Cd73 inhibitor and Anti-cd38 agent combination therapy

Abstract

The present disclosure relates to methods of treating a subject having multiple myeloma, including refractory / resistant multiple myeloma, comprising administering to the subject a CD73 inhibitor and an anti-CD38 agent.

Description

CD73 INHIBITOR AND ANTLCD38 AGENT COMBINATION THERAPYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 594,836 filed October 31, 2023; which is hereby incorporated by reference in its entirety.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under one or more of grant nos. R01CA207237, P01CA155258, R01CA050947, and P50CA100707 awarded by the National Institutes of Health. The government has certain rights in the invention.JOINT RESEARCH AGREEMENT

[0003] Certain embodiments disclosed herein were made under a joint research agreement, as defined in 35 U.S.C. § 100(h), between Dana-Farber Cancer Institute, Inc. and ORIC Pharmaceuticals, Inc., that was in effect on or before the effective filing date of such disclosed embodiments, and the disclosed embodiments were made as a result of activities undertaken within the scope of the joint research agreement.BACKGROUND

[0004] Multiple myeloma is a type of cancer that affects plasma cells, which are a type of white blood cell that produces antibodies. In multiple myeloma, cancerous plasma cells accumulate in the bone marrow and interfere with the production of normal blood cells. Subjects exhibiting multiple myeloma may be treated using one or more regimens including chemotherapy, radiation therapy, stem cell transplantation / therapy, targeted therapy, immunotherapy, and supportive care. The disease in a majority of subjects will become resistant to existing therapies and their disease will relapse and require further treatment. Kumar et al., Blood Cancer Journal, 2022, 12:98. Additionally, some subjects exhibit multiple myeloma that is refractory to the majority of existing treatments options prior to receiving any of those existing treatments. Moreau et al. The Lancet Oncology, 2021, 22, p. el05. There is a need, therefore, to develop new treatment regimens for subjects having multiple myeloma, including subjects exhibiting resistant or refractory multiple myeloma.

[0005] CD73, also known as ecto-5'-nucleotidase, is an enzyme that is found on the surface of various cells in the body, including immune cells, endothelial cells, and tumor cells. CD73 plays a crucial role in the regulation of immune responses, inflammation, and tissue homeostasis. CD73 catalyzes the hydrolysis of extracellular adenosine monophosphate (AMP) into adenosine, which is an immunosuppressive molecule that inhibits the activity of immune cells, such as T cells and natural killer cells. CD73 thus promotes an immunosuppressive microenvironment that allows tumor cells to evade immune surveillance and facilitates tumor growth and metastasis. CD73 is overexpressed in many types of cancers, includingbreast cancer, colorectal cancer, and lung cancer, and is associated with poor prognosis and resistance to immunotherapy.

[0006] CD38 is a transmembrane glycoprotein that is expressed on the surface of various cells in the body, including immune cells, endothelial cells, and neurons. CD38 plays a crucial role in the regulation of immune responses, inflammation, and cellular metabolism. CD38 functions as an ectoenzyme, catalyzing the conversion of nicotinamide adenine dinucleotide (NAD+) into cyclic ADP -ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP+). These molecules are involved in intracellular calcium signaling, which regulates a wide range of physiological processes, including neurotransmitter release, insulin secretion, and immune cell activation. CD38 is also involved in the regulation of cell adhesion and migration, as well as in the modulation of the activity of various cytokines, such as interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-a). CD38 is overexpressed in many types of cancers, including multiple myeloma, lymphoma, and leukemia, and is associated with tumor growth, survival, and drug resistance.

[0007] CD38 has emerged as a promising target for cancer therapy. Several CD38 -targeted therapies, including monoclonal antibodies and small molecule inhibitors, are currently being developed and approved for the treatment of multiple myeloma. These therapies target CD38 -expressing cancer cells, leading to their destruction through various mechanisms, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction of apoptosis. However, there is clinical evidence demonstrating that the use of certain anti-CD38 agents for the treatment of subjects having multiple myeloma, including daratumumab and isatuximab, leads to the development of resistant / refractory multiple myeloma. Saltarella et al., Cells, 2020, 9, p. 167; Franseen et al., J. Clin. Med., 2020, 9, p. 1195.

[0008] There is an urgent need, therefore, to develop new treatment paradigms and regimens for the treatment of subjects having multiple myeloma, including multiple myeloma in subjects that is refractory or resistant to existing therapies.SUMMARY

[0009] The present disclosure relates to methods of treating subjects having multiple myeloma, including resistant or refractory multiple myeloma, the method comprising administering to the subject a combination of a CD73 inhibitor, an anti-CD38 agent and, optionally, one or more other agents.

[0010] Provided herein are methods of treating a subject having multiple myeloma, comprising administering to the subject a CD73 inhibitor and an anti-CD38 agent. In some embodiments, the CD73 inhibitor is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single-chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate. In other embodiments, the CD73 inhibitor is selected from Compound 1, AB680 (quemliclustat), CB-708 (ATG-037), ATG-047, and LY3475070, or a pharmaceutically acceptable salt of each, oleclumab, BMS-986179, NZV930, mupadolimab, uliledlimab, INCA00186, Sym024, IBI325, AK119, JAB-BX102, IPH5301, HLX23, and GS-1423. In still other embodiments, theanti-CD38 agent is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single-chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate. In further embodiments, the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0011] Methods of treating a subject having multiple myeloma are also provided. The methods comprise administering to the subject a CD73 inhibitor, an anti-CD38 agent, and optionally, one or more additional agents. When present, the one or more additional agents are selected from immunomodulatory agents (IMiDs), proteasome inhibitors (Pls), and monoclonal antibodies.

[0012] Methods of treating a subject having multiple myeloma, wherein the multiple myeloma in the subject is relapse or refractory multiple myeloma are also provided. The methods comprise administering to the subject a CD73 inhibitor and an anti-CD38 agent, and optionally one or more additional agents, wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma. When present, the one or more additional agents are selected from immunomodulatory agents ), proteasome inhibitors , and monoclonal antibodies.

[0013] Methods of treating a subject having multiple myeloma wherein the multiple myeloma in the subject is light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma, are also provided. The methods comprise administering to the subject a CD73 inhibitor and an anti-CD38 agent, and optionally one or more additional agents, . When present, the one or more additional agents are selected from immunomodulatory agents ), proteasome inhibitors , and monoclonal antibodies.

[0014] Methods of treating a subject having multiple myeloma wherein the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 6 months following treatment via one of the described methods are also provided. The methods comprise administering to the subject a CD73 inhibitor and an anti-CD38 agent, and optionally one or more additional agents. When present, the one or more additional agents are selected from immunomodulatory agents , proteasome inhibitors , and monoclonal antibodies.

[0015] Methods of treating a subject having multiple myeloma wherein the subject achieves minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following treatment via one of the described methods are also provided. The methods comprise administering to the subject a CD73 inhibitor and an anti-CD38 agent, and optionally one or more additional agents, When present, the one or more additional agents are selected from immunomodulatory agents , proteasome inhibitors , and monoclonal antibodies.INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized, and the accompanying drawings of which:

[0018] FIG. 1 shows induced cytolytic activity of multiple myeloma cells following treatment with Compound 1, daratumumab, or a combination of Compound 1 and daratumumab as described in Example 12.

[0019] FIG. 2 shows induced cytolytic activity of multiple myeloma cells from subjects determined to be refractory to daratumumab following treatment with Compound 1 , daratumumab, or a combination of Compound 1 and daratumumab as described in Example 12.

[0020] FIG. 3 shows induced cytolytic activity of multiple myeloma cells from individual subjects determined to be refractory to daratumumab following treatment with Compound 1 , daratumumab, or a combination of Compound 1 and daratumumab as described in Example 12.DETAILED DESCRIPTION

[0021] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, melting points, or chemical properties, such as chemical formulae, all combinations and sub -combinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that, in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consists of’ or “consists essentially of’ the described features.

[0022] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0023] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue or target cells, or to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue (such as bone marrow) or cells to which it is targeted. Thus, the term “administering,” when used in conjunction with a composition described herein, can include, but is not limited to, providing a composition into or onto the target tissue (such as bone marrow) or into the physiological space comprising the target cells; providing a composition systemically to a subject by, e.g., oral administration, whereby the therapeutic reaches the target tissue(such as bone marrow) or the physiological space comprising the target cells. “Administering” a composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0024] The terms “crystalline” and “crystallinity” refer to a solid composition having some measure of long-range order in the position of its molecules, as measured by analytical techniques known to those having ordinary skill in the art, such as x-ray powder diffraction (XRPD).

[0025] The term “differential scanning calorimetry,” as used herein means a method of thermal analysis described in USP <891>.

[0026] The term “pharmaceutically acceptable,” means a carrier, diluent or excipient that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0027] The term “pharmaceutical composition” shall mean a composition comprising one or more active ingredients, whereby the pharmaceutical composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human) . Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the therapeutic needs of the subject.

[0028] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, prevent, or improve an unwanted condition or disease of a subject.

[0029] A “therapeutically effective amount” or “effective amount” as used herein refers to an amount of an inhibitor or agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include one or more of the following: (1) preventing a disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the progression of a disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0030] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment, e.g., the attainment of beneficial or desired clinical results, in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or inhibit the progression of an undesired physiological condition, disorder, or disease. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder ordisease. Treatment includes eliciting a clinically significant response while minimizing side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As disclosed herein, various measures known to those having ordinary skill in the art, including but not limited to progression-free survival (PFS), overall survival (OS), and minimum residual disease (MRD), may be used to assess the impact of a particular treatment regimen in a subject having multiple myeloma.

[0031] As used herein, the term “x-ray powder diffraction (XRPD)” means the technique of characterizing a solid for crystallinity or partial crystallinity by use of powder x-ray diffraction as set forth in USP <941>.

[0032] As used herein, the term “CD73 inhibitor” means an agent that binds to CD73 and inhibits the CD73-mediated conversion of adenosine monophosphate (AMP) to adenosine. CD73 inhibitors may include, but are not limited to, peptides, polypeptides, proteins, small molecules, antibodies, antibody fragments, single-chain antibodies, single-chain variable fragments, and antibody-drug conjugates.

[0033] As used herein, the term “anti-CD38 agent” means an agent that binds to CD38, for example on tumor cells, and inhibits the function of CD38 on cells, including on tumor cells. An anti-CD38 agent may inhibit the growth of CD38 -expressing tumor cells by inducing cell death through mechanisms including, but not limited to, Fc-mediated cross linking, immune-mediated tumor cell lysis through complement dependent cytotoxicity (CDC), antibody-dependent cell mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). Anti-CD38 agents may include, but are not limited to, peptides, polypeptides, proteins, small molecules, antibodies, antibody fragments, single-chain antibodies, single-chain variable fragments, and antibody-drug conjugates.

[0034] As used herein, the terms “immunomodulatory agent(s)” and “IMiD(s)” mean agents that have a modulatory effect on the immune cells of a subject to which they are administered. Examples of IMiDs include, but are not limited to, thalidomide, lenalidomide, pomalidomide.

[0035] As used herein, the term “International Myeloma Working Group (IMWG) criteria” means those criteria established for measuring the response, including durability of response, of multiple myeloma disease in a subject that are known to those of ordinary skill in the art, including, but not limited to, those set forth in Durie et al., Leukemia, 2006, 20, pp. 1467 to 1473; and Kumar et al., The Lancet Oncology, 2016, 17, pp. e328 to e346.

[0036] As used herein, the term “proteasome inhibitor (PI)” means an agent that inhibits the function of one or more proteasomes in the cells of a subject to which they are administered. Examples of proteasome inhibitors include, but are not limited to, bortezomib, carfilzomib, and ixazomib .

[0037] The phrases “relapsed multiple myeloma,” “refractory multiple myeloma,” “relapsed / refractory multiple myeloma,” are meant to indicate a multiple myeloma that is or has become non-responsive to one or more agents, inhibitors or treatments. Criteria for determining whether a multiple myeloma disease in a subject is relapsed / refractory are known to those having ordinary skill in the art and include, but are not limited to, the criteria developed by the International Multiple Myeloma Working Group (IMWG)and / or the NCI Multiple Myeloma Steering Committee. See Kumar et al., Blood Cancer Journal, 2022, 12:98; Moreau et al. The Lancet Oncology, 2021, 22, p. el05; Kumar et al., The Lancet Oncology, 2016, 17, pp. e328 to e346.

[0038] In some embodiments, relapse of multiple myeloma is indicated by one or more the following: (a) direct indicators of increasing disease and / or end organ dysfunction related to the underlying clonal plasma-cell proliferative disorder (including, but not limited to calcium elevation, renal insufficiency, anemia, and development or worsening of bone lesions), (b) development of new soft tissue plasmacytomas or bone lesions, (c) an increase in the size of existing plasmacytomas or bone lesions of at least 50% (and > 1 cm), as measured serially by the sum of the product of the diameters (SPD) of the measurable lesion, (d) hypercalcemia ( > 11 mg / dL), (e) a decrease in hemoglobin of > 2 g / dL not related to therapy or other non-myeloma-related conditions, (f) a rise in serum creatinine by 2 mg / dL or more from the start of the therapy and attributable to myeloma, and (g) hyperviscosity related to serum paraprotein.

[0039] Relapse of multiple myeloma from complete response is indicated by one or more the following: (a) the reappearance of serum or urine M-protein by immunofixation or electrophoresis, (b) the development of >5% plasma cells in the bone marrow, and (c) the appearance of any other sign of progression including, but not limited to, the development of new plasmacytoma(s), the development of lytic bone lesion(s), or hypercalcemia ( > 11 mg / dL). In other embodiments, the subject is determined to exhibit relapse of multiple myeloma from minimum residual disease (MRD) according to one or more of the following: (a) the loss of MRD negative state (as shown by evidence of clonal plasma cells on nextgeneration flow (NGF) or next-generation sequencing (NGS), or positive imaging study for recurrence of myeloma), (b) the reappearance of serum or urine M-protein by immunofixation or electrophoresis, (c) the development of > 5% clonal plasma cells in the bone marrow, and (d) the appearance of any other sign of progression, including, but not limited to, the development of new plasmacytoma(s), the development of lytic bone lesion(s), or hypercalcemia ( > 11 mg / dL).

[0040] The phrase “sequential administration” as used herein , is meant to indicate that the CD73 inhibitor and the anti-CD38 agent, and optionally one or more additional agents, are administered in sequence, rather than concurrently.

[0041] Compound 1 is ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3- hydroxypropan-2-yl)phosphonic acid:the disclosed methods, Compound 1 may be used in the form a free base. In some embodiments, Compound 1 may beused in the form of a pharmaceutically acceptable salt. In some embodiments, Compound 1 is used in the form of a gentisate.

[0042] The terms “gentisate” or “gentisate form,” as used herein, refer to a form of Compound 1 in association with gentisic acid. As contemplated herein, a gentisate or gentisate form may be (a) a salt form comprising Compound 1 and gentisic acid, (b) a co-crystal comprising Compound 1 and gentisic acid, or (c) a mixture of a salt comprising Compound 1 and gentisic acid and a co-crystal comprising Compound 1 and gentisic acid.

[0043] The term “co-crystal” as used herein means a crystalline material comprising two or more different molecules, one of which is Compound 1 , in a defined stoichiometric ratio within the same crystal lattice that are associated by nonionic and noncovalent bonds. In one embodiment is provided a co-crystal comprising Compound 1 and gentisic acid.

[0044] The term “gentisate salt,” as used herein means a salt formed between Compound 1 and gentisic acid.

[0045] The term “gentisic acid” as used herein means the compound having Chemical Abstracts Registry No. 490-79-9, the chemical name 2, 5 -dihydroxybenzoic acid, and the chemical structure below:

[0046] Provided herein are methods of treating a subject having multiple myeloma, comprising administering to the subject a CD73 inhibitor and an anti-CD38 agent.

[0047] In some embodiments, the CD73 inhibitor is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single-chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate.

[0048] In some embodiments, the CD73 inhibitor is a small molecule. In some such embodiments, the CD73 inhibitor may have a molecular weight of less than or equal to 1000 Daltons, or less than or equal to 750 Daltons. For example, the small molecule CD73 inhibitor may have a molecular weight between 300 Daltons and 1000 Daltons, or between 400 Daltons and 1000 Daltons, or between 500 Daltons and 1000 Daltons, or between 600 Daltons and 1000 Daltons, or between 700 Daltons and 1000 Daltons, or between 900 Daltons and 1000 Daltons. In other such embodiments, the small molecule CD73 inhibitor may have a molecular weight between 300 Daltons and 900 Daltons, or between 300 Daltons and 800 Daltons, or between 300 Daltons and 700 Daltons, or between 300 Daltons and 600 Daltons, or between 300 Daltons and 500 Daltons, or between 300 Daltons and 400 Daltons.

[0049] In some embodiments, the CD73 inhibitor is selected from Compound 1, AB680 (quemliclustat), CB-708 (ATG-037), ATG-047, LY3475070, or a pharmaceutically acceptable salt thereof. In some embodiments, the CD73 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the CD73 inhibitor is the free base of Compound 1. In some embodiments, the CD73 inhibitor is a pharmaceutically acceptable salt of Compound 1. In some embodiments, the CD73 inhibitoris agentisate form of Compound 1. In some embodiments, the CD73 inhibitor is AB680 (quemliclustat), or a pharmaceutically acceptable salt thereof. In some embodiments, the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof. In some embodiments, the CD73 inhibitor is ATG- 047, or a pharmaceutically acceptable salt thereof. In some embodiments, the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the CD73 inhibitor is an antibody. In some embodiments, the CD73 inhibitor is an antibody selected from oleclumab, BMS-986179, NZV930, mupadolimab, uliledlimab, INCA00186, Sym024, IBI325, AK119, JAB-BX102, IPH5301, HLX23, and GS-1423. In some embodiments, the CD73 inhibitor is oleclumab. In some embodiments, the CD73 inhibitor is BMS- 986179. In some embodiments, the CD73 inhibitor is NZV930. In some embodiments, the CD73 inhibitor is mupadolimab. In some embodiments, the CD73 inhibitor is uliledlimab. In some embodiments, the CD73 inhibitor is INCA00186. In some embodiments, the CD73 inhibitor is Sym024. In some embodiments, the CD73 inhibitor is IBI325. In some embodiments, the CD73 inhibitor is AK119. In some embodiments, the CD73 inhibitor is JAB-BX102. In some embodiments, the CD73 inhibitor is IPH5301 . In some embodiments, the CD73 inhibitor is HLX23. In some embodiments, the CD73 inhibitor is GS- 1423.

[0051] In some embodiments, the anti-CD38 agent is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single-chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate. In some embodiments, the anti-CD38 agent is an antibody. In some embodiments, the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the anti-CD38 agent is daratumumab. In some embodiments, the anti-CD38 agent is isatuximab. In some embodiments, the anti-CD38 agent is MOR202. In some embodiments, the anti-CD38 agent is TAK-079.

[0052] In some embodiments, the CD73 inhibitor is a small molecule, and the anti-CD38 agent is an antibody.

[0053] In some embodiments, the CD73 inhibitor is selected from Compound 1, AB680, CB-708 (ATG- 037), ATG-047, LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is an antibody selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0054] In some embodiments, the CD73 inhibitor is the free base of Compound 1, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is a pharmaceutically acceptable salt of Compound 1, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is a gentisate form of Compound 1, and the anti-CD38 agent is an antibody.

[0055] In some embodiments, the CD73 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is the free base of Compound 1, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is a pharmaceutically acceptable salt of Compound 1, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is a gentisate form of Compound 1, and the anti-CD38 agent is daratumumab.

[0056] In some embodiments, the CD73 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is the free base of Compound 1, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is a pharmaceutically acceptable salt of Compound 1, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is a gentisate form of Compound 1, and the anti-CD38 agent is isatuximab.

[0057] In some embodiments, the CD73 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is the free base of Compound 1, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is a pharmaceutically acceptable salt of Compound 1, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is a gentisate form of Compound 1, and the anti-CD38 agent is MOR202.

[0058] In some embodiments, the CD73 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079. In some embodiments, the CD73 inhibitor is the free base of Compound 1, and the anti-CD38 agent is TAK-079. In some embodiments, the CD73 inhibitor is a pharmaceutically acceptable salt of Compound 1, and the anti-CD38 agent is TAK-079. In some embodiments, the CD73 inhibitor is a gentisate form of Compound 1, and the anti-CD38 agent is TAK- 079.

[0059] In some embodiments, the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0060] In some embodiments, the CD73 inhibitor is CB-708 (ATG-037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is CB-708 (ATG-037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is CB-708 (ATG-037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is CB-708 (ATG-037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is CB-708 (ATG-037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0061] In some embodiments, the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti- CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is ATG-047, or a pharmaceuticallyacceptable salt thereof, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0062] In some embodiments, the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0063] In some embodiments, the CD73 inhibitor is an antibody, and the anti-CD38 agent is an antibody. In some embodiments, the CD73 inhibitor is selected from oleclumab, BMS-986179, NZV930, mupadolimab, uliledlimab, INCA00186, Sym024, IBI325, AK119, JAB-BX102, IPH5301, HLX23, and GS-1423, and the anti-CD38 agent is an antibody. In some embodiments, the anti-CD38 agent is an antibody selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0064] In some embodiments, the CD73 inhibitor is oleclumab, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is oleclumab, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is oleclumab, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is oleclumab, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is oleclumab, and the anti-CD38 agent is TAK-079.

[0065] In some embodiments, the CD73 inhibitor is BMS-986179, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is BMS-986179, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is BMS-986179, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is BMS- 986179, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is BMS-986179, and the anti-CD38 agent is TAK-079.

[0066] In some embodiments, the CD73 inhibitor is NZV930, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is NZV930, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is NZV930, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is NZV930, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is NZV930, and the anti- CD38 agent is TAK-079.

[0067] In some embodiments, the CD73 inhibitor is mupadolimab, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is mupadolimab, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is mupadolimab, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor ismupadolimab, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is mupadolimab, and the anti-CD38 agent is TAK-079.

[0068] In some embodiments, the CD73 inhibitor is uliledlimab, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is uliledlimab, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is uliledlimab, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is uliledlimab, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is uliledlimab, and the anti-CD38 agent is TAK-079.

[0069] In some embodiments, the CD73 inhibitor is INCA00186, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is INCA00186, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is INCA00186, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is INCA00186, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is INCA00186, and the anti-CD38 agent is TAK-079.

[0070] In some embodiments, the CD73 inhibitor is Sym024, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is Sym024, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is Sym024, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is Sym024, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is Sym024, and the anti-CD38 agent is TAK-079.

[0071] In some embodiments, the CD73 inhibitor is IBI325, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is IBI325, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is IBI325, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is IBI325, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is IBI325, and the anti-CD38 agent is TAK- 079.

[0072] In some embodiments, the CD73 inhibitor is AK119, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is AK119, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is AK119, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is AK119, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is AK119, and the anti-CD38 agent is TAK- 079.

[0073] In some embodiments, the CD73 inhibitor is JAB-BX102, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is JAB-BX102, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is JAB- BX102, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is JAB-BX102, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is JAB-BX102, and the anti-CD38 agent is TAK-079.

[0074] In some embodiments, the CD73 inhibitor is IPH5301, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is IPH5301, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is IPH5301, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is IPH5301, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is IPH5301, and the anti- CD38 agent is TAK-079.

[0075] In some embodiments, the CD73 inhibitor is HLX23, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is HLX23, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is HLX23, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is HLX23, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is HLX23, and the anti-CD38 agent is TAK- 079.

[0076] In some embodiments, the CD73 inhibitor is GS-1423, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, the CD73 inhibitor is GS- 1423, and the anti-CD38 agent is daratumumab. In some embodiments, the CD73 inhibitor is GS-1423, and the anti-CD38 agent is isatuximab. In some embodiments, the CD73 inhibitor is GS-1423, and the anti-CD38 agent is MOR202. In some embodiments, the CD73 inhibitor is GS-1423, and the anti-CD38 agent is TAK-079.

[0077] Provided herein are methods of treating a subject having multiple myeloma, comprising administering to the subject (i) a CD73 inhibitor; (ii) an anti-CD38 agent; and (iii) one or more additional agents. In some embodiments, the one or more additional agents are selected from immunomodulatory agents , proteasome inhibitors , and monoclonal antibodies. In some embodiments, the one or more additional agents are selected from one or more immunomodulatory agents . In some embodiments, the one or more immunomodulatory agents are selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, the immunomodulatory agent (IMiD) is thalidomide. In some embodiments, the immunomodulatory agent (IMiD) is lenalidomide. In some embodiments, the immunomodulatory agent (IMiD) is pomalidomide. In some embodiments, the one or more additional agents are selected from one or more proteasome inhibitors . In some embodiments, the one or more proteasome inhibitors are selected from bortezomib, carfilzomib, and ixazomib. In some embodiments, the proteasome inhibitor (PI) is bortezomib. In some embodiments, the proteasome inhibitor (PI) is carfilzomib. In some embodiments, the proteasome inhibitor (PI) is ixazomib. In some embodiments, the one or more additional agents are selected from one or more monoclonal antibodies. In some embodiments, the one or more monoclonal antibodies are selected from elotuzumab and belantamab. In some embodiments, the one or more additional agents are selected from bortezomib, melphalan and prednisone. In some embodiments, the one or more additional agents are selected from bortezomib, thalidomide, and dexamethasone. In some embodiments, the one or more additional agents are selected from pomalidomide and dexamethasone. In some embodiments, the one or more additional agent is bortezomib. In some embodiments, the one or more additional agent is melphalan. In some embodiments, the one or more additional agent is prednisone.In some embodiments, the one or more additional agent is thalidomide. In some embodiments, the one or more additional agent is pomalidomide. In some embodiments, the one or more additional agent is dexamethasone.

[0078] In some embodiments, the subject is ineligible for autologous stem cell transplant.

[0079] In some embodiments, wherein the subject has received at least one prior therapy prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent, and wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma. In some embodiments, the multiple myeloma in the subject is determined to exhibit clinical relapse, relapse from complete response, or relapse from minimum residual disease (MRD). In some embodiments, the multiple myeloma in the subject is determined to exhibit clinical relapse. In some embodiments, the multiple myeloma in the subject is determined to exhibit relapse from complete response. In some embodiments, the multiple myeloma in the subject is determined to exhibit relapse from minimum residual disease (MRD).

[0080] In some embodiments, the method further comprises administering to the subject bortezomib, melphalan and prednisone, and wherein the subject is ineligible for autologous stem cell transplant.

[0081] In some embodiments, the method further comprises administering to the subject bortezomib, thalidomide, and dexamethasone, and wherein the subject is eligible for autologous stem cell transplant.

[0082] In some embodiments, the method further comprises administering to the subject bortezomib and dexamethasone, and wherein the subject has received at least one prior therapy prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent.

[0083] In some embodiments, the method further comprises administering to the subject carfilzomib and dexamethasone, and wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma. In some embodiments, the multiple myeloma in the subject is determined to exhibit clinical relapse, relapse from complete response, or relapse from minimum residual disease (MRD). In some embodiments, the multiple myeloma in the subject is determined to exhibit clinical relapse. In some embodiments, the multiple myeloma in the subject is determined to exhibit relapse from complete response. In some embodiments, the multiple myeloma in the subject is determined to exhibit relapse from minimum residual disease (MRD).

[0084] In some embodiments, the subject has received one to three prior lines of therapy prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent.

[0085] In some embodiments, the method further comprises administering to the subject pomalidomide and dexamethasone, and wherein the subject has received at least two prior therapies prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent including lenalidomide and a proteasome inhibitor.In some embodiments, the subject has received at least three prior therapies prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent including a proteasome inhibitor and an immunomodulatory agent. In some embodiments, the subject has received at least three prior therapies prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent including a proteasome inhibitor and an immunomodulatory agent, and the multiple myeloma in the subject isrelapsed or refractory multiple myeloma. In some embodiments, the multiple myeloma in the subject is determined to exhibit clinical relapse, relapse from complete response, or relapse from minimum residual disease (MRD). In some embodiments, the multiple myeloma in the subject is determined to exhibit clinical relapse. In some embodiments, the multiple myeloma in the subject is determined to exhibit relapse from complete response. In some embodiments, the multiple myeloma in the subject is determined to exhibit relapse from minimum residual disease (MRD).

[0086] In some embodiments, the CD73 inhibitor and the anti-CD38 agent are administered to the subject sequentially. In some embodiments, the CD73 inhibitor and the anti-CD38 agent are administered to the subject up to 8 weeks apart. In some embodiments, the CD73 inhibitor and the anti-CD38 agent are administered to the subject 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4, hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks apart.

[0087] In some embodiments, the CD73 inhibitor and the anti-CD38 agent are administered to the subject simultaneously.

[0088] In some embodiments, the CD73 inhibitor is administered to the subject once per day, twice per day, or three times per day. In some embodiments, the CD73 inhibitor is administered to the subject once per day. In some embodiments, the CD73 inhibitor is administered to the subject twice per day. In some embodiments, the CD73 inhibitor is administered to the subject three times per day.

[0089] In some embodiments, the anti-CD38 agent is administered to the subject once weekly. In some embodiments, the anti-CD38 agent is administered to the subject once weekly for a total of 8 weeks. In some embodiments, the anti-CD38 agent is administered to the subject once every two weeks. In some embodiments, the anti-CD38 agent is administered to the subject once every two weeks for a total of 8 weeks. In some embodiments, the anti-CD38 agent is administered to the subject once every four weeks. In some embodiments, the anti-CD38 agent is administered to the subject once every week for four weeks, followed by once every two weeks.

[0090] In some embodiments of a method of treating multiple myeloma, the subject has undergone autologous stem cell transplantation (ASCT) prior to administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0091] In some embodiments, the multiple myeloma in the subject is light chain myeloma, non -secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma. In some embodiments, the multiple myeloma in the subject is light chain myeloma. In some embodiments, the multiple myeloma in the subject is non- secretory myeloma. In some embodiments, the multiple myeloma in the subject is solitary plasmacytoma. In some embodiments, the multiple myeloma in the subject is extramedullary plasmacytoma. In some embodiments, the multiple myeloma in the subject is monoclonal gammopathy of undetermined significance (MGUS). In some embodiments, the multiple myeloma in the subject is smoldering multiple myeloma (SMM). In some embodiments, the multiple myeloma in the subject is immunoglobulin D (IgD)myeloma. In some embodiments, the multiple myeloma in the subject is immunoglobulin E (IgE) myeloma.

[0092] In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 1 month following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 2 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 3 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression- free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 4 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 5 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 6 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 7 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 8 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 9 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 10 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 11 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 12 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 18 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 2 years following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0093] In some embodiments, the subject experiences overall survival (OS) of at least 1 month following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 2 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 3 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 4 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 5 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 6 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 7 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 8 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 9 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 10 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 11 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 12 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 18 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject experiences overall survival (OS) of at least 2 years following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0094] In some embodiments, the subject achieves minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, following administration to the subject of the CD73 inhibitor and the anti-CD38 agent the subject achieves (a) flow minimum residual disease (MRD) negative status, (b) sequencing minimum residual disease (MRD) negative status, (c) flow minimum residual disease (MRD) negative status and imaging negative status, or (d) sequencing minimum residual disease (MRD) negative status and imaging negative status, each based on International Myeloma Working Group (IMWG) criteria.

[0095] In some embodiments, the subject achieves flow minimum residual disease (MRD) negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, a sample of bone marrow aspirate from the subject exhibits an absence of phenotypically aberrant clonal plasma cells by use of one or more next-generation flow techniques on bone marrow aspirates using the EuroFlow standard operationprocedure for minimum residual disease detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105nucleated cells or higher. Techniques and methods that may be used to determine flow minimum residual disease (MRD) negative status are known to those having ordinary skill in the art, including those disclosed in Kumar et al., The Lancet Oncology, 2016, 17, pp. e328 to e346.

[0096] In some embodiments, the subject achieves sequencing minimum residual disease (MRD) negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, a sample of bone marrow aspirate from the subject exhibits an absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using methods and techniques known to those having ordinary skill in the art, including, but not limited to, the LymphoSIGHT platform (or validated equivalent method), with a minimum sensitivity of 1 in 105nucleated cells or higher. Techniques and methods that may be used to determine sequencing minimum residual disease (MRD) negative status are known to those having ordinary skill in the art, including those disclosed in Kumar et al., The Lancet Oncology, 2016, 17, pp. e328 to e346.

[0097] In some embodiments, the subject achieves imaging minimum residual disease (MRD) negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, minimum residual disease (MRD) negative status indicates the disappearance of every area of increased tracer uptake found at baseline or a preceding positron emission tomography (PET) scan and / or computed tomography (CT) scan or decrease to less mediastinal blood pool standard uptake value (SUV) or decrease to less than that of surrounding normal tissue. Techniques and methods that may be used to determine imaging minimum residual disease (MRD) negative status are known to those having ordinary skill in the art, including those disclosed in Kumar et al., The Lancet Oncology, 2016, 17, pp. e328 to e346.

[0098] In some embodiments, the subject achieves flow minimum residual disease (MRD) negative status and imaging negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, a sample of bone marrow aspirate from the subject exhibits (a) an absence of phenotypically aberrant clonal plasma cells by use of one or more next-generation flow techniques on bone marrow aspirates using the EuroFlow standard operation procedure for minimum residual disease detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105nucleated cells or higher, and (b) the disappearance of every area of increased tracer uptake found at baseline or a preceding positron emission tomography (PET) scan and / or computed tomography (CT) scan or decrease to less mediastinal blood pool standard uptake value (SUV) or decrease to less than that of surrounding normal tissue.

[0099] In some embodiments, the subject achieves sequencing minimum residual disease (MRD) negative status and imaging negative status based on International Myeloma Working Group (IMWG)criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, a sample of bone marrow aspirate from the subject exhibits (a) an absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using methods and techniques known to those having ordinary skill in the art, including, but not limited, to the LymphoSIGHT platform (or validated equivalent method), with a minimum sensitivity of 1 in 105nucleated cells or higher, and (b) the disappearance of every area of increased tracer uptake found at baseline or a preceding positron emission tomography (PET) scan and / or computed tomography (CT) scan or decrease to less mediastinal blood pool standard uptake value (SUV) or decrease to less than that of surrounding normal tissue.

[0100] In some embodiments, the subject achieves sustained minimum residual disease (MRD) for a minimum of six months based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In other embodiments, the subject achieves sustained minimum residual disease (MRD) for a minimum of one year based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In other embodiments, the subject achieves sustained minimum residual disease (MRD) for a minimum of 18 months based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent. In some embodiments, the subject achieves minimum residual disease (MRD) negativity in a sample of bone the marrow for a time period, such as six months, 1 year, 18 months, or longer, as determined by (a) next- generation flow (NGF) or next-generation sequencing (NGS), or both by NGF and NGS, and (b) imaging in which the presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using methods and techniques known to those having ordinary skill in the art, including, but not limited to, the LymphoSIGHT platform (or validated equivalent method), with a minimum sensitivity of 1 in 105nucleated cells or higher.

[0101] In some embodiments, the CD73 inhibitor administered to the subject is Compound 1. In some embodiments, the CD73 inhibitor administered to the subject is Compound 1 in the form of the free base. In some embodiments, the CD73 inhibitor administered to the subject is Compound 1 in the form of a pharmaceutically acceptable salt. In some embodiments, the CD73 inhibitor administered to the subject is Compound 1 in the form of a gentisate. In some embodiments, the molar ratio between Compound 1 and gentisic acid is about 1 : 1 . In some embodiments, the molar ratio between Compound 1 and gentisic acid is about 2: 1 . In some embodiments, the molar ratio between Compound 1 and gentisic acid is about 1:2. In some embodiments, agentisate form is in a hydrated form. In some embodiments, the hydrated form of a gentisate form of Compound 1 is selected from hemi-hydrate, mono-hydrate, and di-hydrate forms. In some embodiments, the hydrated form is a hemi-hydrate. In some embodiments, the hydrated form is a mono-hydrate. In some embodiments, the hydrated form is a di-hydrate.

[0102] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form. In some embodiments, such a crystalline form exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 9.25 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits further peaks in an x-raypowder diffraction (XRPD) pattern at 6.97 ± 0.2° 2-theta, 20.53 ± 0.2° 2-theta, and 26.08 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 14.61 ± 0.2° 2-theta and 18.89 ± 0.2° 2-theta.

[0103] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form that exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 9.3 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 7.1 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 20.1 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 19.0 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 26.2 ± 0.2° 2-theta. In still further embodiments, the crystalline form exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 4.8 ± 0.2° 2-theta, 10.5 ± 0.2° 2-theta, and 14.8 ± 0.2° 2- theta.

[0104] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form comprises apeak in a differential scanning calorimetry pattern of from about 150 °C to about 170 °C. In still further embodiments, the crystalline form comprises a peak in a differential scanning calorimetry pattern of from about 150 °C to about 165 °C. In still further embodiments, the crystalline form comprises apeak in a differential scanning calorimetry pattern of from about 161 °C to about 162 °C.

[0105] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits a loss in mass in a thermal gravimetric analysis of between about 1% to about 5% upon heating from about 31 °C to about 150 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a loss in mass in a thermal gravimetric analysis of between about 3% to about 5% upon heating from about 31 °C to about 150 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a loss in mass in a thermal gravimetric analysis of about 5% upon heating from about 31 °C to about 150 °C.

[0106] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C. In further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 10 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C. In further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 15 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C. In further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 20 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C. In further embodiments is provided a crystalline form of a gentisate form ofCompound 1 , wherein the crystalline form exhibits a solubility of at least 25 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C.

[0107] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits a solubility of between about 10 mg / mL and about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of between about 15 mg / mL and about 30 mg / mL in an aqueous solution having a pH of 1.7 and a temperature of 37 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of between about 20 mg / mL and about 30 mg / mL in an aqueous solution having a pH of 1 .7 and a temperature of 37 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1 , wherein the crystalline form exhibits a solubility of between about 25 mg / mL and about 30 mg / mL in an aqueous solution having a pH of 1 .7 and a temperature of 37 °C.

[0108] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 2.5 and atemperature of 37 °C. In still further embodiments is provided a crystalline form of agentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 7.5 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 10 mg / mL in an aqueous solution having a pH of 2.5 and a temperature of 37 °C.

[0109] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits a solubility of at least 1 mg / mL in an aqueous solution having a pH of 4.4 and atemperature of 37 °C. In still further embodiments is provided a crystalline form of agentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 2.5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37 °C. In still further embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits a solubility of at least 7.5 mg / mL in an aqueous solution having a pH of 4.4 and a temperature of 37 °C.[OOHOJIn some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 5 °C for at least 7 days. In other embodiments is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 5 °C for at least 7 days. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein thecrystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 5 °C for at least one month. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 5 °C for at least one month. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 5 °C for at least 3 months. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 5 °C for at least 3 months.[OOlllJIn some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 25 °C and 60% relative humidity for at least 7 days. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 25 °C and 60% relative humidity for at least 7 days. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 25 °C and 60% relative humidity for at least one month. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 25 °C and 60% relative humidity for at least one month. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 25 °C and 60% relative humidity for at least 3 months. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 25 °C and 60% relative humidity for at least 3 months.

[0112] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits less than about 10% degradation when the form is stored at 40 °C and 75% relative humidity for at least 7 days. In other embodiments is provided crystalline form of a gentisate form of Compound 1, wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% of the total amount of a gentisate form of Compound 1 when the form is stored at 40 °C and 75% relative humidity for at least 7 days.

[0113] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 60 °C for one or more days. In still further embodiments is provided crystalline form of a gentisate form of Compound 1 , wherein the crystalline form exhibits less than about 9%, or less than about 8%, or less than about 7%, or less than about 6%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, or less than about 0.5% degradation of the total amount of a gentisate form of Compound 1 when the form is stored at 60 °C for one or more days.

[0114] In some embodiments, a gentisate form of Compound 1 may be used in a crystalline form, wherein the crystalline form exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8.26 ± 0.2° 2-theta. Further provided herein is a crystalline form of a gentisate form of Compound 1, wherein the crystalline form further exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 26.43 ± 0.2° 2- theta. In another embodiment is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form further exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 15.81 ± 0.2° 2-theta and 15.40 ± 0.2° 2-theta. In another embodiment is provided a crystalline form of a gentisate form of Compound 1, wherein the crystalline form further exhibits peaks in an x-ray powder diffraction (XRPD) pattern at 14.94 ± 0.2° 2-theta and 20.44 ± 0.2° 2-theta.

[0115] Also provided herein are the disclosed methods wherein the CD73 inhibitor, such as Compound 1, or a pharmaceutically acceptable salt thereof, is in the form of a pharmaceutical composition, comprising the CD73 inhibitor, and one or more pharmaceutically acceptable excipients. Also provided herein are the disclosed methods wherein the CD73 inhibitor is a gentisate form of Compound 1 in the form of a pharmaceutical composition, comprising a gentisate form of Compound 1, and one or more pharmaceutically acceptable excipients. Further provided herein are the disclosed methods wherein the anti-CD38 agent is in the form of a pharmaceutical composition, comprising the anti-CD38 agent, and one or more pharmaceutically acceptable excipients.

[0116] Also provided herein are the disclosed methods wherein the CD73 inhibitor is Compound 1 in the form of a pharmaceutical composition, comprising Compound 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises Compound 1 in the form of a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipient. In some embodiments, the pharmaceuticalcomposition comprises a gentisate form of Compound 1, and one or more pharmaceutically acceptable excipient.

[0117] Further provided herein are such pharmaceutical compositions, wherein the one or more pharmaceutically acceptable excipients comprises one or more diluents, binders, disintegrants, lubricants, antiadhesives, glidants, coloring agents, flavors, sweeteners, coating agents, plasticizers wetting agents, buffers, or adsorbents.

[0118] Among the one or more diluents that may be used are lactose, mannitol, xylitol, microcrystalline cellulose, dibasic calcium phosphate and starch. In some embodiments, the one or more diluents comprises from about 1% to about 80%, or from about 10% to about 80%, or from about 10% to about70%, or from about 15% to about 80%, or from about 20% to about 80%, or from about 15% to about75%, or from about 20% to about 75%, or from about 25% to about 75%, or from about 50% to about80%, or from about 50% to about 75%, or from about 60% to about 80%, or from about 60% to 75% of the total weight of the pharmaceutical compositions. In some embodiments, the diluent is lactose. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is xylitol. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is dibasic calcium phosphate. In some embodiments, the diluent is starch.

[0119] Also provided herein are such pharmaceutical compositions, wherein the one or more pharmaceutically acceptable excipients comprises one or more binders, wherein the one or more binders comprises from about 1% to about 80%, or from about 10% to about 80%, or from about 10% to about70%, or from about 15% to about 80%, or from about 20% to about 80%, or from about 15% to about75%, or from about 20% to about 75%, or from about 25% to about 75%, or from about 50% to about80%, or from about 50% to about 75%, or from about 60% to about 80%, or from about 60% to 75% of the total weight of the pharmaceutical compositions. In some embodiments, the one or more binders is selected from selected from methyl cellulose, microcrystalline cellulose, starch, and gums such as guar gum, and tragacanth, or a mixture thereof.

[0120] Also provided herein are such pharmaceutical compositions, wherein the one or more pharmaceutically acceptable excipients comprises one or more disintegrants, and wherein the one or more disintegrants comprises from about 0. 1% to about 10%, or from about 0. 1% to about 5%, or from about 0. 1% to about 4%, or from about 0. l%to about 3%, or from about 0. 1% to about 2%, or from about 0. 1% to about 1%, or from about 0. 1% to aboutO.75%, or from about 0.2% to about 1%, or from about 0.3% to about 1%, or from about 0.4% to about 1%, or from about 0.2% to about 0.8%, or from about 0.3% to about 0.75%, or from about 0.3%to about 0.7%, or from about 0.3% to about 0.6% by weight of the total weight of the pharmaceutical compositions. In some embodiments the one or more disintegrants is selected from starch, sodium starch glycolate, sodium alginate, carboxymethylcellulose sodium, methyl cellulose, croscarmellose sodium and crospovidone, or mixtures thereof. In some embodiments, the disintegrant is starch. In some embodiments, the disintegrant is sodium starch glycolate. In some embodiments, the disintegrant is sodium alginate. In some embodiments, the disintegrant is carboxymethylcellulose sodium. In some embodiments, the disintegrant is methyl cellulose. In someembodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is crospovidone.

[0121] Also provided herein are such pharmaceutical compositions, wherein the one or more pharmaceutically acceptable excipients comprises one or more lubricants, and wherein the one or more lubricants comprises from about 0. 1% to about 10%, or from about 0. l%to about 5%, or from about 0. 1% to about 4%, or from about 0. 1% to about 3%, or from about 0. 1% to about 2%, or from about 0. 1% to about 1%, or from about 0. 1% to about 0.75%, or from about 0.2% to about 1%, or from about 0.3% to about 1%, or from about 0.4% to about 1%, or from about 0.2% to about 0.8%, or from about 0.3% to about 0.75%, or from about 0.3%to about 0.7%, or from about 0.3% to about 0.6%by weight of the total weight of the pharmaceutical compositions. In a further embodiment, the one or more lubricants is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, and stearic acid, or mixtures thereof. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is calcium stearate. In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is stearic acid.

[0122] In some embodiments, the pharmaceutical compositions disclosed herein may comprise additional excipients including, but not limited, to buffering agents, glidants, preservatives, and coloring agents. Additional excipients such as bulking agents, tonicity agents, and chelating agents are also within the scope of the embodiments.

[0123] Non-limiting examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide / sodium bicarbonate co precipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.

[0124] In some embodiments, the pharmaceutical compositions disclosed herein may comprise a glidant. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, and the like. In some embodiments, the glidant is calcium phosphate tribasic. In some embodiments, the glidant is calcium silicate. In some embodiments, the glidant is cellulose. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is magnesium silicate. In some embodiments, the glidant is magnesium trisilicate. In some embodiments, the glidant is silicon dioxide. In some embodiments, the glidant is starch. In some embodiments, the glidant is talc.

[0125] In some embodiments, the pharmaceutical compositions disclosed herein may comprise a preservative. Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Exemplary preservatives include ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (methyl-, ethyl-, butyl-), benzoic acid, potassium sorbate, vanillin, and the like.

[0126] In some embodiments, the pharmaceutical compositions disclosed herein may comprise a coloring agent for identity and / or aesthetic purposes of the resultant liquid form. Suitable coloring agents illustratively include FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, and mixtures thereof.

[0127] Additional excipients are contemplated in the pharmaceutical compositions disclosed herein. These additional excipients are selected based on function and compatibility with the pharmaceutical compositions described herein and may be found, for example in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, PA: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, (Easton, PA: Mack Publishing Co 1975); Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms (New York, NY : Marcel Decker 1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed (Lippincott Williams & Wilkins 1999), herein incorporated by reference in their entirety.

[0128] The pharmaceutical compositions disclosed herein may be in a form suitable for oral dosage to a subject in need. Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of Compound 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. Capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings. In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and / or perfuming agents.

[0129] Also provided herein are the disclosed methods wherein the CD73 inhibitor is Compound 1, or a pharmaceutically acceptable salt thereof, and is in the form of tablets comprising Compound 1 , or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, colloidal silica dioxide, sodium stearyl fumarate, crospovidone, and magnesium stearate. Also provided herein are the disclosed methods wherein the CD73 inhibitor is a gentisate form of Compound 1 in the form of tablets comprising a gentisate form of Compound 1, microcrystalline cellulose, colloidal silica dioxide, sodium stearylfumarate, crospovidone, and magnesium stearate. In further embodiments, the tablets disclosed herein are as set forth in Table 1.Table 1

[0130] In another embodiment, the pharmaceutical compositions of the CD73 inhibitor and / or anti-CD38 agent disclosed herein may comprise a parenteral dose form. “Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and / or suspending agents.

[0131] In another embodiment, the pharmaceutical compositions disclosed herein may comprise atopical dose form. “Topical administration” includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compositions disclosed herein are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J. Pharm. Sci., 88(10), 955-958, by Finnin and Morgan (October 1999).

[0132] For intranasal administration or administration by inhalation, the pharmaceutical compositions disclosed herein are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the subject or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1,2-tetrafluoroethane or 1, 1, 1,2, 3, 3, 3 -heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

[0133] Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions disclosed herein may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3. sup. rd Ed.), American Pharmaceutical Association, Washington, 1999.

[0134] The doses of the compositions comprising the CD73 inhibitor or the anti-CD38 agent used according to the methods disclosed herein may differ, depending upon the subject’s (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors. An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the subject, the type and severity of the subject’s disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the subject. Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Numbered Embodiments

[0135] Embodiment 1: A method of treating a subject having multiple myeloma, comprising administering to the subject a CD73 inhibitor and an anti-CD38 agent.

[0136] Embodiment 2: The method of embodiment 1, wherein the CD73 inhibitor is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single -chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate.

[0137] Embodiment 3: The method of embodiment 2, wherein the CD73 inhibitor is a small molecule.

[0138] Embodiment 4: The method of embodiment 3, wherein the CD73 inhibitor is a small molecule having a molecular weight of equal to or less than 1000 Daltons.

[0139] Embodiment 5: The method of embodiment 3, wherein the CD73 inhibitor is a small molecule having a molecular weight of equal to or less than 750 Daltons.

[0140] Embodiment 6: The method of any one of embodiments 3 to 5, wherein the CD73 inhibitor is selected from(Compound 1), AB680 (quemliclustat), CB-708(ATG-037), ATG-047, and LY3475070, or a pharmaceutically acceptable salt thereof.

[0141] Embodiment 7: The method of any one of embodiments 3 to 5, wherein the CD73 inhibitor is(Compound 1), or pharmaceutically acceptable salt thereof.

[0142] Embodiment 8: The method of any one of embodiments 3 to 5, wherein the CD73 inhibitor is a gentisate form(Compound 1).

[0143] Embodiment 9: The method of embodiment 6, wherein the CD73 inhibitor is AB680 (quemliclustat), or a pharmaceutically acceptable salt thereof.

[0144] Embodiment 10: The method of embodiment 6, wherein the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof.

[0145] Embodiment 11: The method of embodiment 6, wherein the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof.

[0146] Embodiment 12: The method of embodiment 6, wherein the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof.

[0147] Embodiment 13: The method of any one of embodiments 1 to 2, wherein the CD73 inhibitor is an antibody.

[0148] Embodiment 14: The method of embodiment 13, wherein the CD73 inhibitor is an antibody selected from oleclumab, BMS-986179, NZV930, mupadolimab, uliledlimab, INCA00186, Sym024, IBI325, AK119, JAB-BX102, IPH5301, HLX23, and GS-1423.

[0149] Embodiment 15: The method of embodiment 14, wherein the CD73 inhibitor is oleclumab.

[0150] Embodiment 16: The method of embodiment 14, wherein the CD73 inhibitor is BMS-986179.

[0151] Embodiment 17: The method of embodiment 14, wherein the CD73 inhibitor is NZV930.

[0152] Embodiment 18: The method of embodiment 14, wherein the CD73 inhibitor is mupadolimab.

[0153] Embodiment 19: The method of embodiment 14, wherein the CD73 inhibitor is uliledlimab.

[0154] Embodiment 20: The method of embodiment 14, wherein the CD73 inhibitor is INCA00186.

[0155] Embodiment 21: The method of embodiment 14, wherein the CD73 inhibitor is Sym024.

[0156] Embodiment 22: The method of embodiment 14, wherein the CD73 inhibitor is IBI325.

[0157] Embodiment 23: The method of embodiment 14, wherein the CD73 inhibitor is AK119.

[0158] Embodiment 24: The method of embodiment 14, wherein the CD73 inhibitor is JAB-BX102.

[0159] Embodiment 25: The method of embodiment 14, wherein the CD73 inhibitor is IPH5301.

[0160] Embodiment 26: The method of embodiment 14, wherein the CD73 inhibitor is HLX23.

[0161] Embodiment 27: The method of embodiment 14, wherein the CD73 inhibitor is GS-1423.

[0162] Embodiment 28: The method of any one of embodiments 1 to 27, wherein the anti-CD38 agent is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single-chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate.

[0163] Embodiment 29: The method of embodiment 28, wherein the anti-CD38 agent is an antibody.

[0164] Embodiment 30: The method of embodiment 29, wherein the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0165] Embodiment 31: The method of embodiment 30, wherein the anti-CD38 agent is daratumumab.

[0166] Embodiment 32: The method of embodiment 30, wherein the anti-CD38 agent is isatuximab.

[0167] Embodiment 33: The method of embodiment 30, wherein the anti-CD38 agent is MOR202.

[0168] Embodiment 34: The method of embodiment 30, wherein the anti-CD38 agent is TAK-079.

[0169] Embodiment 35: The method of embodiment 1, wherein the CD73 inhibitor is a small molecule, and the anti-CD38 agent is an antibody.

[0170] Embodiment 36: The method of embodiment 35, wherein the CD73 inhibitor is selected from(Compound 1), AB680, CB-708 (ATG-037), ATG-047, andLY3475070, or a pharmaceutically acceptable salt thereof.

[0171] Embodiment 37: The method of embodiment 35, wherein the CD73 inhibitor is a gentisate form(Compound 1).

[0172] Embodiment 38: The method of embodiment 35, wherein the CD73 inhibitor is(Compound 1), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab.

[0173] Embodiment 39: The method of embodiment 35, wherein the CD73 inhibitor is a gentisate form(Compound 1), and the anti-CD38 agent is daratumumab.

[0174] Embodiment 40: The method of embodiment 35, wherein the CD73 inhibitor is(Compound 1), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab.

[0175] Embodiment 41: The method of embodiment 35, wherein the CD73 inhibitor is a gentisate form(Compound 1), and the anti-CD38 agent is isatuximab.

[0176] Embodiment 42: The method of embodiment 35, wherein the CD73 inhibitor is(Compound 1), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202.

[0177] Embodiment 43: The method of embodiment 35, wherein the CD73 inhibitor is a gentisate form(Compound 1), and the anti-CD38 agent is MOR202.

[0178] Embodiment 44: The method of embodiment 35, wherein the CD73 inhibitor is(Compound 1), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0179] Embodiment 45: The method of embodiment 35, wherein the CD73 inhibitor is a gentisate form(Compound 1), and the anti-CD38 agent is TAK-079.

[0180] Embodiment 46: The method of embodiment 35, wherein the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof.

[0181] Embodiment 47: The method of embodiment 46, wherein the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab.

[0182] Embodiment 48: The method of embodiment 46, wherein the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab.

[0183] Embodiment 49: The method of embodiment 46, wherein the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202.

[0184] Embodiment 50: The method of embodiment 46, wherein the CD73 inhibitor is AB680, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0185] Embodiment 51 : The method of embodiment 35, wherein the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof.

[0186] Embodiment 52: The method of embodiment 51, wherein the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab.

[0187] Embodiment 53: The method of embodiment 51, wherein the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab.

[0188] Embodiment 54: The method of embodiment 51, wherein the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202.

[0189] Embodiment 55: The method of embodiment 51, wherein the CD73 inhibitor is CB-708 (ATG- 037), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0190] Embodiment 56: The method of embodiment 35, wherein the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof.

[0191] Embodiment 57: The method of embodiment 56, wherein the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab.

[0192] Embodiment 58: The method of embodiment 56, wherein the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab.

[0193] Embodiment 59: The method of embodiment 56, wherein the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202.

[0194] Embodiment 60: The method of embodiment 56, wherein the CD73 inhibitor is ATG-047, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0195] Embodiment 61 : The method of embodiment 35, wherein the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof.

[0196] Embodiment 62: The method of embodiment 61, wherein the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab.

[0197] Embodiment 63: The method of embodiment 61, wherein the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab.

[0198] Embodiment 64: The method of embodiment 61, wherein the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is MOR202.

[0199] Embodiment 65: The method of embodiment 61, wherein the CD73 inhibitor is LY3475070, or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is TAK-079.

[0200] Embodiment 66: The method of embodiment 1, wherein the CD73 inhibitor is an antibody, and the anti-CD38 agent is an antibody.

[0201] Embodiment 67: The method of embodiment 66, wherein the CD73 inhibitor is selected from oleclumab, BMS-986179, NZV930, mupadolimab, uliledlimab, INCA00186, Sym024, IBI325, AK119, JAB-BX102, IPH5301, HLX23, and GS-1423.

[0202] Embodiment 68: The method of embodiment 67, wherein the anti-CD38 agent is an antibody selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0203] Embodiment 69: The method of embodiment 67, wherein the CD73 inhibitor is oleclumab, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0204] Embodiment 70: The method of embodiment 69, wherein the anti-CD38 agent is daratumumab.

[0205] Embodiment 71 : The method of embodiment 69, wherein the anti-CD38 agent is isatuximab.

[0206] Embodiment 72: The method of embodiment 69, wherein the anti-CD38 agent is MOR202.

[0207] Embodiment 73: The method of embodiment 69, wherein the anti-CD38 agent is TAK-079.

[0208] Embodiment 74: The method of embodiment 67, wherein the CD73 inhibitor is BMS-986179 and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0209] Embodiment 75: The method of embodiment 74, wherein the anti-CD38 agent is daratumumab.

[0210] Embodiment 76: The method of embodiment 74, wherein the anti-CD38 agent is isatuximab.

[0211] Embodiment 77: The method of embodiment 67, wherein the CD73 inhibitor is NZV930, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0212] Embodiment 78: The method of embodiment 77, wherein the anti-CD38 agent is daratumumab.

[0213] Embodiment 79: The method of embodiment 77, wherein the anti-CD38 agent is isatuximab.

[0214] Embodiment 80: The method of embodiment 77, wherein the anti-CD38 agent is MOR202.

[0215] Embodiment 81: The method of embodiment 77, wherein the anti-CD38 agent is TAK-079.

[0216] Embodiment 82: The method of embodiment 67, wherein the CD73 inhibitor is mupadolimab, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0217] Embodiment 83: The method of embodiment 82, wherein the anti-CD38 agent is daratumumab.

[0218] Embodiment 84: The method of embodiment 82, wherein the anti-CD38 agent is isatuximab.

[0219] Embodiment 85: The method of embodiment 82, wherein the anti-CD38 agent is MOR202.

[0220] Embodiment 86: The method of embodiment 82, wherein the anti-CD38 agent is TAK-079.

[0221] Embodiment 87: The method of embodiment 67, wherein the CD73 inhibitor is uliledlimab, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0222] Embodiment 88: The method of embodiment 87, wherein the anti-CD38 agent is daratumumab.

[0223] Embodiment 89: The method of embodiment 87, wherein the anti-CD38 agent is isatuximab.

[0224] Embodiment 90: The method of embodiment 87, wherein the anti-CD38 agent is MOR202.

[0225] Embodiment 91: The method of embodiment 87, wherein the anti-CD38 agent is TAK-079.

[0226] Embodiment 92: The method of embodiment 67, wherein the CD73 inhibitor is INCA00186, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0227] Embodiment 93: The method of embodiment 92, wherein the anti-CD38 agent is daratumumab.

[0228] Embodiment 94: The method of embodiment 92, wherein the anti-CD38 agent is isatuximab.

[0229] Embodiment 95: The method of embodiment 92, wherein the anti-CD38 agent is MOR202.

[0230] Embodiment 96: The method of embodiment 92, wherein the anti-CD38 agent is TAK-079.

[0231] Embodiment 97: The method of embodiment 67, wherein the CD73 inhibitor is Sym024, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0232] Embodiment 98: The method of embodiment 97, wherein the anti-CD38 agent is daratumumab.

[0233] Embodiment 99: The method of embodiment 97, wherein the anti-CD38 agent is isatuximab.

[0234] Embodiment 100: The method of embodiment 97, wherein the anti-CD38 agent is MOR202.

[0235] Embodiment 101: The method of embodiment 97, wherein the anti-CD38 agent is TAK-079.

[0236] Embodiment 102: The method of embodiment 67, wherein the CD73 inhibitor is IBI325, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0237] Embodiment 103: The method of embodiment 102, wherein the anti-CD38 agent is daratumumab.

[0238] Embodiment 104: The method of embodiment 102, wherein the anti-CD38 agent is isatuximab.

[0239] Embodiment 105: The method of embodiment 67, wherein the CD73 inhibitor is AK119, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0240] Embodiment 106: The method of embodiment 105, wherein the anti-CD38 agent is daratumumab.

[0241] Embodiment 107: The method of embodiment 105, wherein the anti-CD38 agent is isatuximab.

[0242] Embodiment 108: The method of embodiment 105, wherein the anti-CD38 agent is MOR202.

[0243] Embodiment 109: The method of embodiment 105, wherein the anti-CD38 agent is TAK-079.

[0244] Embodiment 110: The method of embodiment 67, wherein the CD73 inhibitor is JAB-BX102, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0245] Embodiment 111 : The method of embodiment 110, wherein the anti-CD38 agent is daratumumab.

[0246] Embodiment 112: The method of embodiment 110, wherein the anti-CD38 agent is isatuximab.

[0247] Embodiment 113: The method of embodiment 110, wherein the anti-CD38 agent is MOR202.

[0248] Embodiment 114: The method of embodiment 110, wherein the anti-CD38 agent is TAK-079.

[0249] Embodiment 115: The method of embodiment 67, wherein the CD73 inhibitor is IPH5301, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0250] Embodiment 116: The method of embodiment 115, wherein the anti-CD38 agent is daratumumab.

[0251] Embodiment 117: The method of embodiment 115, wherein the anti-CD38 agent is isatuximab.

[0252] Embodiment 118: The method of embodiment 115, wherein the anti-CD38 agent is MOR202.

[0253] Embodiment 119: The method of embodiment 115, wherein the anti-CD38 agent is TAK-079.

[0254] Embodiment 120: The method of embodiment 67, wherein the CD73 inhibitor is HLX23, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0255] Embodiment 121 : The method of embodiment 120, wherein the anti-CD38 agent is daratumumab.

[0256] Embodiment 122: The method of embodiment 120, wherein the anti-CD38 agent is isatuximab.

[0257] Embodiment 123: The method of embodiment 120, wherein the anti-CD38 agent is MOR202.

[0258] Embodiment 124: The method of embodiment 120, wherein the anti-CD38 agent is TAK-079.

[0259] Embodiment 125: The method of embodiment 67, wherein the CD73 inhibitor is GS-1423, and the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[0260] Embodiment 126: The method of embodiment 125, wherein the anti-CD38 agent is daratumumab.

[0261] Embodiment 127: The method of embodiment 125, wherein the anti-CD38 agent is isatuximab.

[0262] Embodiment 128: The method of embodiment 125, wherein the anti-CD38 agent is MOR202.

[0263] Embodiment 129: The method of embodiment 125, wherein the anti-CD38 agent is TAK-079.

[0264] Embodiment 130: The method of any one of embodiments 1 to 129, further comprising administering to the subject one or more additional agents.

[0265] Embodiment 131 : The method of embodiment 130, wherein the one or more additional agents are selected from immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies.

[0266] Embodiment 132: The method of embodiment 131, wherein the one or more additional agents are selected from one or more immunomodulatory agents .

[0267] Embodiment 133: The method of embodiment 132, wherein the one or more immunomodulatory agents are selected from thalidomide, lenalidomide, and pomalidomide.

[0268] Embodiment 134: The method of embodiment 131, wherein the one or more additional agents are selected from one or more proteasome inhibitors .

[0269] Embodiment 135: The method of embodiment 134, wherein the one or more proteasome inhibitors are selected from bortezomib, carfilzomib, and ixazomib.

[0270] Embodiment 136: The method of embodiment 131, wherein the one or more additional agents are selected from one or more monoclonal antibodies.

[0271] Embodiment 137: The method of embodiment 136, wherein the one or more monoclonal antibodies are selected from elotuzumab and belantamab.

[0272] Embodiment 138: The method of any one of embodiments 1 to 137, wherein the subject is ineligible for autologous stem cell transplant.

[0273] Embodiment 139: The method of any one of embodiments 1 to 138, wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma.

[0274] Embodiment 140: The method of any one of embodiments 1 to 139, wherein the subject has received at least one prior therapy prior to the administration to the subject of the CD73 inhibitor and anti- CD38 agent, and the multiple myeloma in the subject is relapsed or refractory multiple myeloma.

[0275] Embodiment 141: The method of embodiment 140, further comprising administering to the subject bortezomib, melphalan and prednisone, and wherein the subject is ineligible for autologous stem cell transplant.

[0276] Embodiment 142: The method of embodiment 130, further comprising administering to the subject bortezomib, thalidomide, and dexamethasone, and wherein the subject is eligible for autologous stem cell transplant.

[0277] Embodiment 143: The method of embodiment 130, further comprising administering to the subject bortezomib and dexamethasone, and wherein the subject has received at least one prior therapy prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent.

[0278] Embodiment 144: The method of embodiment 130, further comprising administering to the subject carfilzomib and dexamethasone, and wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma.

[0279] Embodiment 145: The method of embodiment 144, wherein the subject has received one to three prior lines of therapy prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent.

[0280] Embodiment 146: The method of embodiment 130, further comprising administering to the subject pomalidomide and dexamethasone, and wherein the subject has received at least two prior therapies prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent including lenalidomide and a proteasome inhibitor.

[0281] Embodiment 147 : The method of embodiment 146, wherein the subject has received at least three prior therapies prior to the administration to the subject of the CD73 inhibitor and anti-CD38 agent including a proteasome inhibitor and an immunomodulatory agent.

[0282] Embodiment 148: The method of embodiment 147, wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma.

[0283] Embodiment 149: The method any one of embodiments 1 to 148, wherein the CD73 inhibitor and the anti-CD38 agent are administered to the subject sequentially.

[0284] Embodiment 150: The method any one of embodiments 1 to 148, wherein the CD73 inhibitor and the anti-CD38 agent are administered to the subject simultaneously.

[0285] Embodiment 151 : The method of any one of embodiments 1 to 150, wherein the CD73 inhibitor is administered to the subject once per day, twice per day, or three times per day.

[0286] Embodiment 152: The method of embodiment 151, wherein the CD73 inhibitor is administered to the subject once per day.

[0287] Embodiment 153: The method of embodiment 151, wherein the CD73 inhibitor is administered to the subject twice per day.

[0288] Embodiment 154: The method of embodiment 151, wherein the CD73 inhibitor is administered to the subject three times per day.

[0289] Embodiment 155: The method of any one of embodiments 1 to 154, wherein the anti-CD38 agent is administered to the subject once weekly.

[0290] Embodiment 156: The method of embodiment 155, wherein the anti-CD38 agent is administered to the subject once weekly for a total of 8 weeks.

[0291] Embodiment 157: The method of any one of embodiments 1 to 154, wherein the anti-CD38 agent is administered to the subject once every two weeks.

[0292] Embodiment 158: The method of embodiment 157, wherein the wherein the anti-CD38 agent is administered to the subject once every two weeks for a total of 8 weeks.

[0293] Embodiment 159: The method of any one of embodiments 1 to 154, wherein the anti-CD38 agent is administered to the subject once every four weeks.

[0294] Embodiment 160: The method of embodiment 159, wherein the anti-CD38 agent is administered to the subject once every week for four weeks, followed by once every two weeks.

[0295] Embodiment 161: The method of any one of embodiments 1 to 160, wherein the subject has undergone autologous stem cell transplantation (ASCI) prior to administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0296] Embodiment 162: The method of any one of embodiments 1 to 161, wherein the multiple myeloma in the subject is light chain myeloma, non-secretory myeloma, solitary plasmacytoma, extramedullary plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), immunoglobulin D (IgD) myeloma, or immunoglobulin E (IgE) myeloma.

[0297] Embodiment 163: The method of any one of embodiments 1 to 162, wherein the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 6 months following administration to the subject of the CD73 inhibitor and the anti- CD38 agent.

[0298] Embodiment 164: The method of any one of embodiments 1 to 163, wherein the subject experiences overall survival (OS) of at least 6 months following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0299] Embodiment 165: The method of any one of embodiments 1 to 164, wherein the subject achieves minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0300] Embodiment 166: The method of any one of embodiments 1 to 165, wherein the subject achieves flow minimum residual disease (MRD) negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0301] Embodiment 167: The method of any one of embodiments 1 to 166, wherein the subject achieves sequencing minimum residual disease (MRD) negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0302] Embodiment 168: The method of any one of embodiments 1 to 167, wherein the subject achieves flow minimum residual disease (MRD) negative status and imaging negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0303] Embodiment 169: The method of any one of embodiments 1 to 168, wherein the subject achieves sequencing minimum residual disease (MRD) negative status and imaging negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.

[0304] Embodiment 170: The method of any one of embodiments 1 to 169, wherein the subject achieves sustained minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the CD73 inhibitor and the anti-CD38 agent.EXAMPLESExample 1. Preparation of ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro- 4-(cyclopentylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-3-hydroxypropan-2-yl)phosphonic acidStep A. (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(4,6-dichloro-lH-pyrazolo[3,4-d]pyrimidin-l- yl)tetrahydrofuran-3,4-diyl diacetate (la)

[0305] P-D-Ribofuranose 1,2,3,5-tetraacetate (5.73 g, 17.99 mmol) was heated at 90 °C for 10 min, 4,6- dichloro-lH-pyrazolo[3,4-d]pyrimidine (1.5 g, 17.99 mmol) and SnCh (60 mg) was added successively. After the mixture was heated at 130 °C under reduced pressure for 15 min, it was cooled to rt, diluted with water, and extracted with DCM. The combined organics were washed with water, brine, dried and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate from 10: 1 to 5: 1) to give the title compound (la) (2.4 g, 68%) as a yellow solid.Step B. (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(6-chloro-4-(cyclopentylamino)-lH-pyrazolo[3,4- d]pyrimidin-l-yl)tetrahydrofuran-3,4-diyl diacetate (lb)

[0306] To an oven-dried flask was added la (5.2 g, 11.63 mmol) followed by ethanol (53.24 mL). To this solution was added triethylamine (2.43 mL, 17.44 mmol) followed by cyclopentylamine (1.38 mL, 13.95 mmol). After the mixture was stirred and heated at 50 °C for 15 min, it was cooled to rt, concentrated, and purified by column chromatography (20 to 45% ethyl acetate / hexanes, a gradient elution) to provide the title compound (lb) (5.02 g, 87%) as a white solid, m / z (ESI, +ve ion) = 496.1 [M+H]+.Step C. (2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(4-((tert-butoxycarbonyl)(cyclopentyl)amino)-6-chloro- lH-pyrazolo[3,4-d]pyrimidin-l-yl)tetrahydrofuran-3,4-diyl diacetate (1c)

[0307] To a solution of lb (12.6 g, 25.4 mmol) in MeCN (120 mL) was added triethylamine (5.14 g, 50.9 mmol) followed by di-tert-butyl dicarbonate (44.35 g, 203.6 mmol) and 4 -dimethylaminopyridine (0.31 g, 2.54 mmol). After the mixture was allowed to stir overnight, it was concentrated and partitioned between EtOAc (50 mL) and sat. NaHCCL. The organic layer was washed with brine, dried with Na2SOr, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate:8: 1) to provide the title compound (1c) (10.56 g, 70% yield) as a yellow solid, m / z (ESI, +ve ion) = 596.72 [M+H]+.Step D. tert-Butyl (6-chloro-l-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2- yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (Id)

[0308] To an oven-dried flask was added 1c (10.56 g, 17.78 mmol), followed by ammonia (5.0 M, 140 mL) in methanol. The mixture was stirred overnight and then concentrated. The crude oil was purified by column chromatography to afford the title compound (Id) (7.39 g, 89% yield) as a yellow solid, m / z (ESI, +ve ion) = 470.3 [M+H]+.Step E. tert-Butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3,4-d][l,3] dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4- yl)(cyclopentyl)carbamate (le)

[0309] To a solution of Id (7.39 g, 15.75 mmol) and 2,2-dimethoxypropane (4.92 g, 47.27 mmol) in DMF (75 mL) was added TsOHEfcO (0.6 g, 3. 15 mmol). After the mixture was stirred at 70 °C for 1 h, it was cooled down and quenched with sat. NaHCCh (100 mL). The mixture was extracted with EtOAc (50 mL) and the combined organic layers were washed with brine, dried with Na2SC>4, filtered, and concentrated. The crude oil was purified by column chromatography (petroleum ether / ethyl acetate: 8: 1) to afford the title compound (le) (5.5 g, 68% yield) as a yellow solid, m / z (ESI, +ve ion) = 510.4 [M+H]+.Step F. Ethyl 2-(((3aR,4R,6R,6aR)-6-(4-((tert-butoxycarbonyl)(cyclopentyl)amino)-6-chloro-lH- pyrazolo[3,4-d]pyrimidin-l-yl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3] dioxol-4-yl)methoxy)-2- (diethoxyphosphoryl)acetate (If)

[0310] To a solution of ethyl 2-diazo-2-(diethoxyphosphoryl)acetate (13.5 g, 54.13 mmol) and le (5.5 g, 10.83 mmol) in toluene (80 mL) was added Rh2(OAc)4 (0.96 g, 2. 17 mmol) under N2. After the mixture was stirred at 95 °C overnight, it was concentrated and purified by column chromatography (petroleum ether / ethyl acetate: 5: 1) to afford the title compound (If) (6 g, 76% yield) as a yellow oil. m / z (ESI, +ve ion) = 732.2 [M+H]+.Step G. Ethyl 2-[[(3aR,4R,6R,6aR)-4-[4-[tert-butoxycarbonyl(cyclopentyl)amino]-6-chloro- pyrazolo[3,4-d]pyrimidin-l-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [l,3] dioxol-6- yl]methoxy]-2-diethoxyphosphoryl-3-(2-trimethylsilylethoxy)propanoate (1g)

[0311] To a solution of the compound If (1.2 g, 1.64 mmol) in THF (33 mL) was added dropwise sodium bis(trimethylsilyl)amide (1.0 M in THF, 2.13 mL, 2. 13 mmol) at -15 °C. After stirring at -15 °C for 25 min, tetra-w-butylammonium iodide (303 mg, 0.820 mmol) was added, immediately followed by the dropwise addition of 2-(chloromethoxy)ethyl](trimethyl)silane (0.863 mL, 4.92 mmol) to the solution. The mixture was stirred at the same temperature for 1 h and then quenched with sat. aq. NH4CI. The solution was diluted with EtOAc and water, extracted with EtOAc. The combined organic layers were washed (brine), dried (Na2SC>4), and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (5-30% acetone / hexanes, a gradient elution) provided the title compound (1g) (1.03 g, 73%) as a light -yellow oil. m / z (ESI, +ve ion) = 862.3 [M+H]+.Step H. tert-Butyl N-[l-[(3aR,4R,6R,6aR)-6-[[l-diethoxyphosphoryl-l-(hydroxymethyl)-2-(2- trimethylsilylethoxy)eth oxy] methyl] -2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [l,3]dioxol-4-yl]-6- chloro-pyrazolo[3,4-d]pyrimidin-4-yl]-N-cyclopentyl-carbamate (Ih)

[0312] To a stirred solution of ethyl 2-[[(3aR,4R,6R,6aR)-4-[4-[tert-butoxycarbonyl(cyclopentyl)amino]- 6-chloro-pyrazolo[3,4-d]pyrimidin-l-yl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][l,3]dioxol-6- yl]methoxy]-2-diethoxyphosphoryl-3-(2-trimethylsilylethoxy)propanoate (1g) (1.03 g, 1.19 mmol) in EtOH (18 mL) was added calcium dichloride (596 g, 5.37 mmol), followed by addition of sodiumborohydride (203 mg, 5.37 mmol) in a single portion at 0 °C. The mixture was allowed to warm to rt and stirred for 3 h. The mixture was then cooled back to 0 °C, and the mixture was quenched with aq. IN HC1, diluted with EtOAc and water. The solution was extracted (EtOAc) and the combined organic layers were washed (brine), dried (Na2SOr), and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography ( 1-5% MeOH / DCM, a gradient elution) provided the title compound (Ih) (755 mg, 77%) as a white foamy solid, m / z (ESI, +ve ion) = 820.3 [M+H]+.Step I. tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-(((2-(diethoxyphosphoryl)-l-(2- (trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2- yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4- yl)(cyclopentyl)carbamate (li)

[0313] To a solution oftert-Butyl N-[l-[(3aR,4R,6R,6aR)-6-[[l-diethoxyphosphoryl-l-(hydroxymethyl)- 2-(2-trimethylsilylethoxy)ethoxy]methyl]-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d] [l,3]dioxol-4-yl]- 6-chloro-pyrazolo[3,4-d]pyrimidin-4-yl]-N-cyclopentyl-carbamate (Ih) (632 mg, 0.770 mmol) and 5- (bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole (1.13 g, 3.85 mmol) and in DMF (5.0 mb) at 0 °C was added NaH (60% mineral oil, 77.0 mg, 1.93 mmol) in one portion. After the mixture was stirred at 0 °C for 30 min, the mixture was quenched by sat. aq. NH4CI, diluted with EtOAc and water. The solution was extracted (EtOAc) and the combined organic layers were washed (brine), dried (Na2SOr), and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-30% acetone / hexanes, a gradient elution) to afford the title compound (li) (697 mg, 88%) as a light-yellow gum.Step J. tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-l-(2- (trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2- yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4- yl)(cyclopentyl)carbamate (Ij)

[0314] The diastereomers from Step I were separated by chiral chromatography (CHIRALPAK, AD-H, 21x250 mm, 5 pm, 5% IPA / hexanes, an isocratic elution, a flow rate of 20 mL / min), and the second eluted isomer was identified as the title compound (Ij) and was collected.Step K. diethyl ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((3aR,4R,6R,6aR)-6-(6-chloro-4- (cyclopentylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,2-dimethyltetrahydrofuro[3,4- d] [1,3] dioxol-4-yl)methoxy)-3-hydroxypropan-2-yl)phosphonate (Ik)

[0315] To a solution of tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-l-(2- (trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2- yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4- yl)(cyclopentyl)carbamate (Ij) (325 mg, 0.315 mmol) in DCM (16 mb) was added dropwise boron trifluoride diethyl etherate (0.233 mb, 1.89 mmol) at 0 °C. The reaction was allowed to warm to rt. After stirring at rt for 3.5 h, the reaction was quenched with triethylamine (3.6 mb) and the resulting mixture was stirred at rt for 10 min. sat. aq. NaHCCh (7.2 mb) was added to the mixture and the solution was diluted with DCM and water. The solution was extracted (DCM) and the combined organic layers were washed (brine), dried (Na2SOr), and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (0-20% MeOH / DCM, a gradient elution) to afford the title compound (Ik) (189 mg, 86%) as an off-white foamy solid, m / z (ESI, +ve ion) = 702.3 [M+H]+.Step L. ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-hydroxypropan-2- yl)phosphonic acid (1)

[0316] To a solution of diethyl ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((3aR,4R,6R,6aR)-6-(6-chloro-4- (cyclopentylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4- yl)methoxy)-3-hydroxypropan-2-yl)phosphonate (Ik) (189 mg, 0.269 mmol) in MeCN (13.5 mL) was added triethylamine (0.751 mL, 5.38 mmol) followed by bromotrimethylsilane (0.528 mL, 4.04 mmol) at rt under argon atmosphere. After the solution was stirred at rt for 4 h, it was concentrated under reduced pressure. The residue was dissolved in TFA / water (1 / 3, 10 mL) and it was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (15 -40% ACN / H2O, 0.1% TFA, a gradient elution) to provide the title compound (1) as an off-white solid (TFA salt, 107 mg, 55%). !H NMR (400 MHz, methanol-d4) 8 8.08 (d, J= 0.8 Hz, 1H), 6.25-6.20 (m, 1H), 4.96 (s, 2H), 4.72-4.69 (m, 1H), 4.57-4.47 (m, 2H), 4.19-4.16 (m, 1H), 4.08 (dd, J = 10.4, 4.0 Hz, 1H), 4.01- 3.92 (m, 4H), 3.84 (dd, J= 12.4, 7.6Hz, 1H), 2.13-2.06 (m, 2H), 1.84-1.57 (m, 6H); m / z (ESI, +ve ion)= 606.1 [M+H]+.

[0317] Alternatively, Example 1, ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4- (cyclopentylamino)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3- hydroxypropan-2-yl)phosphonic acid, was prepared by Steps M to O below.Step M. tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-l-hydroxy-3-(2- (trimethylsilyl)ethoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3] dioxol-4-yl)- lH-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (Im)

[0318] Diastereomers from Step H (Ih) were separated by chiral chromatography (CHIRALPAK, AD-H, 21x250 mm, 5 pm, 5% IPA / hexanes, an isocratic elution, a flow rate of 20 mL / min, and the second eluted isomer was identified as the title compound (Im) and was collected.Step N. tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-l-(2- (trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4- yl)(cyclopentyl)carbamate (In)

[0319] To a solution of tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-l- hydroxy-3-(2-(trimethylsilyl)ethoxy)propan-2-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-yl)(cyclopentyl)carbamate (Im) (2.07 g, 2.52 mmol) and 5-(bromomethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazole (2.96 g, 10.1 mmol) in DMF (12.5 mL) at 0 °C was added NaH (60% mineral oil, 252 mg, 6.31 mmol) in one portion. After the mixture was stirred at 0°C for 30 min, the mixture was quenched by sat. aq. NH4CI, diluted with EtOAc and water. The solution was extracted (EtOAc) and the combined organic layers were washed (brine), dried (Na2SOr), and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5-30% acetone / hexanes, a gradient elution) to afford the title compound (In) (2.2 g, 84%) as a light-yellow gum .Step O. ((S)-l-((2H-tetrazol-5-yl)methoxy)-2-(((2R,3S,4R,5R)-5-(6-chloro-4-(cyclopentylamino)-lH- pyrazolo[3,4-d]pyrimidin-l-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-3-hydroxypropan-2- yl)phosphonic acid (1)

[0320] To a solution of tert-butyl (6-chloro-l-((3aR,4R,6R,6aR)-6-((((R)-2-(diethoxyphosphoryl)-l-(2- (trimethylsilyl)ethoxy)-3-((2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)methoxy)propan-2- yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d] [l,3]dioxol-4-yl)-lH-pyrazolo[3,4-d]pyrimidin-4- yl)(cyclopentyl)carbamate (In) (8.00 g, 7.75 mmol) in MeCN (300 mL) was added triethylamine (16.2 mL, 116 mmol) followed by bromotrimethylsilane (10.1 mL, 77.5 mmol) at rt under argon atmosphere. After the solution was stirred for 15 h, it was concentrated under reduced pressure and azeotropically distilled with toluene (2 times) . The residue was partitioned between EtOAc and water. The organic layerwas collected, and the aqueous layer was extracted two times with EtOAc. The combined organic layers were washed once more with water and concentrated under reduced pressure. The crude solid was dissolved in TFA / water (1 / 1, 280 mL) and it was stirred at rt for 24 h. The mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC (15-35% ACN / H2O, 0.1% TFA, a gradient elution) to provide the title compound (1) as a white solid (TFA salt, 3.1 g, 56%).XH NMR (400 MHz, methanol-d4) 3 8.08 (d, J= 0.8 Hz, 1H), 6.25-6.20 (m, 1H), 4.96 (s, 2H), 4.72-4.69 (m, 1H), 4.57-4.47 (m, 2H), 4. 19-4. 16 (m, 1H), 4.08 (dd, J= 10.4, 4.0 Hz, 1H), 4.01-3.92 (m, 4H), 3.84 (dd, J = 12.4, 7.6 Hz, 1H), 2.13-2.06 (m, 2H), 1.84-1.57 (m, 6H); m / z (ESI, +ve ion)= 606.1 [M+H]+.Example 2: Preparation of Form 1 of gentisate form of Compound 1

[0321] Into a vial were placed an amount of Compound 1 (20 mg, free base) and an equimolar amount of gentisic acid in THF / H2O (9: 1, v / v) and the resulting mixture was stirred for three days at room temperature and then for another three days at 5 °C for 3 days, resulting in a clear solution. An amount of acetonitrile (about 5 mL) was then added, resulting in a clear solution which was transferred to an open vessel. The solvents were allowed to evaporate to provide a solid precipitate that was collected to afford Form 1 of a gentisate form of Compound 1.Example 3: Preparation of Form 2 of gentisate form of Compound 1

[0322] Into a vial were placed an amount of Compound 1 (50.2 mg, free base) and gentisic acid (12.5 mg) were added into a 5-mL glass vial, to which were added 1 mL of a mixture of tetrahydrofuran / water (9: 1, v / v) into the vial to afford a slurry that was stirred at room temperature for 1 day until a clear solution was obtained. An amount of acetonitrile (3 mL) was added to the solution to afford a clear solution. The solvents were then allowed to evaporate at room temperature to provide a solid precipitate that was collected to afford Form 2 of a gentisate form of Compound 1.Example 4: Preparation of Form 2 of gentisate form of Compound 1

[0323] To a solution of the trifluoracetic acid form of Compound 1 from Example 1 in a mixture of water / n-propanol (2:98, 3 volumes) was added gentisic acid (3 molar equivalents) and the resulting mixture was stirred at 25 °C. To the resulting solution was added a seed of Form 2 gentisate form of Compound 1 (which may be prepared according to methods similar to Example 4) ( 1 mol%) and the resulting mixture was stirred for > 1 h. Heptane (2 volumes) was then added over >1 h and the resulting mixture was stirred for >12 h. Additional heptane (19 volumes) was added to the mixture over > 10 h, and the mixture was stirred for >8 h. The mixture was filtered, the solid washed three times with a water / n- propanol / heptane mixture (1:37: 100, 2 volumes), deliquored, and dried at 40 °C under vacuum and with the humidity inside the dryer controlled to 25% to 45% relative humidity to afford Form 2 of a gentisate form of Compound 1.Example 5: X-ray powder diffraction (XRPD) analysis of polymorphic forms of a gentisate form of Compound 1

[0324] XRPD analyses of polymorphic forms of gentisate forms of Compound 1 were performed using Panalytical Empyrean and X’pert3 X-ray powder diffractometers. Samples were spread on the middle of a zero-background Si holder. The parameters used for the analyses are set forth in Table 2.Table 2

[0325] Form 1 of a gentisate form of Compound 1 was analyzed by XRPD as set forth above and exhibited the peaks set forth in Table 3. The error associated with each °2theta position was determined to be ± 0.2 “theta.Table 3

[0326] Form 2 of a gentisate form of Compound 1 was analyzed by XRPD as set forth above and exhibited the peaks set forth in Table 4. The error associated with each °2theta position was determined to be ± 0.2 “theta.Table 4Example 6: Thermal gravimetric analyses and differential scanning calorimetry analyses of a gentisate form of Compound 1

[0327] Thermal gravimetric analysis (TGA) data were collected using a TA Q5000 and Discovery TGA 5500 TGA from TA Instruments. Differential scanning calorimetry (DSC) analyses were performed using a TA Q2000 DSC from TA Instruments using the parameters set forth in Table 5.Table 5Example 7: Solubility of polymorphic forms of a gentisate form of Compound 1

[0328] The solubility of a polymorphic form of a gentisate form of Compound 1 was measured in water, simulated gastric fluid (SGF), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) after 4 hours and at 37 °C as follows.

[0329] The SGF media was prepared by weighing 49.5 mg of NaCl and 25.4 mg of Triton X-100 into a 100-mL volumetric flask. A volume of purified water was added to the flask and the resulting mixture was sonicated until all solids were dissolved. About 1.632 mb of HC1 solution (I M) were then added and sufficient purified water to the target volume and to adjust the pH to 1.8. The solution was then diluted to volume with purified water, mixed well and the pH value was measured to be 1.83.

[0330] A FaSSIF buffer was prepared by weighing 340.8 mg of NaH2?O4, 43.0 mg of NaOH and 619.6 mg of NaCl into a 100-mL volumetric flask. A volume of purified water was added to the flask and the resulting mixture was sonicated until the solids had dissolved. A second volume of purified water was added to the flask to adjust the pH to 6.5. The solution was diluted with another volume of purified water, mixed, and the pH value was measured to be 6.54. The FaSSIF media was prepared by weighing 110.4 mg of SIF powder into a 50-mL volumetric flask to which a volume of FaSSIF dissolving buffer was added. The resulting mixture was sonicated until the SIF powder dissolved. Then mixture was then diluted to volume with FaSSIF dissolving buffer and mixed well. The FaSSIF solution was equilibrated for 2 hours at room temperature before it was used.

[0331] A FeSSIF dissolving buffer was prepared by weighing 0.82 mb of glacial acetic acid, 404.9 mg of NaOH and 1188.2 mg of NaCl into a 100-mL volumetric flask. A volume of purified water was added to the flask and the mixture was sonicated until the solids were dissolved. A second volume of purified water was added to the target volume to adjust the pH to 5.0. The solution was diluted with a volume of purified water, mixed well the pH value was measured to be 4.96. FeSSIF media was prepared by weighing 559.6 mg of SIF powder into a 50-mL volumetric flask. A volume of FeSSIF dissolving buffer was added to the flask and the resulting mixture was sonicated the SIF powder was dissolved. A second volume FeSSIF dissolving buffer was added and the resulting mixture was mixed well. The FeSSIF solution was equilibrated for 2 hours to room temperature before use.

[0332] An Agilent 1260 high performance liquid chromatography (HPLC) instrument equipped with aDAD detector, a Waters H-Class UPLC with PDA detector was used in the solubility measurements using the conditions set forth in Table 6.Table 6

[0333] About 10 mg of a gentisate Form 2 of Compound 1 (calculated by weight of the free base of Compound 1) was placed into a 3 m glass vial and 1 mb of the respective media (water, SGF, FaSSIF and FeSSIF) was added into each glass vial. A cap was placed on each of the vials and they were rolled at 37 °C (25 rpm) for 4 hours. The suspension was then extracted into a centrifugation tube prior to centrifugation (10000 rpm, 37 °C, 5 min) and filtration (0.22 pm PTFE membrane). The resulting supernatant was analyzed by HPLC and the pH was determined. The solubility of the polymorphic form of a gentisate Form 2 of Compound 1 measured was as set forth above was as set forth in Table 7.Table 7Example 8: Tablets comprising a gentisate form of Compound 1

[0334] Tablets comprising 261 mg of a Form 2 of a gentisate form of Compound 1 (200 mg of the free base of Compound 1) were prepared according to the following method. The quantities of each component used were as set forth in Table 8, each of which other than magnesium stearate and sodium stearyl fumarate were passed through a #20 mesh sieve before use. Magnesium stearate and sodium stearyl fumarate were passed through a #35 mesh sieve before use.Table 8

[0335] Into a 10 liter bin were placed one-third of sieved microcrystalline cellulose which was blended at a 20 rpm for 5 minutes. To the bin were then added an additional one-third of the microcrystalline cellulose, a gentisate form of Compound l,and the remaining one-third of the microcrystalline cellulose (which was used to rinse the bag that contained the gentisate form of Compound 1), the first portion of crospovidone Kollidon CL, the first portion of colloidal silicon dioxide Aerosil 200 Pharma, and the first portion of sodium stearyl fumarate. The resulting mixture was then blended at 20 rpm for 20 minutes. The blended mixture was passed through a #20 mesh sieve and the sieved mixture was added to a 10 liter bin and further blended at 20 rpm for 15 minutes. The first portion of the magnesium stearate was then addedto the center of the blended mixture and further blended at 20 rpm for 5 minutes. The resulting mixture was then discharged into low-density polyethylene bags.

[0336] A roller compactor was equipped with the following settings: (a) roller width: 40 mm; (b) upper roller surface: knurled; (c) lower roller surface: knurled; (d) coarse RFG screen: 2.0 mm, wired; (e) fine RFG screen: 1.0 mm, wired. The feed hopper of the roller compactor was then charged with the blended mixture from above and the materials were processed using the parameters for the roller compactor set forth in Table 9. The granules (1454.25 g) were collected into low-density polyethylene bags.Table 9

[0337] The granules produced by the roller compactor (1454.25 g) were placed into a 10 liter bin, to which were added sodium stearyl fumarate (7.725 g), colloidal silica dioxide Aerosil 200 Pharma (7.78 g), crospovidone Kollidon CL (22.503 g), and the resulting mixture was blended at 20 rpm for 15 minutes. To the blended mixture was added magnesium stearate (7.72 g) and the mixture was blended at 20 rpm for 5 minutes to afford a final blend.

[0338] A tableting machine was equipped with the following: (a) upper punch, lower punch, and die = 19 mm by 8.51 mm; (b) punch numbers = 2; and (c) fill cam size = 8 mm to 14 mm. The tableting machine was set with the parameters set forth in Table 10 to afford tablets that were within the target parameters set forth in Table 11.Table 10Table 11Example 9: Preparation of Form 2 of a gentisate form of Compound 1

[0339] To a reactor under nitrogen at about 25 °C were placed 2.8 kg of a 2:98 mixture of water / n- propanol and 1.73 kg of the trifluoroacetic acid form of Compound 1. The resulting mixture was stirred at a temperature of about 25 °C until the solids dissolved, after which 1.31 kg of 2,5 -dihydroxybenzoic acid (1.31 kg) was added, followed by additional portions of the 2:98 water / n-propanol mixture. The resulting mixture was stirred at about 25 °C until the solids dissolved, after which a portion of Form 2 of a gentisate form of Compound 1 (about 0.02 kg) was added to the mixture, which was stirred at about 25 °C for an additional period of about 30 minutes. To the resulting mixture was added n -heptane (about 22 kg) and the resulting mixture was stirred at about 25 °C for an additional period of about 16 hours. The resulting solids were filtered, washed, and dried under vacuum in an oven set to a temperature of about 40 °C to about 50 °C and at relative humidity of about 30% to about 40% to provide Form 2 of a gentisate form of Compound 1 (about 2 kg) .Example 10: X-ray powder diffraction (XRPD) analysis of Form 2 of a gentisate form of Compound 1

[0340] A sample of Form 2 of a gentisate form of Compound 1 that was prepared using a method analogous to that described in Example 9 was analyzed by XRPD and exhibited the peaks set forth in Table 12. The error associated with each °2theta position was determined to be ± 0.2 “theta.Table 12Example 11: Stability of Form 2 of a gentisate form of Compound 1

[0341] To measure stability of the Form 2 of a gentisate form of Compound 1 under storage conditions, samples of Form 2 of a gentisate form of Compound 1 were placed in double low-density polyethylene bags with desiccant between the bags and each was placed into a high -density polyethylene drum. One drum was stored at a temperature of 5 °C and samples of the material were taken at 1 month and 3 months, and the samples were analyzed for the presence of impurities. The other drum was stored at a temperature of 25 °C and at 60% relative humidity (RH), samples of the materials were taken at 1 month and 3 months, and the samples were analyzed for the presence of impurities. The amount of the Form 2 of a gentisate form of Compound 1, and the amount of any impurities, in each sample was measured by reverse-phase high performance liquid chromatography using the test conditions set and solvent gradients forth in Table 13 and Table 14. The samples were tested to determine the amount remaining of Form 2 at each time point, and the measurements were conducted by x-ray powder diffraction (XRPD) according to USP <941>.Table 13Table 14

[0342] The results of the stability tests for Form 2 of a gentisate form of Compound 1 under both storage conditions is set forth in Table 15.Table 15

[0343] The results demonstrated that Form 2 of a gentisate form of Compound 1 was stable up to 3 months when stored at 5 °C, and was stable up to 3 months when stored at 25 °C and at 60% RH.Example 12: Evaluation of combination of Compound 1 and the anti-CD38 Ab daratumumab enhances autologous multiple myeloma (MM) cell killing in BM-MNC samples

[0344] Studies with patient MM cells were performed following IRB-approved protocols at Dana-Farber Cancer Institute and Brigham and Women’s Hospital (Boston, MA, USA). Informed consent was obtained from all patients, and patient samples were de-identified prior to their use (everything in accordance with the Helsinki protocol ). Most of the BM samples used here were from patients with relapsed / refractory MM after at least three lines of therapy including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies. Autologous ex vivo assays were performed using freshly isolated BM aspirates from MM patients to investigate changes in CD 138+ MM tumor cell viability and adenosine generation following CD73 blockade by Compound 1 . Statistical Analysis Statistical significance was obtained using Student’s t, with the minimal level of significance at p value < 0.05 (Graph Pad PRISM version 8).

[0345] Total BM-MNCs were obtained from four from MM subjects, wherein three of the four subjects had received prior treatment with daratumumab and were determined to be daratumumab refractory. The samples were treated with Compound 1 (0.5 pM) or daratumumab (0.5 pg / ml), or both for 3-4 days, and autologous CD 138+ tumor cell lysis was assessed using multicolor flow analysis. The combination of Compound 1 and daratumumab demonstrated enhanced toxicity of multiple myeloma cells compared to either Compound 1 or daratumumab alone (FIG. 1), and demonstrated enhanced toxicity of multiple myeloma cells compared to either Compound 1 or daratumumab alone in samples from subjects that had been determined to be daratumumab refractory (FIG. 2 and FIG. 3).

[0346] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:

1. A method of treating a subject having multiple myeloma, comprising administering to the subject a CD73 inhibitor and an anti-CD38 agent.

2. The method of claim 1, wherein the CD73 inhibitor is selected from(Compound 1), AB680 (quemliclustat), CB-708(ATG-037), ATG-047, and LY3475070, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the CD73 inhibitor i(Compound 1), or pharmaceutically acceptable salt thereof.

4. The method of claim 1, wherein the CD73 inhibitor is an antibody.

5. The method of claim 4, wherein the CD73 inhibitor is an antibody selected from oleclumab, BMS-986179, NZV930, mupadolimab, uliledlimab, INCA00186, Sym024, IBI325, AK119, JAB- BX102, IPH5301, HLX23, and GS-1423.

6. The method of any one of claims 1 to 5, wherein the anti-CD38 agent is selected from a peptide, a polypeptide, a protein, a small molecule, an antibody, an antibody fragment, a single -chain antibody, a single-chain variable fragment, a bi-specific antibody, and an antibody-drug conjugate.

7. The method of claim 6, wherein the anti-CD38 agent is an antibody.

8. The method of claim 7, wherein the anti-CD38 agent is selected from daratumumab, isatuximab, MOR202, and TAK-079.

9. The method of claim 1, wherein the CD73 inhibitor i(Compound 1), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is daratumumab.

10. The method of claim 1, wherein the CD73 inhibitor i(Compound 1), or a pharmaceutically acceptable salt thereof, and the anti-CD38 agent is isatuximab.

11. The method of any one of claims 1 to 10, further comprising administering to the subject one or more additional agents.

12. The method of claim 11, wherein the one or more additional agents are selected from immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies.

13. The method of claim 12, wherein the one or more immunomodulatory agents are selected from thalidomide, lenalidomide, and pomalidomide.

14. The method of claim 12, wherein the one or more proteasome inhibitors are selected from bortezomib, carfilzomib, and ixazomib.

15. The method of claim 12, wherein the one or more monoclonal antibodies are selected from elotuzumab and belantamab.

16. The method of any one of claims 1 to 15, wherein the multiple myeloma in the subject is relapsed or refractory multiple myeloma.

Images