a brief ammonium chloride red blood cell lysis step. See, for example, Pont, M. et al., Blood 134:1585-97 (2019). Pre-measurement procedures can be adapted from established protocols for next-generation flow cytometry analysis of bone marrow using a flow cytometer. The bone marrow aspirate can be diluted with an appropriate solution and incubated under appropriate conditions. Cells can then be harvested, washed with flow cytometry buffer (e.g., PBS containing 1% fetal bovine serum), and stained with a Live / Dead viability dye. Surface staining can be performed using a mixture of antibodies against one or more of the following: CD45, CD19, CD138, CD38, CD14, CD56, CD20, CD3, CD269 (BCMA), or CD274 (PD-L1). An aliquot of normal donor PBMC cells can be stained in parallel as a control. The cells can then be washed, permeabilized / fixed using Cytofix / Cytoperm reagent for an appropriate time at room temperature, washed, and stained with a mixture of antibodies against kappa and lambda immunoglobulin light chains. The samples can then be washed, resuspended in PBS, and acquired on a flow cytometer equipped with an appropriate laser. A minimum number of cells (e.g., 5 x 10) can be used per sample. 6 The number of cells can be obtained. The results can be analyzed using software.

[0077] In another embodiment, Form A of nirogacestat dihydrobromide increases the density of membrane-bound BCMA on the surface of BCMA-positive cancer cells. In some embodiments, Form A of nirogacestat dihydrobromide increases the density of membrane-bound BCMA on the surface of BCMA-positive cancer cells of a subject by 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 21-fold, 22-fold, 23-fold, 24-fold, 25-fold, 50-fold, 75-fold, 100-fold, 125-fold, 150-fold, 175-fold, 200-fold, 225-fold, or 250-fold.

[0078] In one embodiment, surface expression of human BCMA can be detected using flow cytometry and an appropriate secondary antibody.

[0079] In another embodiment, Form A of nirogacestat dihydrobromide can be administered to enhance the activity of a BCMA-directed therapy in a subject. In one embodiment, the activity of an effective amount of Form A of nirogacestat dihydrobromide in combination with a BCMA-directed therapy is measured by cancer cell killing and / or immune-mediated cancer cell killing or clearance.

[0080] In another embodiment, Form A of nirogacestat dihydrobromide allows a lower dose of BCMA-directed therapy to be administered to a subject compared to the amount of BCMA-directed therapy administered alone to achieve an equivalent level of efficacy (e.g., one or more of the treatment endpoints described above (e.g., CR, nCR, sCR, MRD)). In some embodiments, Form A of nirogacestat dihydrobromide allows a lower or the same dose of BCMA-directed therapy to be administered to a subject compared to the amount of BCMA-directed therapy administered alone, while achieving a high level of efficacy (e.g., one or more of the treatment endpoints discussed above (e.g., CR, nCR, sCR, MRD)).

[0081] In one embodiment, Form A of nirogacestat dihydrobromide is administered at a dose ranging from about 0.1 mg to about 1000 mg per day. In one embodiment, a subject is administered about 50 mg to about 500 mg of Form A of nirogacestat dihydrobromide daily. In another embodiment, a subject is administered about 100 mg to about 400 mg of Form A of nirogacestat dihydrobromide daily. In another embodiment, a subject is administered about 20 mg to about 220 mg of Form A of nirogacestat dihydrobromide daily. In another embodiment, a subject is administered about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 220 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, or about 400 mg of nirogacestat dihydrobromide Form A per day. The total daily dose can be administered as a single dose or divided doses (i.e., once, twice, three times, or four times a day). In one embodiment, the total daily dose is administered as two doses. For example, a total daily dose of 300 mg or 200 mg can be administered to a subject as two separate doses of 150 mg or 100 mg, respectively. In one embodiment, a subject can be administered three tablets containing 50 mg of nirogacestat form A dihydrobromide twice daily, or a 200 mg daily dose can be administered two tablets containing 50 mg of nirogacestat form A dihydrobromide twice daily.

[0082] In one embodiment, a subject is administered Form A of nirogacestat dihydrobromide orally and a BCMA-directed therapy is administered intravenously or subcutaneously. In one embodiment, the subject is a human. [Example]

[0083] A. Abbreviations and Acronyms [Table 5-1] [Table 5-2] B. Experimental Methods Example 1: Approximate kinetic solubility

[0084] Weighed samples of material were treated with aliquots of a given solvent at ambient temperature. Typically, samples were sonicated between additions to promote dissolution. Complete dissolution was confirmed by visual inspection. Solubility was calculated based on the total amount of solvent added to achieve complete dissolution and may be greater than the reported value due to incremental solvent addition and the inherent kinetics of dissolution. If dissolution was not confirmed, the value is reported as "less than." If dissolution was observed upon the initial addition of solvent, the value is reported as "greater than." Table 1 shows the kinetic solubility of the dihydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide. [Table 1-1] [Table 1-2] (a) Solubility was estimated using the solvent addition method with visual evaluation of the sample. If no dissolution was observed, the value was rounded to the nearest whole number and reported as "<". (b) Non-cGMP sample Example 2: Stable Form and Hydrate Screening Method a: Grinding experiment

[0085] Samples of the dihydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide were ground in the solvent system at ambient or set temperature. After approximately 24 hours, the solid was isolated by centrifugation using an Eppendorf centrifuge equipped with a 0.45 μm nylon filter. Stirring was then continued in fresh solvent for a total of approximately 1 and 3 weeks, after which the solid was isolated as described above, viewed under polarized light, and analyzed by XRPD. Method B: Equilibrium solubility test

[0086] The equilibrium solubility of the isolated solids was determined gravimetrically as follows: A measured aliquot of the mother liquor solution from the 3-week slurry was placed in a pre-weighed aluminum TGA pan. The solvent was then evaporated under ambient conditions or using vacuum. The remaining solid was weighed.

[0087] Table 2 shows the results of the stable form and hydrate screen. [Table 2-1] [Table 2-2] [Table 2-3] (a) Experiments were conducted for a total of approximately one week and three weeks, with the solvent changed approximately one day after slurrying. Solvent ratios (v / v) and experimental durations are approximate. Unless otherwise stated, experiments were conducted at ambient conditions. (b) Solubility was determined gravimetrically. (c) After the first solvent exchange, there was an insufficient amount of solids to use as a further slurry. (d) Carried out in a refrigerator (e) Non-cGMP samples Example 3: Preparation of Form A of Nirogacestat Dihydrobromide

[0088] Unless otherwise stated, (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide hydrobromide was used as the starting material.

[0089] The starting material was subjected to the crystallization techniques summarized below: Solids were typically isolated by vacuum filtration, viewed under polarized light, and analyzed by XRPD. Method a: Crushing experiment

[0090] The solid was combined with a small amount of solvent and transferred to an agate grinding vessel. Agate balls were added and the vessel was attached to a Retsch mill. Samples were typically ground at 30 Hz for one 20-minute cycle or recharged and the cycle repeated for another 20 minutes. Method b: Slurry experiments

[0091] The solid was suspended in a given solvent. The suspension was then stirred at ambient or set temperature. After a certain period of time, the solid was isolated. Method c: Solvent / antisolvent precipitation

[0092] Solutions of the starting materials were prepared at ambient or elevated temperatures and filtered through a 0.2 μm nylon filter. They were then mixed with an appropriate antisolvent at elevated temperatures. If no solids were observed, the sample was cooled to ambient or subambient temperatures or other crystallization techniques were applied. Method D: Crush Sedimentation

[0093] Solutions of starting materials were prepared at elevated temperatures in the appropriate solvents and hot filtered through 0.2 μm nylon filters into an appropriate antisolvent pre-cooled in a dry ice / acetone or water / ice bath. If solids precipitated, they were immediately isolated by vacuum filtration while still cold. If the solution remained clear, the samples were kept below ambient temperature or further crystallization techniques were applied. Method e: Cooling experiment

[0094] Solutions of starting materials were prepared in the desired solvents at elevated temperatures using a heating hotplate. These were typically filtered hot through 0.2 μm nylon filters into warm receiving vials. The vials were quickly transferred to a subambient bath (typically dry ice / acetone) for rapid cooling (CC), removed from the heat for rapid cooling (FC), or turned off to allow for slow cooling (SC). If solids precipitated, they were isolated at low temperatures by vacuum filtration. If the solution remained clear, the sample was kept subambient or further crystallization techniques were applied. Method F: Evaporation experiment

[0095] Solutions of starting materials were partially evaporated or evaporated to dryness at ambient or elevated temperatures from open vials for fast evaporation (FE) or from aluminum foil-covered vials with pinholes for slow evaporation (SE). Prior to evaporation, the solutions were filtered at ambient or elevated temperatures using a 0.2 μm nylon filter. Method g: Liquid-vapor diffusion experiments

[0096] Solutions of the starting materials were prepared at ambient temperature and filtered through a 0.2 μm nylon filter into a receiving vial. The open vial was then placed in a secondary container containing a suitable antisolvent. This container was sealed and allowed to stand at ambient conditions. Method h: Steam stress experiment

[0097] The starting solid was transferred to a vial, which was uncapped and placed in a secondary container containing a suitable antisolvent, which was sealed and allowed to stand at ambient or sub-ambient conditions. Method I: Low relative humidity stress experiment

[0098] The starting solid was transferred to a vial, which was then placed, uncapped, into an RH jar containing P2O5, which was kept at ambient temperature for a specified period of time. Method J: Drying experiment

[0099] The starting solids were dried at ambient temperature or under vacuum at a set temperature for a given period of time.

[0100] Table 3 summarizes the results of the polymorph screening of the dihydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide. [Table 3-1] [Table 3-2] [Table 3-3] (a) Solvent ratios (v / v), temperatures, and experimental durations are approximate. Refrigerator and cold room temperatures: 2–8°C; freezer temperatures: –10°C––25°C. (b) Mother liquor was obtained from the slurry at 2-8°C. Evaporation was carried out at ambient temperature. (c) Non-cGMP sample.

[0101] Table 4 summarizes the polymorph screening results for the dihydrobromide salt of (s)-2-(((s)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-n-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1h-imidazol-4-yl)pentanamide starting from X-ray amorphous material. [Table 4] (a) All samples generated from LIMS 386797 are non-cGMP. (b) Solvent ratios (v / v), temperatures, and experimental durations are approximate. Refrigerator and cold room temperatures: 2–8°C; freezer temperatures: –10°C––25°C. Example 4: Evaluation of BCMA expression in human multiple myeloma cell lines after treatment with form A of nirogacestat dihydrobromide

[0102] BCMA-expressing multiple myeloma cell lines MM.1S, Molp-8, H929, and OPM2, and the BCMA-negative acute lymphoblastic leukemia cell line REH are grown in RPMI medium containing L-glutamine and 5-10% FBS in a humidified CO2 incubator set at 37°C. Cells are plated in 96-well plates (1 x 10 6 The cells are transferred to a 5000 x g (1000 x 1000 cells / mL) and cultured in the presence of increasing concentrations (0.01 nM to 3000 nM) of form A nirogacestat dihydrobromide or vehicle (control) for 5 to 24 hours in a humidified CO2 incubator set at 37°C. Cells are harvested by centrifugation at 400 x g for 5 minutes and washed with an appropriate buffer. Cells are then suspended in 100 μL of an appropriate buffer containing an anti-human BCMA antibody and stained for 30 to 60 minutes at 4°C. For flow cytometry analysis, cells are washed twice with the appropriate buffer. Cell viability is determined by a commercially available assay as described by the manufacturer. BCMA expression levels (mean fluorescence intensity) are determined by flow cytometry. Example 5: Evaluation of sBCMA shedding in multiple myeloma cell lines following treatment with form A of nirogacestat dihydrobromide

[0103] BCMA-expressing multiple myeloma cell lines MM.1S, Molp-8, H929, and OPM2, and the BCMA-negative acute lymphoblastic leukemia cell line REH are grown in RPMI medium containing L-glutamine and 5-10% FBS in a humidified CO2 incubator set at 37°C. Cells are plated in 96-well plates (1 x 10 6 Cells are transferred to 1000 cells / mL and cultured in the presence of increasing concentrations (0.01 nM to 3000 nM) of form A nirogacestat dihydrobromide or vehicle (control) for 5 to 24 hours in a humidified CO2 incubator set at 37°C. Cell culture medium is collected throughout and / or after the designated time periods and analyzed for sBCMA concentration using a commercially available sBCMA ELISA kit according to the manufacturer's instructions. Example 6

[0104] BCMA-expressing multiple myeloma cell lines MM.1S, Molp-8, H929, and OPM2, and the BCMA-negative acute lymphoblastic leukemia cell line REH are grown in RPMI medium containing L-glutamine and 5-10% FBS in a humidified CO2 incubator set at 37°C. Cells are plated in 96-well plates (1 x 10 6 The cells are transferred to a 300-well plate (300 cells / mL) and cultured in the presence of a fixed dose (e.g., 1 μM) of form A of nirogacestat dihydrobromide or vehicle (control) in a humidified CO2 incubator set at 37°C. Targeted BCMA therapy can be added at various concentrations to assess the effect of the combination on the proliferation of multiple myeloma cells in a 3-day cell proliferation assay (e.g., Cell-Titre Glo). Example 7

[0105] The antibody-dependent cellular cytotoxicity (ADCC) activity of BCMA-targeting antibodies is measured using a BCMA-directed IgG1 monoclonal antibody in combination with nirogacestat dihydrobromide form A. ADCC activity against BCMA-expressing multiple myeloma cell lines (e.g., MM.1S, Molp-8, RPMI8226, ARH77, GA10, LP1, L363) is measured using a commercially available assay (e.g., Promega Jurkat ADCC assay) in which various concentrations of nirogacestat dihydrobromide form A are combined with various concentrations of the BCMA-targeting monoclonal antibody. Example 8

[0106] Bispecific cytotoxicity assays are performed by mixing purified human CD3+ T cells and luciferase-labeled myeloma cell lines, 5:1 E:T, and serial dilutions of bispecific antibodies. After 2 days of incubation, cell viability is assessed using OneGlo luciferase reagent (Promega). Example 9

[0107] The T cell-dependent cytotoxicity (TDCC) activity of the BCMA x CD3 bispecific antibody is measured in combination with form A of nirogacestat dihydrobromide. The assay is performed by mixing CD3+ T cells with luciferase-labeled multiple myeloma cell lines (e.g., MM.1S, Molp-8, RPMI8226, ARH77, GA10, LP1, L363) using a 5:1 effector-to-target ratio. Serial dilutions of the bispecific antibody and form A of nirogacestat dihydrobromide result in various concentrations of each molecule being evaluated. After 2 days of incubation, cell viability is assessed using a luciferase-based assay (Promega OneGlo). Example 10

[0108] The T cell-dependent cytotoxicity (TDCC) activity of BCMA-targeting chimeric antigen T cell (CAR-T) cells was measured in combination with nirogacestat dihydrobromide form A. TDCC activity against BCMA-expressing multiple myeloma cell lines (e.g., MM.1S, Molp-8, RPMI8226, ARH77, GA10, LP1, and L363) was measured using a custom-developed TDCC assay (similar to the format described by Nazarian, AA et al., J. Biomol. Screen, 20:519-27 (2015)), in which varying concentrations of nirogacestat dihydrobromide form A were combined with varying concentrations of BCMA-targeting CAR-T cell numbers. Example 11

[0109] T cell activation by BCMA-targeted therapies (CAR-T cells, bispecific antibodies, and monoclonal antibodies) in the presence of BCMA-expressing multiple myeloma cell lines (e.g., MM.1S, Molp-8, RPMI8226, ARH77, GA10, LP1, L363) in combination with form A of nirogacestat dihydrobromide is determined. Co-cultures of T cells and multiple myeloma cell lines are incubated with a fixed concentration of form A of nirogacestat dihydrobromide. Serial dilutions of the BCMA-targeted therapy are added, and T cell activation is measured by cytokine release assays and / or flow cytometry. ****

[0110] It is understood that the Detailed Description section, and not the Summary and Abstract sections, is intended to be used to interpret the claims. The Summary and Abstract sections describe one or more (but not all) exemplary embodiments of the invention contemplated by the inventors, and therefore are not intended to limit the scope of the invention and the appended claims in any way.

[0111] The present invention has been described above using functional building blocks that illustrate the implementation of certain functions and relationships thereof. The boundaries of these functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternative boundaries may be defined so long as the certain functions and relationships thereof are appropriately performed.

[0112] The foregoing description of specific embodiments fully reveals the general nature of the present invention, and others can readily modify and / or adapt such specific embodiments for various uses by applying knowledge within the art without departing from the general concept of the present invention and without undue experimentation. Such adaptations and modifications are therefore intended to be within the meaning and range of equivalents of the disclosed embodiments, based on the teaching and guidance presented herein. It should be understood that the phrases or terminology herein are for the purpose of description rather than limitation, and therefore, that the terms or phrases herein will be interpreted by one of ordinary skill in the art in light of the teaching and guidance.

[0113] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0114] In addition to the various embodiments described herein, the present disclosure includes the following embodiments, numbered E1 through E81. This list of embodiments is provided as an exemplary list, and the present application is not limited to these embodiments.

[0115] E1. A method of treating cancer in a subject in need thereof, comprising administering to said subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy.

[0116] E2. The method of E1, wherein the cancer is characterized by insufficient expression of B-cell maturation antigen (BCMA).

[0117] E3. The method of E1, wherein said cancer is characterized by a detectable level of soluble B-cell maturation antigen (BCMA) in a serum sample from said subject.

[0118] E4. The method of E1, wherein said cancer is a hematological cancer.

[0119] E5. The method of E4, wherein said hematological cancer is multiple myeloma.

[0120] E6. The method of E1, wherein the cancer is selected from the group consisting of Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML).

[0121] E7. A method of treating light chain amyloidosis in a subject in need thereof, comprising administering to the subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy.

[0122] E8. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide reduces shedding of B-cell maturation antigen (BCMA) from the surface of BCMA-positive cells in said subject.

[0123] E9. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide reduces the level of soluble B-cell maturation antigen (BCMA) in a serum sample from said subject.

[0124] E10. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide increases the proportion of B-cell maturation antigen (BCMA)-positive multiple myeloma cells in said subject.

[0125] E11. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide increases the density of membrane-bound B-cell maturation antigen (BCMA) on the surface of BCMA-positive cancer cells in said subject.

[0126] E12. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide enhances the activity of B-cell maturation antigen (BCMA)-directed therapy in said subject.

[0127] E13. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide allows a lower dose of said B-cell maturation antigen (BCMA)-directed therapy to be administered to said subject compared to the amount of said BCMA-directed therapy administered alone, while maintaining an equivalent level of efficacy.

[0128] E14. The method of E1 or E7, wherein said Form A of nirogacestat dihydrobromide allows a lower dose or the same dose of said B-cell maturation antigen (BCMA)-directed therapy to be administered to said subject compared to the amount of said BCMA-directed therapy administered alone, while achieving an increased level of efficacy.

[0129] E15. The method of any one of E1-E14, wherein said subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg.

[0130] E16. The method of any one of E1-E15, wherein said subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily.

[0131] E17. The method of any one of E1-E16, wherein said subject is administered Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily.

[0132] E18. The method of any one of E1-E16, wherein said subject is administered Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily.

[0133] E19. The method of E16, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily for at least one week.

[0134] E20. The method of E19, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily for at least one week.

[0135] E21. The method of E19, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily for at least one week.

[0136] E22. The method of any one of E1-E21, wherein said subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 200 mg.

[0137] E23. The method of any one of E1-E21, wherein said subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 150 mg.

[0138] E24. The method of any one of E1-E21, wherein said subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 100 mg.

[0139] E25. The method of any one of E1-E21, wherein said subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 75 mg.

[0140] E26. The method of any one of E1-E21, wherein said subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 50 mg.

[0141] E27. The method of any one of E1-E26, wherein said Form A of nirogacestat dihydrobromide is administered to said subject prior to, concurrently with, or after administering said B-cell maturation antigen (BCMA) directed therapy to said subject.

[0142] E28. The method of any one of E1-E27, wherein said subject is administered said combination therapy as a first line therapy.

[0143] E29. The method of any one of E1-E27, wherein said effective amount of Form A of nirogacestat dihydrobromide and B-cell maturation antigen (BCMA) directed therapy is administered to said subject after said subject has previously been treated for said cancer or light chain amyloidosis.

[0144] E30. The method of E29, wherein said subject has previously been treated for said cancer or light chain amyloidosis with one or more of a proteasome inhibitor, immunomodulatory therapy, immunotherapy, stem cell transplant, chemotherapy, targeted therapy, or B-cell maturation antigen (BCMA) directed therapy not in combination with nirogacestat dihydrobromide.

[0145] E31. The method of E30, wherein said immunotherapy is a monoclonal antibody.

[0146] E32. The method of E31, wherein said monoclonal antibody is directed against CD38.

[0147] E33. The method of any one of E1-E32, wherein said Form A of nirogacestat dihydrobromide is administered orally and said B-cell maturation antigen (BCMA) directed therapy is administered intravenously or subcutaneously to said subject.

[0148] E34. The method of any one of E1-E33, wherein said B-cell maturation antigen (BCMA) directed therapy comprises one or more of allogeneic chimeric antigen receptor T cell therapy, autologous chimeric antigen receptor T cell therapy, immunotherapy, antibody drug conjugate therapy, or bispecific antibody therapy having dual specificity for BCMA and an immune related target.

[0149] E35. The method of E34, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least allogeneic chimeric antigen receptor T-cell therapy.

[0150] E36. The method of E34, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least autologous chimeric antigen receptor T-cell therapy.

[0151] E37. The method of E34, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least immunotherapy.

[0152] E38. The method of E34 or E37, wherein said immunotherapy is a monoclonal antibody.

[0153] E39. The method of E34, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least an antibody-drug conjugate therapy.

[0154] E40. The method of E34, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least a bispecific antibody therapy having dual specificity for BCMA and an immune-related target.

[0155] E41. The method of any one of E1-E40, wherein said Form A of nirogacestat dihydrobromide is administered in tablet form.

[0156] E42. The method of any one of E1-E41, wherein the subject is a human.

[0157] E43. Use of a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA) directed therapy in treating cancer in a subject in need thereof.

[0158] E44. The use of E43, wherein said cancer is characterized by insufficient expression of B-cell maturation antigen (BCMA).

[0159] E45. The use of E43, wherein said cancer is characterized by a detectable level of soluble B-cell maturation antigen (BCMA) in a serum sample from said subject.

[0160] E46. The use of E43, wherein said cancer is a blood cancer.

[0161] E47. The use of E46, wherein said hematological cancer is multiple myeloma.

[0162] E48. The use of E43, wherein said cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML).

[0163] E49. Use of a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy in treating light chain amyloidosis in a subject in need thereof.

[0164] E50. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide reduces shedding of B-cell maturation antigen (BCMA) from the surface of BCMA-positive cells in said subject.

[0165] E51. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide reduces the level of soluble B-cell maturation antigen (BCMA) in said subject.

[0166] E52. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide increases the proportion of B-cell maturation antigen (BCMA)-positive multiple myeloma cells in said subject.

[0167] E53. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide increases the density of membrane-bound B-cell maturation antigen (BCMA) on the surface of BCMA-positive cancer cells in said subject.

[0168] E54. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide enhances the activity of said B-cell maturation antigen (BCMA) directed therapy in said subject.

[0169] E55. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide allows the subject to use a lower dose of said B-cell maturation antigen (BCMA) directed therapy compared to the amount of said BCMA directed therapy administered alone, while maintaining an equivalent level of efficacy.

[0170] E56. The use of E43 or E49, wherein said Form A of nirogacestat dihydrobromide allows the subject to use a lower dose or the same dose of said B-cell maturation antigen (BCMA) directed therapy compared to the amount of said BCMA directed therapy administered alone, while achieving an increased level of efficacy.

[0171] E57. The use of any one of E43 to E56, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg.

[0172] E58. The use of any one of E43 to E57, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily.

[0173] E59. The use of any one of E43 to E58, wherein said subject is administered Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily.

[0174] E60. The use of any one of E43 to E58, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily.

[0175] E61. The use of E58, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily for at least one week.

[0176] E62. The use of E61, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily for at least one week.

[0177] E63. The use of E61, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily for at least one week.

[0178] E64. The use of any one of E43 to E63, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a total daily dose of about 200 mg.

[0179] E65. The use of any one of E43 to E63, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a total daily dose of about 150 mg.

[0180] E66. The use of any one of E43 to E63, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a total daily dose of about 100 mg.

[0181] E67. The use of any one of E43 to E63, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a total daily dose of about 75 mg.

[0182] E68. The use of any one of E43 to E63, wherein said subject is administered said Form A of nirogacestat dihydrobromide at a total daily dose of about 50 mg.

[0183] E69. The use of any one of E43 to E68, wherein said Form A of nirogacestat dihydrobromide is administered to said subject prior to, concurrently with, or after administering said B-cell maturation antigen (BCMA) directed therapy to said subject.

[0184] E70. The use of any one of E43 to E69, wherein said combination therapy is administered to said subject as a first line therapy.

[0185] E71. The use of any one of E43-E69, wherein said effective amount of Form A of nirogacestat dihydrobromide and B-cell maturation antigen (BCMA) directed therapy is administered to said subject after said subject has previously been treated for said cancer or light chain amyloidosis.

[0186] E72. The use of E71, wherein said subject has previously been treated with one or more of a proteasome inhibitor, immunomodulatory therapy, immunotherapy, stem cell transplant, chemotherapy, targeted therapy, or B-cell maturation antigen (BCMA) directed therapy not in combination with form A of nirogacestat dihydrobromide.

[0187] E73. The use of E72, wherein said immunotherapy is a monoclonal antibody.

[0188] E74. The use of E73, wherein said monoclonal antibody is directed against CD38.

[0189] E75. The use of any one of E43-E74, wherein said B-cell maturation antigen (BCMA) directed therapy comprises one or more of allogeneic chimeric antigen receptor T cell therapy, autologous chimeric antigen receptor T cell therapy, immunotherapy, antibody drug conjugate therapy, or bispecific antibody therapy having dual specificity for BCMA and an immune related target.

[0190] E76. The use of E75, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least allogeneic chimeric antigen receptor T-cell therapy.

[0191] E77. The use of E75, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least autologous chimeric antigen receptor T-cell therapy.

[0192] E78. The use of E75, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least immunotherapy.

[0193] E79. The use of E75 or E78, wherein said immunotherapy is a monoclonal antibody.

[0194] E80. The use of E79, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least an antibody-drug conjugate therapy.

[0195] E81. The use of E79, wherein said B-cell maturation antigen (BCMA)-directed therapy comprises at least a bispecific antibody therapy having dual specificity for BCMA and an immune-related target. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of Form A of nirogacestat dihydrobromide and a combination therapy comprising a B-cell maturation antigen (BCMA)-directed therapy. (Item 2) 2. The method of claim 1, wherein the cancer is characterized by insufficient expression of B-cell maturation antigen (BCMA). (Item 3) 2. The method of claim 1, wherein the cancer is characterized by a detectable level of soluble B-cell maturation antigen (BCMA) in a serum sample from the subject. (Item 4) Item 1. The method of item 1, wherein the cancer is a blood cancer. (Item 5) 5. The method of claim 4, wherein the hematological cancer is multiple myeloma. (Item 6) 2. The method of item 1, wherein the cancer is selected from the group consisting of Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML). (Item 7) 1. A method of treating light chain amyloidosis in a subject in need thereof, comprising administering to the subject a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy. (Item 8) 8. The method of item 1 or 7, wherein said form A of nirogacestat dihydrobromide reduces shedding of B-cell maturation antigen (BCMA) from the surface of BCMA-positive cells in said subject. (Item 9) 8. The method of item 1 or 7, wherein said Form A of nirogacestat dihydrobromide reduces the level of soluble B-cell maturation antigen (BCMA) in a serum sample from said subject. (Item 10) 8. The method of item 1 or 7, wherein said Form A of nirogacestat dihydrobromide increases the percentage of B-cell maturation antigen (BCMA)-positive multiple myeloma cells in said subject. (Item 11) 8. The method of item 1 or 7, wherein said form A of nirogacestat dihydrobromide increases the density of membrane-bound B-cell maturation antigen (BCMA) on the surface of BCMA-positive cancer cells in said subject. (Item 12) 8. The method of item 1 or 7, wherein said Form A of nirogacestat dihydrobromide enhances the activity of B-cell maturation antigen (BCMA)-directed therapy in said subject. (Item 13) 8. The method of item 1 or 7, wherein the form A of nirogacestat dihydrobromide allows a lower dose of the B-cell maturation antigen (BCMA)-directed therapy to be administered to the subject compared to the amount of the BCMA-directed therapy administered alone, while maintaining an equivalent level of efficacy. (Item 14) 8. The method of item 1 or 7, wherein the Form A of nirogacestat dihydrobromide allows a lower dose or the same dose of the B-cell maturation antigen (BCMA)-directed therapy to be administered to the subject compared to the amount of the BCMA-directed therapy administered alone, while achieving an increased level of efficacy. (Item 15) 15. The method of any one of items 1 to 14, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg. (Item 16) Item 17. The method according to any one of Items 1 to 15, wherein Form A of nirogacestat dihydrobromide is administered to the subject at a dose of about 20 mg to about 220 mg once or twice daily. 17. The method of any one of items 1 to 16, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily. (Item 18) 17. The method of any one of items 1 to 16, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily. (Item 19) 17. The method of item 16, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily for at least one week. (Item 20) 20. The method of item 19, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily for at least one week. (Item 21) 20. The method of item 19, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily for at least one week. (Item 22) 22. The method of any one of items 1 to 21, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 200 mg. (Item 23) 22. The method of any one of items 1 to 21, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 150 mg. (Item 24) 22. The method of any one of items 1 to 21, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 100 mg. (Item 25) 22. The method of any one of items 1 to 21, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 75 mg. (Item 26) 22. The method of any one of items 1 to 21, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 50 mg. (Item 27) said Form A of nirogacestat dihydrobromide being administered to said subject prior to, concurrently with, or after said B-cell maturation antigen (BCMA)-directed therapy; 27. The method of any one of items 1 to 26, wherein the method is administered to a subject. (Item 28) 28. The method of any one of items 1 to 27, wherein the combination therapy is administered to the subject as a first-line therapy. (Item 29) 28. The method of any one of items 1-27, wherein the effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy is administered to the subject after the subject has previously been treated for the cancer or light chain amyloidosis. (Item 30) 30. The method of claim 29, wherein the subject has been previously treated for the cancer or light chain amyloidosis with one or more of the following: a proteasome inhibitor, immunomodulatory therapy, immunotherapy, stem cell transplant, chemotherapy, targeted therapy, or a B-cell maturation antigen (BCMA)-directed therapy not in combination with nirogacestat dihydrobromide. (Item 31) 31. The method of claim 30, wherein the immunotherapy is a monoclonal antibody. (Item 32) 32. The method of item 31, wherein the monoclonal antibody is directed against CD38. (Item 33) 33. The method of any one of items 1 to 32, wherein Form A of nirogacestat dihydrobromide is administered orally and B-cell maturation antigen (BCMA)-directed therapy is administered intravenously or subcutaneously to the subject. (Item 34) 34. The method of any one of items 1 to 33, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises one or more of allogeneic chimeric antigen receptor T-cell therapy, autologous chimeric antigen receptor T-cell therapy, immunotherapy, antibody drug conjugate therapy, or bispecific antibody therapy having dual specificity for BCMA and an immune-related target. (Item 35) 35. The method of item 34, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least allogeneic chimeric antigen receptor T-cell therapy. (Item 36) 35. The method of item 34, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least autologous chimeric antigen receptor T-cell therapy. (Item 37) 35. The method of item 34, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least immunotherapy. (Item 38) 38. The method of claim 34 or 37, wherein the immunotherapy is a monoclonal antibody. (Item 39) 35. The method of item 34, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least an antibody-drug conjugate therapy. (Item 40) 35. The method of item 34, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least a bispecific antibody therapy having dual specificity for BCMA and an immune-related target. (Item 41) 41. The method according to any one of items 1 to 40, wherein said Form A of nirogacestat dihydrobromide is administered in tablet form. (Item 42) 42. The method according to any one of items 1 to 41, wherein the subject is a human. (Item 43) 1. Use of a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy in treating cancer in a subject in need thereof. (Item 44) 44. The use of item 43, wherein the cancer is characterized by insufficient expression of B-cell maturation antigen (BCMA). (Item 45) 44. The use of item 43, wherein the cancer is characterized by a detectable soluble B-cell maturation antigen (BCMA) level in a serum sample from the subject. (Item 46) 44. The use according to item 43, wherein the cancer is a blood cancer. (Item 47) 47. The use of item 46, wherein the blood cancer is multiple myeloma. (Item 48) 44. The use of item 43, wherein the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL), mantle cell lymphoma (MCL), and myeloid leukemia (ML). (Item 49) 1. Use of a combination therapy comprising an effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy in treating light chain amyloidosis in a subject in need thereof. (Item 50) 50. The use of item 43 or 49, wherein said form A of nirogacestat dihydrobromide reduces shedding of B-cell maturation antigen (BCMA) from the surface of BCMA-positive cells in said subject. (Item 51) 50. The use of item 43 or 49, wherein the form A of nirogacestat dihydrobromide reduces the level of soluble B-cell maturation antigen (BCMA) in the subject. (Item 52) 50. The use of item 43 or 49, wherein said Form A of nirogacestat dihydrobromide increases the percentage of B-cell maturation antigen (BCMA)-positive multiple myeloma cells in said subject. (Item 53) 50. The use of item 43 or 49, wherein said form A of nirogacestat dihydrobromide increases the density of membrane-bound B-cell maturation antigen (BCMA) on the surface of BCMA-positive cancer cells in said subject. (Item 54) 50. The use of item 43 or 49, wherein said Form A of nirogacestat dihydrobromide enhances the activity of said B-cell maturation antigen (BCMA)-directed therapy in said subject. (Item 55) 50. The use of item 43 or 49, wherein the form A of nirogacestat dihydrobromide allows the subject to use a lower dose of the B-cell maturation antigen (BCMA)-directed therapy compared to the amount of the BCMA-directed therapy administered alone, while maintaining an equivalent level of efficacy. (Item 56) 50. The use of item 43 or 49, wherein the form A of nirogacestat dihydrobromide allows the subject to use a lower dose or the same dose of the B-cell maturation antigen (BCMA)-directed therapy compared to the amount of the BCMA-directed therapy administered alone, while achieving an increased level of efficacy. (Item 57) 57. The use of any one of items 43 to 56, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg. (Item 58) 58. The use of any one of items 43 to 57, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily. (Item 59) 59. The use according to any one of items 43 to 58, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily. (Item 60) 59. The use according to any one of items 43 to 58, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily. (Item 61) 59. The use of item 58, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 20 mg to about 220 mg once or twice daily for at least one week. (Item 62) 62. The use of item 61, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 100 mg once or twice daily for at least one week. (Item 63) 62. The use of item 61, wherein the subject is administered Form A of nirogacestat dihydrobromide at a dose of about 50 mg once or twice daily for at least one week. (Item 64) 64. The use of any one of items 43 to 63, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 200 mg. (Item 65) 64. The use of any one of items 43 to 63, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 150 mg. (Item 66) 64. The use of any one of items 43 to 63, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 100 mg. (Item 67) 64. The use of any one of items 43 to 63, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 75 mg. (Item 68) 64. The use of any one of items 43 to 63, wherein the subject is administered Form A of nirogacestat dihydrobromide at a total daily dose of about 50 mg. (Item 69) 69. The use of any one of items 43 to 68, wherein said Form A of nirogacestat dihydrobromide is administered to said subject prior to, concurrently with, or after administering said B-cell maturation antigen (BCMA)-directed therapy to said subject. (Item 70) 70. The use of any one of items 43 to 69, wherein the subject is administered the combination therapy as a first-line therapy. (Item 71) 70. The use of any one of items 43 to 69, wherein the effective amount of Form A of nirogacestat dihydrobromide and a B-cell maturation antigen (BCMA)-directed therapy is administered to the subject after the subject has previously been treated for the cancer or light chain amyloidosis. (Item 72) 72. The use of item 71, wherein the subject has been previously treated with one or more of a proteasome inhibitor, immunomodulatory therapy, immunotherapy, stem cell transplantation, chemotherapy, targeted therapy, or B-cell maturation antigen (BCMA)-directed therapy not in combination with form A of nirogacestat dihydrobromide. (Item 73) 73. The use of item 72, wherein the immunotherapy is a monoclonal antibody. (Item 74) 74. The use of item 73, wherein the monoclonal antibody is directed against CD38. (Item 75) 75. The use of any one of items 43 to 74, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises one or more of allogeneic chimeric antigen receptor T-cell therapy, autologous chimeric antigen receptor T-cell therapy, immunotherapy, antibody drug conjugate therapy, or bispecific antibody therapy having dual specificity for BCMA and an immune-related target. (Item 76) 76. The use of item 75, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least allogeneic chimeric antigen receptor T-cell therapy. (Item 77) 76. The use of item 75, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least autologous chimeric antigen receptor T-cell therapy. (Item 78) 76. The use of item 75, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least immunotherapy. (Item 79) 79. The use of item 75 or 78, wherein the immunotherapy is a monoclonal antibody. (Item 80) 80. The use of item 79, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least an antibody-drug conjugate therapy. (Item 81) 80. The use of item 79, wherein the B-cell maturation antigen (BCMA)-directed therapy comprises at least a bispecific antibody therapy having dual specificity for BCMA and an immune-related target.

Claims

[Claim 1] The invention described in the present specification.

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