WO2025111247A1

WO2025111247A1 - Treatment of refractory multiple myeloma

Info

Publication number: WO2025111247A1
Application number: PCT/US2024/056489
Authority: WO
Inventors: Pratik Sharad MULTANI; Edna Chow Maneval; Lori S. Friedman; Anneleen Daemen
Original assignee: Oric Pharmaceuticals Inc
Current assignee: Oric Pharmaceuticals Inc
Priority date: 2023-11-20
Filing date: 2024-11-19
Publication date: 2025-05-30
Anticipated expiration: 2026-05-20

Abstract

The present disclosure relates to methods of treating a subject having multiple myeloma, wherein the multiple myeloma has been determined to be refractory multiple myeloma, comprising administering to the subject a pharmaceutically acceptable form of Compound 1 and wherein the pharmaceutically acceptable from is selected from a gentisate form and a succinate form.

Description

TREATMENT OF REFRACTORY MULTIPLE MYELOMA

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63/601, 141 filed November 20, 2023, U.S. Provisional Application Serial No. 63/601,633 filed November 21, 2023, and U.S. Provisional Application Serial No. 63/686,963 filed August 26, 2024; which are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] Multiple myeloma (MM) is an incurable malignancy of plasma cells. Despite the development of new agents for the treatment of subjects with multiple myeloma, including immunomodulatory drugs (IMiDs), proteasome inhibitors (Pls), and monoclonal antibodies, the vast majority of patients with multiple myeloma eventually develop disease recurrences, which become increasingly resistant or refractory to available anti-MM agents with successive lines of therapy. As such, there exists a need for the development of new treatment paradigms for subjects exhibiting resistant or refractory multiple myeloma.

[0003] One approach for such new treatment paradigms for use in subjects exhibiting resistant or refractory multiple myeloma is the use of CD73 inhibitors. CD73 is a glycosylphosphatidylinositol (GPI) anchored cell surface protein that catalyzes the hydrolysis of AMP to adenosine, and works in concert with CD39, which converts ATP into AMP. The resulting adenosine functions as a signaling molecule that activates the Pl receptors expressed on the cell surface in many different tissues. Four G protein - coupled Pl or adenosine receptors have been cloned and designated as Al, A2A, A2B, and A3.

Adenosine impacts a wide range of physiological processes including neural function, vascular perfusion, and immune responses. In doing so, this metabolite regulates CNS, cardiovascular, and immune system functions, to name a few. Elevated levels of CD73 were initially linked to resistance to a variety of chemotherapeutic agents including vincristine and doxorubicin. CD73 has also been shown to be involved in immunotherapy resistance by inhibiting the activation, clonal expansion, and homing of tumor-specific T cells (in particular, T helper and cytotoxic T cells); impairing tumor cell killing by cytolytic effector T lymphocytes; driving, via pericellular generation of adenosine, the suppressive capabilities of Treg and Th 17 cells; enhancing the conversion of type 1 macrophages into tumor-promoting type 2 macrophages; and promoting the accumulation of MDSCs. In addition to being a prognostic biomarker in cancer patients, overexpression of CD73 has also been found to be functionally linked to therapy resistance. [0004] CD73 inhibitors have demonstrated the ability to restore and enhance immune function by blocking adenosine production from AMP, including in MM patient bone marrow (BM) samples that contain multiple cell types expressing CD73, including immune cells, cancer-associated fibroblasts, mesenchymal stem cells, and endothelial cells. As such, the use of CD73 inhibitors, and pharmaceutical compositions comprising them, may be advantageously used in the treatment of subjects having refractory multiple myeloma.

SUMMARY OF THE INVENTION

[0005] Provided herein are methods of treating a subject having multiple myeloma, comprising administering to the subject a pharmaceutically acceptable form of Compound 1 :

Compound 1, wherein the multiple myeloma has been determined to be refractory multiple myeloma, and wherein the pharmaceutically acceptable from of Compound 1 is selected from a gentisate form and a succinate form. In some embodiments, the pharmaceutically acceptable from of Compound 1 is a gentisate form. In some embodiments, the pharmaceutically acceptable from of Compound 1 is a succinate form. In some embodiments, the multiple myeloma in the subject has been determined to be triple -class refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In other embodiments, the multiple myeloma in the subject has been determined to be penta- refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. 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 pharmaceutically acceptable form of Compound 1. In some embodiments, the subject experiences overall survival (OS) of at least 6 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In other embodiments, the subject achieves minimum residual disease (MRD) based on IMWG criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1. In further embodiments, the subject achieves flow minimum residual disease (MRD) negative status based on IMWG criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1. In other embodiments, the subject achieves sequencing minimum residual disease (MRD) negative status based on IMWG criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1. In yet other embodiments, the subject achieves flow minimum residual disease (MRD) negative status and imaging negative status based on IMWG criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1. In other embodiments, the subject achieves sequencing minimum residual disease (MRD) negative status and imaging negative status based on IMWG criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1. In another embodiment, the subject achieves sustained minimum residual disease (MRD) based on IMWG criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIG. 1 demonstrates the soluble CD73 activity at the indicated timepoints in the serum of subjects administered a gentisate form of Compound 1 at doses that provided (from left to right) about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD of the free base of Compound 1 as described in Example 13.

[0007] FIG. 2 demonstrates the absolute change in the number of CD8 -positive T cells from pretreatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the blood of subjects administered a gentisate form of Compound 1 at doses that provided about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD of the free base of Compound 1 as described in Example 13.

[0008] FIG. 3 demonstrates the percent change from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in number of CD25 -expressing CD8-positive T cells in the blood of subjects treated with a gentisate form of Compound 1 at doses that provided about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD of the free base of Compound 1 as described in Example 13.

[0009] FIG. 4 demonstrates the absolute change in the number of NK cells from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the blood of subjects treated with a gentisate form of Compound 1 at doses that provided about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD of the free base of Compound 1 as described in Example 13.

[0010] FIG. 5 demonstrates the percent change from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the number of CD69-expressing NK cells in the blood of subjects treated with a gentisate form of Compound 1 at doses that provided about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD of the free base of Compound 1 as described in Example 13 .

[0011] FIG. 6 demonstrates the mean unbound concentration of Compound 1 in the plasma of subjects over time treated with a gentisate form of Compound 1 at doses that provided about 400 mg QD, about 800 mg QD, about 1200 mg QD, and about 1600 mg QD of the free base of Compound 1 as described in Example 13.

[0012] FIG. 7 demonstrates the best percent change from pre-treatment to any on-treatment timepoint or end of treatment in soluble BCMA (sBCMA) levels in serum in subjects that were treated with a gentisate form of Compound 1 at doses that provided (from left to right) about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD of the free base of Compound 1 as described in Example 13. [0013] FIG. 8 demonstrates a decrease in standardized uptake values (SUV) in FDG-PT/CT scans in three lesions from a 74-year old male subject with extramedullary multiple myeloma that received a gentisate form of Compound 1 as described in Example 14.

[0014] FIG. 9 demonstrates a decrease in serum paraprotein by treatment cycle 3, day 1 in a 55 -year old female subject with multiple myeloma that received a gentisate form of Compound 1 as described in Example 15.

DETAILED DESCRIPTION OF THE INVENTION

[0015] 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, “consist of’ or “consist essentially of’ the described features.

[0016] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0017] “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 to administer a therapeutic to a subject whereby the therapeutic positively impacts the tissue to which it is targeted. Thus, as used herein, 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; providing a composition systemically to a subject by, e.g., oral administration whereby the therapeutic reaches the target tissue or 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.

[0018] The term “amorphous,” as used herein, refers to a solid composition having no measurable 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).

[0019] 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). [0020] The term “differential scanning calorimetry,” as used herein means a method of thermal analysis described in USP <891>.

[0021] The term “free base of Compound 1,” as used herein, means Compound 1 not in a gentisate form or a succinate form. For example, the present disclosure contemplates that the gentisate form of Compound 1 or the succinate form of Compound 1 may be administered to a subject as an oral dosage form, a tablet for example. The amount of Compound 1 in the oral dosage form may be recited as the total weight of the gentisate form of Compound 1 or the total weight of the succinate form of Compound 1 , as the case may be, comprising the oral dosage form. Alternatively, the amount of Compound 1 in the oral dosage form may be recited as the amount of the free base of Compound 1 comprising the oral dosage form, and such amounts are calculated may be calculated follows (using a gentisate form of Compound 1 as an example) : [(weight of gentisate form of Compound 1 in oral dosage form) x (molecular weight of Compound l)/(molecular weight of Compound 1 + molecular weight of gentisic acid)] . For example, the molecular formula of the free base form of Compound 1 is C20H29CIN9O9P (having a molecular weight of 605.93 g/mole), and the molecular formula of the gentisate form of Compound 1 has a molecular formula of C27H35CIN9O13P (having a molecular weight of 760.05 g/mole). In the event a dosage form comprising a gentisate form of Compound 1, a tablet for example, comprises about 251 mg of a gentisate form of Compound 1, such a tablet could be recited herein as comprising, or providing, about 200 mg of the free base of Compound 1.

[0022] The terms “gentisate salt,” as used herein means a salt formed between Compound 1 and gentisic acid. 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:

[0023] The term “gentisate,” as used herein refers to a form of Compound 1 in association with gentisic acid. As contemplated herein, a gentisate 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.

[0024] 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. In another embodiment is provided a co-crystal comprising compound 1 and succinic acid.

[0025] The term “pharmaceutically acceptable,” means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0026] The term “pharmaceutical composition” shall mean a composition comprising one or more active ingredients, whereby the 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 needs of the artisan.

[0027] The terms “refractory” and/or “resistant,” as used herein with respect to multiple myeloma, means the multiple myeloma disease in a subject is non-responsive to therapy, disease that progresses within 60 days of the last line of therapy, and/or disease that was previously treated but that has progressed after prior therapy and requires new therapy.

[0028] The term “substantially amorphous,” as used herein, refers to a composition having little or no long range order in the position of its molecules. For example, substantially amorphous materials have less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). As contemplated herein, the term substantially amorphous includes a composition which includes no measurable crystalline materials, as measured by analytical techniques known to those having ordinary skill in the art, such as x-ray powder diffraction (XRPD).

[0029] The term “succinate salt,” as used herein means a salt formed between Compound 1 and succinic acid. The term “succinic acid” as used herein means the compound having Chemical Abstracts Registry No. 110-15-6, the chemical names 1,2 -ethanedicarboxylic acid and 1,4-butanedioic acid, and the chemical structure below:

[0030] The term “succinate,” as used herein refers to a form of Compound 1 in association with succinic acid. As contemplated herein, a succinate may be (a) a salt form comprising Compound 1 and succinic acid, (b) a co-crystal comprising Compound 1 and succinic acid, or (c) a mixture of a salt comprising Compound 1 and succinic acid and a co-crystal comprising Compound 1 and succinic acid.

[0031] 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.

[0032] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical 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 includes one or more of the following: (1) preventing the 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 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).

[0033] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. 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 or disease. Treatment includes eliciting a clinically significant response without excessive levels of 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 used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.

[0034] 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>.

[0035] Provided herein are methods of treating a subject having multiple myeloma, comprising administering to the subject a pharmaceutically acceptable form of Compound 1 :

Compound 1, wherein the multiple myeloma has been determined to be refractory multiple myeloma, and wherein the pharmaceutically acceptable from of Compound 1 is selected from a gentisate form and a succinate form. [0036] In some embodiments are provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a gentisate form. In some embodiments, the gentisate form comprises a gentisate salt. In some embodiments, the gentisate form comprises a gentisate co-crystal. In some embodiments, the gentisate form comprises a salt and a co-crystal. In further embodiments is provided a gentisate form of Compound 1, wherein the molar ratio between Compound 1 and gentisic acid is about 1 : 1. In further embodiments is provided a gentisate form of Compound 1 , wherein the molar ratio between Compound 1 and gentisic acid is about 2: 1. In further embodiments is provided a gentisate form of Compound 1, wherein the molar ratio between Compound 1 and gentisic acid is about 1:2. In other embodiments is provided a gentisate form of Compound 1, wherein the gentisate form is a hydrate. In some embodiments, the hydrate of the gentisate form of Compound 1 is selected from a hemi-hydrate, a mono-hydrate, and a di-hydrate forms. In some embodiments, the hydrate is a hemi-hydrate. In some embodiments, the hydrate is a mono-hydrate. In some embodiments, the hydrate is a di-hydrate.

[0037] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a solid. In some embodiments, the solid form of Compound 1 is crystalline. In some embodiments, the crystalline solid form of Compound 1 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 9.25 ± 0.2° 2-theta. In still further embodiments, the crystalline solid form of Compound 1 exhibits further peaks in an x-ray powder 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 solid form of Compound 1 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.

[0038] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a gentisate form of Compound 1, wherein the form is a crystalline solid and exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 9.3 ± 0.2° 2-theta. In still further embodiments, the crystalline solid 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 solid 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 solid 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 solid 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 solid 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.

[0039] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline form comprises a peak in a differential scanning calorimetry pattern of from about 150 °C to about 170 °C. In still further embodiments, the crystalline solid comprises a peak in a differential scanning calorimetry pattern of from about 150 °C to about 165 °C. In still further embodiments, the crystalline solid comprises a peak in a differential scanning calorimetry pattern of from about 161 °C to about 162 °C.

[0040] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid exhibit 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 solid of a gentisate form of Compound 1, wherein the crystalline solid exhibit 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 solid of a gentisate form of Compound 1, wherein the crystalline solid exhibits a loss in mass in a thermal gravimetric analysis of about 5% upon heating from about 31 °C to about 150 °C.

[0041] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1 , wherein the crystalline solid 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 solid of a gentisate form of Compound 1, wherein the crystalline solid 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 solid of a gentisate form of Compound 1 , wherein the crystalline solid 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 solid of a gentisate form of Compound 1, wherein the crystalline solid 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 solid of a gentisate form of Compound 1, wherein the crystalline solid 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.

[0042] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound l is a crystalline solid of a gentisate form of Compound 1 , wherein the crystalline solid 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 atemperature of 37 °C. In still further embodiments is provided a crystalline solid of agentisate form of Compound 1 , wherein the crystalline solid 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 solid of a gentisate form of Compound 1, wherein the crystalline solid 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 solid of a gentisate form of Compound 1, wherein the crystalline solid 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.

[0043] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solids exhibit a solubility of at least 5 mg/mL in an aqueous solution having a pH of 2.5 and a temperature of 37 °C. In still further embodiments is such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid 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 such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid 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.

[0044] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound l is a crystalline solid, wherein the crystalline solid exhibits a solubility of at least 1 mg/mL in an aqueous solution having a pH of 4.4 and a temperature of 37 °C. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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.

[0045] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 5 °C for at least 7 days. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 5 °C for at least 7 days. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 5 °C for at least one month. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 5 °C for at least one month. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 5 °C for at least 3 months. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 5 °C for at least 3 months.

[0046] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 25 °C and 60% relative humidity for at least 7 days. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 25 °C and 60% relative humidity for at least 7 days. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 25 °C and 60% relative humidity for at least one month. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 25 °C and 60% relative humidity for at least one month. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 25 °C and 60% relative humidity for at least 3 months. In other embodiments is provided a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 25 °C and 60% relative humidity for at least 3 months.

[0047] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation when the pharmaceutically acceptable form is stored at 40 °C and 75% relative humidity for at least 7 days. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 agentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 40 °C and 75% relative humidity for at least 7 days.

[0048] In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid exhibits less than about 10% degradation of the total amount of a gentisate form of Compound 1 when the pharmaceutically acceptable form is stored at 60 °C for one or more days. In a further embodiment is provided such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid, wherein the crystalline solid 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 pharmaceutically acceptable form is stored at 60 °C for one or more days.

[0049] Also provided herein are such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8.26 ± 0.2° 2 -theta. Also provided herein are such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid further exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 26.43 ± 0.2° 2 -theta. Also provided herein are such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid 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. Also provided herein are such methods wherein the pharmaceutically acceptable form of Compound 1 is a crystalline solid of a gentisate form of Compound 1, wherein the crystalline solid 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.

[0050] Also provided herein are such methods wherein the pharmaceutically acceptable form of Compound 1 is a succinate form. In some embodiments of the methods, the succinate form comprises a succinate salt. In some embodiments of the methods, the succinate form comprises a succinate co-crystal. In further embodiments is provided a succinate form of Compound 1, wherein the molar ratio between Compound 1 and succinic acid is about 1 : 1. In further embodiments of the methods is provided a succinate form of Compound 1, wherein the molar ratio between Compound 1 and succinic acid is about 2: 1. In further embodiments of the methods is provided a succinate form of Compound 1, wherein the molar ratio between Compound 1 and succinic acid is about 1:2. In other embodiments of the methods is provided such succinate form of Compound 1, wherein the succinate form is a hydrate. In some embodiments of the methods, the hydrate of the succinate form of Compound 1 is selected from a hemi hydrate, a mono-hydrate, and a di-hydrate forms. In some embodiments of the methods, the hydrate is a hemi-hydrate. In some embodiments of the methods, the hydrate is a mono-hydrate. In some embodiments of the methods, the hydrate is a di-hydrate.

[0051] Further provided herein are such methods wherein the pharmaceutically acceptable form of Compound 1 is administered to the subject in the form of a pharmaceutical composition comprising an amount of the pharmaceutically acceptable form of Compound 1, and one or more pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable form of Compound 1 is selected from a gentisate form and a succinate form disclosed herein. In some embodiments of the methods, the pharmaceutical composition comprises a gentisate salt of Compound 1. In some embodiments of the methods, the pharmaceutical composition comprises a gentisate co-crystal of Compound 1. In some embodiments of the methods, the pharmaceutical composition comprises the comprises a gentisate salt and a gentisate co-crystal. In some embodiments of the methods, the pharmaceutical composition comprises a succinate form of Compound 1. In some embodiments of the methods, the pharmaceutical composition comprises a succinate salt of Compound 1 . In some embodiments of the methods, the pharmaceutical composition comprises a succinate co-crystal of Compound 1. In some embodiments of the methods, the pharmaceutical composition comprises a succinate salt of Compound 1 and a succinate co-crystal of Compound 1.

[0052] In some embodiments of the methods disclosed herein, the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with an anti-CD38 agent.

[0053] In some embodiments of the methods, the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with an anti-CD38 agent selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments of the methods, the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with daratumumab. In some embodiments of the methods, the pharmaceutically acceptable form of Compound 1 not administered to the subject in combination with isatuximab. In some embodiments of the methods, the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with MOR202. In some embodiments of the methods, the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with TAK-079.

[0054] In some embodiments of the disclosed methods, the cancer is multiple myeloma. In some embodiments, the multiple myeloma 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.

[0055] In some embodiments of the disclosed methods, the multiple myeloma in the subject has been determined to be refractory according to IMWG criteria prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1 . [0056] In some embodiments of the disclosed methods, the multiple myeloma in the subject has been determined to be refractory to one or more agents selected from (a) immunomodulatory agents, (b) proteasome inhibitors and (c) monoclonal antibody treatments priorto the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0057] In some embodiments, the multiple myeloma in the subject has been determined to be refractory to one or more immunomodulatory agents prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the one or more immunomodulatory agents is selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, the immunomodulatory agent is thalidomide. In some embodiments, the immunomodulatory agent is lenalidomide. In some embodiments, the immunomodulatory agent is pomalidomide.

[0058] In some embodiments, the multiple myeloma in the subject has been determined to be refractory to one or more proteasome inhibitors prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the one or more proteasome inhibitors is selected from bortezomib, carfilzomib, and ixazomib. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the proteasome inhibitor is ixazomib.

[0059] In some embodiments, the multiple myeloma in the subject has been determined to be refractory to one or more monoclonal antibody treatments prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the one or more monoclonal antibody treatments are selected from elotuzumab and belantamab . In some embodiments, the monoclonal antibody treatment is elotuzumab. In some embodiments, the monoclonal antibody treatment is belantamab.

[0060] In some embodiments, the multiple myeloma in the subject has been determined to be refractory to one or more anti-CD38 agents prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the one or more anti-CD38 agents is selected from daratumumab, isatuximab, MOR202, and TAK-079. In some embodiments, anti-CD38 agent is daratumumab. In some embodiments, anti-CD38 agent is isatuximab. In some embodiments, anti-CD38 agent is MOR202. In some embodiments, anti-CD38 agent is TAK-079.

[0061] In some embodiments of the methods, the multiple myeloma in the subject has been determined to be triple-class refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0062] In some embodiments of the methods, the multiple myeloma in the subject has been determined to be penta-refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the multiple myeloma in the subject has been determined to be refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab or isatuximab prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the multiple myeloma in the subject has been determined to be refractory to lenalidomide, pomalidomide, bortezomib, carfdzomib, and daratumumab priorto the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the multiple myeloma in the subject has been determined to be refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and isatuximab prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0063] In some embodiments of the disclosed methods, the subject has received CAR-T therapy prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0064] In some embodiments of the methods, the subject has received therapy with one or more anti- BCMA/CD3 bispecific antibodies prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments, the one or more anti-BCMA/CD3 bispecific antibodies is selected from teclistamab and elranatamab. In some embodiments, the anti-BCMA/CD3 bispecific antibody is teclistamab. In some embodiments, the anti-BCMA/CD3 bispecific antibody is elranatamab.

[0065] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 400 mg QD to about 5000 mg QD of the free base of Compound 1 . The administration of the pharmaceutically acceptable form of Compound 1 may in the form of a pharmaceutical composition as disclosed herein. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 400 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 500 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 600 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 700 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 800 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 900 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1000 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1100 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1200 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1300 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1400 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1500 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1600 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1700 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1800 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 1900 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2000 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2100 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2200 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2300 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2400 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2500 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2600 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2700 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2800 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 2900 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3000 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3100 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3200 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3300 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3400 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3500 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3600 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3700 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3800 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 3900 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4000 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4100 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4200 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4300 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4400 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4500 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4600 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4700 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4800 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 4900 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5000 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5100 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5200 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5300 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5400 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5500 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5600 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5700 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5800 mg QD of the free base of Compound 1. In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 5900 mg QD of the free base of Compound 1 . In some methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides about 6000 mg QD of the free base of Compound 1. In some methods, the pharmaceutically acceptable form of Compound 1 is a gentisate form. In some methods, the pharmaceutically acceptable form of Compound 1 is a succinate form.

[0066] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 400 mg QD to about 6000 mg QD of the free base of Compound 1. The administration of the pharmaceutically acceptable form of Compound 1 may in the form of a pharmaceutical composition as disclosed herein. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 800 mg QD to about 6000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 1200 mg QD to about 6000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 1600 mg QD to about 6000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2000 mg QD to about 6000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 1200 mg QD to about 5000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 1200 mg QD to about 4000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2000 mg QD to about 6000 mg QD of the free base of Compound 1 . In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2400 mg QD to about 6000 mg QD of the free base of Compound 1 . In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2400 mg QD to about 5000 mg QD of the free base of Compound 1 . In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2400 mg QD to about 4000 mg QD of the free base of Compound 1. In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2400 mg QD to about 32000 mg QD of the free base of Compound 1 . In some embodiments, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 2400 mg QD to about 3200 mg QD of the free base of Compound 1.

[0067] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 8 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750 nM, or from about 70 nM to about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nM to about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nM to about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nM to about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nMto about 600 nM, or from about 75 nMto about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nM to about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nM to about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 8 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1 .

[0068] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 12 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750, or from about 70 nMto about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nMto about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nM to about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nMto about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nM to about 600 nM, or from about 75 nMto about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nM to about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nMto about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 12 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0069] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 16 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750, or from about 70 nMto about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nMto about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nM to about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nMto about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nM to about 600 nM, or from about 75 nM to about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nMto about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nMto about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 16 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0070] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 20 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750, or from about 70 nMto about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nMto about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nMto about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nMto about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nM to about 600 nM, or from about 75 nMto about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nMto about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nMto about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 20 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0071] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 24 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750, or from about 70 nMto about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nMto about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nM to about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nMto about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nM to about 600 nM, or from about 75 nMto about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nMto about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nMto about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 24 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0072] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 36 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750, or from about 70 nMto about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nMto about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nM to about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nMto about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nM to about 600 nM, or from about 75 nMto about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nMto about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nMto about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 36 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0073] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 1000 nM for about 48 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1. The pharmaceutically acceptable form of Compound 1 may be administered in the form of a pharmaceutical composition as disclosed herein. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 60 nM to about 1000 nM, or from about 70 nM to about 1000 nM, or from about 80 nM to about 1000 nM, or from about 90 nM to about 1000 nM, or from about 70 nMto about 750, or from about 70 nMto about 700 nM, or from about 70 nM to about 650 nM, or from about 70 nMto about 600 nM, or from about 70 nM to about 550 nM, or from about 70 nM to about 500 nM, or from about 75 nM to about 1000 nM, or from about 75 nM to about 750 nM, or from about 75 nMto about 700 nM, or from about 75 nM to about 650 nM, or from about 75 nM to about 600 nM, or from about 75 nMto about 550 nM, or from about 75 nM to about 500 nM, or from about 80 nM to about 1000 nM, or from about 80 nMto about 750 nM, or from about 80 nM to about 700 nM, or from about 80 nMto about 650 nM, or from about 80 nM to about 600 nM, or from about 80 nM to about 550 nM, or from about 80 nM to about 500 nM for about 48 hours following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0074] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the soluble CD73 activity in the serum of the subject is decreased following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 25% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 50% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 75% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 80% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 85% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 90% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments, the soluble CD73 activity in the serum of the subject is decreased by at least 95% following the administration to the subject as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 .

[0075] In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased following the administration to the subject as compared to the cell- surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 10% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 15% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell -surface CD73 activity in the bone marrow of the subject is decreased by at least 20% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 25% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell -surface CD73 activity in the bone marrow of the subject is decreased by at least 30% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 35% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 40% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 50% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 60% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell -surface CD73 activity in the bone marrow of the subject is decreased by at least 70% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 80% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased by at least 90% following the administration to the subject as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. [0076] In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject following the administration as compared to the amount of CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD 8 -positive T cells in the blood of the subject of at least 25% following the administration as compared to the amount of CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject of at least 50% following the administration as compared to the amount of CD8 -positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject of at least 75% following the administration as compared to the amount of CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject of at least 100% following the administration as compared to the amount of CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject of at least 200% following the administration as compared to the amount of CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject of at least 300% following the administration as compared to the amount of CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 .

[0077] In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells in the blood of the subject following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells of in the blood of the subject of at least 25% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells of in the blood of the subject of at least 50% following the administration as compared to the amount of CD25 -expressing CD8- positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells of in the blood of the subject of at least 75% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25- expressing CD8-positive T cells of in the blood of the subject of at least 100% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells of in the blood of the subject of at least 200% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells of in the blood of the subject of at least 300% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD 8 -positive T cells of in the blood of the subject of at least 400% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells of in the blood of the subject of at least 500% following the administration as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[0078] In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 25% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 50% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 75% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 100% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 200% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 300% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 400% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NK cells in the blood of the subject of at least 500% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[0079] In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject of at least 25% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject of at least 50% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject of at least 75% following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject of at least 100% following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject of at least 200% following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69- expressing NK cells in the blood of the subject of at least 300% following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject of at least 400% following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD69- expressing NK cells in the blood of the subject of at least 500% following the administration as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[0080] In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject of at least 25% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject of at least 50% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject of at least 75% following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject of at least 100% following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject of at least 200% following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25- expressing NK cells in the blood of the subject of at least 300% following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 -expressing NK cells in the blood of the subject of at least 400% following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of CD25 - expressing NK cells in the blood of the subject of at least 500% following the administration as compared to the amount of CD25 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[0081] In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44-expressing NK cells in the blood of the subject following the administration as compared to the amount of NKp44-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44 -expressing NK cells in the blood of the subject of at least 25% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44- expressing NK cells in the blood of the subject of at least 50% following the administration as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44 -expressing NK cells in the blood of the subject of at least 75% following the administration as compared to the amount of NKp44 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44- expressing NK cells in the blood of the subject of at least 100% following the administration as compared to the amount of NKp44-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44-expressing NK cells in the blood of the subject of at least 200% following the administration as compared to the amount of NKp44 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44- expressing NK cells in the blood of the subject of at least 300% following the administration as compared to the amount of NKp44-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44 -expressing NK cells in the blood of the subject of at least 400% following the administration as compared to the amount of NKp44 -expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits an increase in the amount of NKp44- expressing NK cells in the blood of the subject of at least 500% following the administration as compared to the amount of NKp44-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[0082] In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 10% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 20% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 30% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 40% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 50% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 60% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 70% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 80% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 90% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject of at least 95% following the administration as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 .

[0083] In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1 . In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 24 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences progression-free survival (PFS) based on International Myeloma Working Group (IMWG) criteria of at least 36 months following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0084] In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 6 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 7 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 8 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 9 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 10 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 11 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 12 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 24 months following administration to the subject of the pharmaceutically acceptable form of Compound 1. In some embodiments of the disclosed methods, the subject experiences overall survival (OS) of at least 36 months following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0085] In some embodiments of the disclosed methods, the subject experiences minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0086] In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1.

[0087] In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1.

[0088] In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1.

[0089] In some embodiments of the disclosed methods, 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 pharmaceutically acceptable form of Compound 1.

[0090] In some embodiments of the disclosed methods, the subject achieves sustained minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0091] In some embodiments of the disclosed methods, the subject does not experience any Grade 2 or Grade 3 treatment-related adverse events following the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[0092] Further provided herein are methods of treating a subject having multiple myeloma, wherein the multiple myeloma has been determined to be refractory multiple myeloma, comprising administering to the subject (a) a therapeutically effective amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from a gentisate form and a succinate form disclosed herein, and (b) one or more second therapeutic agents. Further provided herein are methods of treating a subject having multiple myeloma, wherein the multiple myeloma has been determined to be refractory multiple myeloma, comprising administering to the subject (a) a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from a gentisate form and a succinate form disclosed herein, and (b) one or more second therapeutic agents. In some embodiments, the second therapeutic agent is a chemotherapeutic agent or an immunotherapy agent.

[0093] In further embodiments, the second therapeutic agent is selected from chemotherapy, corticosteroids, immunomodulating agents, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, monoclonal antibodies against CD38, monoclonal antibodies against SLAMF7, antibody-drug conjugates, and nuclear export inhibitors. In some embodiments, the second therapeutic agent is chemotherapy selected from cyclophosphamide, etoposide (VP- 16), doxorubicin, liposomal doxorubicin, melphalan, melphalan flufenamide (melflufen), and bendamustine. In other embodiments, the second therapeutic agent is selected from corticosteroids including, but not limited to, dexamethasone and prednisone. In other embodiments, the second therapeutic agent is selected from immunomodulating agents including, but not limited to, thalidomide, lenalidomide, and pomalidomide. In further embodiments, the second therapeutic agent is selected from proteasome inhibitors including, but not limited to, bortezomib, carfilzomib, and ixazomib. In other embodiments, the second therapeutic agent is selected from histone deacetylase (HDAC) inhibitors including, but not limited to, Panobinostat. In still further embodiments, the second therapeutic agent is selected from monoclonal antibodies against CD38 including, but not limited to, daratumumab and isatuximab. In some embodiments, the second therapeutic agent is selected from antibodies against SLAMF7 including, but not limited to, elotuzumab. In some embodiments, the second therapeutic agent is selected from antibody-drug conjugates including, but not limited to, belantamab mafodotin. In some embodiments, the second therapeutic agent is selected from nuclear export inhibitors including, but not limited to, selinexor.

[0094] Further provided herein are methods of treating a subject having multiple myeloma, wherein the multiple myeloma has been determined to be refractory multiple myeloma, comprising administering to the subject (a) a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from a gentisate form and a succinate form disclosed herein, and (b) one or more second therapeutic agents, wherein the one or more second therapeutic agents include, but are not limited to, the following combinations of agents: lenalidomide (or pomalidomide or thalidomide) and dexamethasone; carfilzomib (or ixazomib or bortezomib), lenalidomide, and dexamethasone; bortezomib (or carfilzomib), cyclophosphamide, and dexamethasone; elotuzumab (or daratumumab), lenalidomide, and dexamethasone; bortezomib, liposomal doxorubicin, and dexamethasone; panobinostat, bortezomib, and dexamethasone; elotuzumab, bortezomib, and dexamethasone; melphalan and prednisone (MP), with or without thalidomide or bortezomib; vincristine, doxorubicin, and dexamethasone (called VAD); dexamethasone, cyclophosphamide, etoposide, and cisplatin (called DCEP); dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (called DT-PACE), with or without bortezomib; and selinexor, bortezomib, and dexamethasone.

[0095] Further provided herein are compositions for use in treating a subject having multiple myeloma, wherein the multiple myeloma has been determined to be refractory multiple myeloma, comprising administering to the subject the compositions comprising a form of Compound 1. In some embodiments, the compositions comprise a succinate form of Compound 1. In some embodiments, the compositions comprise a gentisate form of Compound 1. In some embodiments, the compositions comprise a gentisate form of Compound 1, wherein the form is crystalline. In some embodiments, the compositions comprise a gentisate form of Compound 1, wherein the form is in crystalline solid 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 solid 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 solid 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 solid 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 solid 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 solid 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. In some embodiments, the multiple myeloma 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. [0096] Also provided herein are pharmaceutical compositions comprising an amount of a pharmaceutically acceptable form of Compound 1, wherein the pharmaceutically acceptable form is selected from a gentisate form and a succinate form, and one or more pharmaceutically acceptable excipients for use in treating a subject having multiple myeloma, wherein the multiple myeloma has been determined to be refractory multiple myeloma. In some embodiments, a gentisate form comprises a gentisate salt. In some embodiments, a gentisate form comprises a gentisate co-crystal. In some embodiments, the gentisate form comprises a salt and a co-crystal. In some embodiments, a succinate form comprises a succinate salt. In some embodiments, a succinate form comprises a succinate co-crystal. In some embodiments, the succinate form comprises a salt and a co-crystal. 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.

[0097] 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 about 70%, or from about 15% to about 80%, or from about 20% to about 80%, or from about 15% to about 75%, or from about 20% to about 75%, or from about 25% to about 75%, or from about 50% to about 80%, 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.

[0098] Also provided herein are such pharmaceutical compositions for use, 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 about 70%, or from about 15% to about 80%, or from about 20% to about 80%, or from about 15% to about 75%, or from about 20% to about 75%, or from about 25% to about 75%, or from about 50% to about 80%, 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.

[0099] Also provided herein are such pharmaceutical compositions for use, 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 some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is crospovidone.

[00100] Also provided herein are such pharmaceutical compositions for use, 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.

[00101] In some embodiments, the pharmaceutical compositions for use 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.

[00102]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.

[00103] In some embodiments, the pharmaceutical compositions disclosed herein for use 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.

[00104] In some embodiments, the pharmaceutical compositions disclosed herein for use 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. [00105] In some embodiments, the pharmaceutical compositions disclosed herein for use 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. [00106] 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.

[00107] The pharmaceutical compositions disclosed herein for use 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 a form of Compound 1 as disclosed herein 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.

[00108] Also provided herein are tablets for use comprising a pharmaceutically acceptable form of Compound 1, microcrystalline cellulose, colloidal silica dioxide, sodium stearyl fumarate, crospovidone, and magnesium stearate. In some embodiments, the pharmaceutically acceptable form of Compound 1 is selected from a gentisate form and a succinate form . In some embodiments, the pharmaceutically acceptable form of Compound 1 is a gentisate form. In some embodiments, the gentisate form comprises a salt. In some embodiments, the gentisate form comprises a co-crystal. In some embodiments, the gentisate form comprises a salt and a co-crystal. In some embodiments, the pharmaceutically acceptable form of Compound 1 is a succinate form. In some embodiments, the succinate form comprises a salt. In some embodiments, the succinate form comprises a co-crystal. In some embodiments, the succinate form comprises a salt and a co-crystal. In further embodiments, the tablets disclosed herein are as set forth in Table 1.

Table 1

[00109] In another embodiment, the pharmaceutical compositions disclosed herein for use may comprise a parenteral dose form. “Parenteral administration” includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrastemal 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. [00110] In another embodiment, the pharmaceutical compositions disclosed herein for use may comprise a topical 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).

[OOlllJFor 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 patient 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.

[00112] 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. [00113] The dose of the composition comprising a form of Compound 1 as described herein may differ, depending upon the patient’s (e.g., human) condition, that is, stage of the disease, general health status, age, and other factors. Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient’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 patient. Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. [00114] Compound 1 may be prepared by methods known to those having ordinary skill in the art, including, but not limited to, the methods set forth in Example 1.

[00115]Among the abbreviations used in the Examples are: rt (room temperature), min (minute(s)), h (hour(s)), MeCN (acetonitrile), DMF (N,N-dim ethylformamide), THF (tetrahydrofuran), MeOH (methanol), sat (saturated), and TsOH (toluene sulfonic acid).

Numbered Embodiments

[00116] Embodiment 1 : A method of treating a subject having multiple myeloma, comprising administering to the subject a pharmaceutically acceptable form of Compound 1:

Compound 1, wherein the multiple myeloma has been determined to be refractory multiple myeloma, and wherein the pharmaceutically acceptable from of Compound 1 is selected from a gentisate form and a succinate form.

[00117]Embodiment 2: The method of embodiment 1, wherein pharmaceutically acceptable form of Compound 1 is a gentisate form.

[00118] Embodiment 3 : The method of embodiment 2, wherein the gentisate form of Compound 1 comprises a gentisate salt.

[00119] Embodiment 4: The method of embodiment 2, wherein the gentisate form of Compound 1 comprises a gentisate co-crystal.

[00120] Embodiment 5: The method of any one of embodiments 1 to 4, wherein in the gentisate form of Compound 1 the molar ratio between Compound 1 and gentisic acid is about 1: 1.

[00121] Embodiment 6: The method of any one of embodiments 1 to 5, wherein the gentisate form of Compound 1 is a hydrate.

[00122] Embodiment 7: The method of embodiment 6, wherein the hydrate of Compound 1 is selected from a hemi-hydrate, a mono-hydrate, and a di-hydrate.

[00123] Embodiment 8: The method of embodiment 7, wherein the hydrate of the gentisate form of Compound 1 is a hemi-hydrate.

[00124] Embodiment 9: The method of embodiment 7, wherein the hydrate of the gentisate form of Compound 1 is a mono-hydrate. [00125] Embodiment 10: The method of embodiment 7, wherein the hydrate of the gentisate form of Compound 1 is a di-hydrate.

[00126] Embodiment 11: The method of any one of embodiments 1 to 10, wherein the pharmaceutically acceptable form of Compound 1 is a solid.

[00127] Embodiment 12: The method of embodiment 11, wherein the solid form of Compound 1 is a crystalline solid form.

[00128] Embodiment 13 : The method of embodiment 12, wherein the crystalline solid form of Compound 1 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 9.25 ± 0.2° 2 -theta. [00129] Embodiment 14: The method of embodiment 13, wherein the crystalline solid form of Compound 1 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 6.97 ± 0.2° 2 -theta, 20.53 ± 0.2° 2-theta, and 26.08 ± 0.2° 2-theta.

[00130] Embodiment 15: The method of embodiment 13 or 14, wherein the crystalline solid form of Compound 1 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.

[00131] Embodiment 16: The method of any one of embodiments 12 to 15, wherein the crystalline solid form of Compound 1 further comprises a peak in a differential scanning calorimetry pattern of from about 150 °C to about 170 °C.

[00132] Embodiment 17: The method of embodiment 16, wherein the crystalline solid form of Compound 1 comprises a peak in a differential scanning calorimetry pattern of from about 150 °C to about 165 °C.

[00133] Embodiment 18: The method of embodiment 16, wherein the crystalline solid form of Compound 1 comprises a peak in a differential scanning calorimetry pattern from about 161 °C to about 162 °C.

[00134] Embodiment 19: The method of any one of embodiments 12 to 18, wherein the crystalline solid form of Compound 1 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.

[00135] Embodiment 20: The method of embodiment 19, wherein the crystalline solid form of Compound 1 further 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.

[00136] Embodiment 21 : The method of embodiment 19, wherein the crystalline solid form of Compound 1 further exhibits a loss in mass in athermal gravimetric analysis of about 5% upon heating from about 31 °C to about 150 °C.

[00137] Embodiment 22: The method of any one of embodiments 1 to 21, wherein the pharmaceutically acceptable form of Compound 1 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.

[00138] Embodiment 23: The method of embodiment 22, wherein the pharmaceutically acceptable form of Compound 1 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. [00139] Embodiment 24: The method of embodiment 23, wherein the pharmaceutically acceptable form of Compound 1 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.

[00140] Embodiment 25 : The method of embodiment 23, wherein the pharmaceutically acceptable form of Compound 1 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.

[00141] Embodiment 26: The method of embodiment 23, wherein the pharmaceutically acceptable form of Compound 1 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.

[00142] Embodiment 27: The method of any one of embodiments 1 to 21, wherein the pharmaceutically acceptable form of Compound 1 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.

[00143] Embodiment 28: The method of embodiment 27, wherein the pharmaceutically acceptable form of Compound 1 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.

[00144] Embodiment 29: The method of embodiment 27, wherein the pharmaceutically acceptable form of Compound 1 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.

[00145] Embodiment 30: The method of embodiment 27, wherein the pharmaceutically acceptable form of Compound 1 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.

[00146] Embodiment 3 1 : The method of any one of embodiments 1 to 30, wherein the pharmaceutically acceptable form of Compound 1 exhibits a solubility of at least 5 mg/mL in an aqueous solution having a pH of 2.5 and a temperature of 37 °C.

[00147] Embodiment 32: The method of embodiment 31, wherein the pharmaceutically acceptable form of Compound 1 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.

[00148] Embodiment 33: The method of embodiment 31, wherein the pharmaceutically acceptable form of Compound 1 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.

[00149] Embodiment 34: The method of any one of embodiments 1 to 33, wherein the pharmaceutically acceptable form of Compound 1 exhibits a solubility of at least 1 mg/mL in an aqueous solution having a pH of 4.4 and a temperature of 37 °C.

[00150] Embodiment 35: The method of embodiment 34, wherein the pharmaceutically acceptable form of Compound 1 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. [00151] Embodiment 36: The method of embodiment 34, wherein the pharmaceutically acceptable form of Compound 1 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.

[00152] Embodiment 37: The method of embodiment 34, wherein the pharmaceutically acceptable form of Compound 1 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.

[00153] Embodiment 38: The method of any one of embodiments 1 to 37, wherein the pharmaceutically acceptable form of Compound 1 exhibits less than about 10% degradation when stored at 25 °C and 60% relative humidity for at least 7 days.

[00154] Embodiment 39: The method of embodiment 38, wherein the pharmaceutically acceptable form of Compound 1 exhibits less than about 1% degradation when stored at 25 °C and 60% relative humidity for at least 7 days.

[00155] Embodiment 40: The method of any one of embodiments 1 to 39, wherein the pharmaceutically acceptable form of Compound 1 exhibits less than about 10% degradation when stored at 40 °C and 75% relative humidity for at least 7 days.

[00156] Embodiment 41 : The method of embodiment 40, wherein the pharmaceutically acceptable form of Compound 1 exhibits less than about 1% degradation when stored at 40 °C and 75% relative humidity for at least 7 days.

[00157] Embodiment 42: The method of any one of embodiments 1 to 41, wherein the pharmaceutically acceptable form of Compound 1 exhibits less than about 10% degradation when stored at 60 °C for one or more day.

[00158] Embodiment 43: The method of embodiment 42, wherein the pharmaceutically acceptable form of Compound 1 exhibits less than about 1% degradation when stored at 60 °C for one or more day.

[00159] Embodiment 44: The method of embodiment 12, wherein the crystalline solid form of Compound 1 exhibits a peak in an x-ray powder diffraction (XRPD) pattern at 8.26 ± 0.2° 2-theta.

[00160] Embodiment 45 : The method of embodiment 44, wherein the crystalline solid form of Compound 1 exhibits a further peak in an x-ray powder diffraction (XRPD) pattern at 26.43 ± 0.2° 2-theta.

[00161] Embodiment 46: The method of embodiment 44 or 45, wherein the crystalline solid form of Compound 1 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 15.81 ± 0.2° 2-theta and 15.40 ± 0.2° 2-theta.

[00162] Embodiment 47: The method of any one of embodiments 44 to 46, wherein the crystalline solid form of Compound 1 exhibits further peaks in an x-ray powder diffraction (XRPD) pattern at 14.94 ± 0.2° 2-theta and 20.44 ± 0.2° 2-theta.

[00163] Embodiment 48 : The method of embodiment 1, wherein the pharmaceutically acceptable form of Compound 1 is a succinate form. [00164] Embodiment 49: The method of embodiment 48, wherein the succinate form of Compound 1 comprises a succinate salt.

[00165] Embodiment 50: The method of embodiment 48, wherein the succinate form of Compound 1 comprises a succinate co-crystal.

[00166] Embodiment 51 : The method of any one of embodiments 1 to 50, wherein the pharmaceutically acceptable form of Compound 1 is administered to the subject in the form of a pharmaceutical composition comprising an amount of the pharmaceutically acceptable form of Compound 1, and one or more pharmaceutically acceptable excipient.

[00167] Embodiment 52: The method of any one of embodiments 1 to 51, wherein the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with an anti-CD38 agent.

[00168] Embodiment 53: The method of embodiment 52, wherein the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with an anti-CD38 agent selected from daratumumab, isatuximab, MOR202, and TAK-079.

[00169] Embodiment 54: The method of embodiment 53, wherein the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with daratumumab.

[00170] Embodiment 55: The method of embodiment 53, wherein the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with isatuximab.

[00171] Embodiment 56: The method of embodiment 53, wherein the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with MOR202.

[00172] Embodiment 57: The method of embodiment 53, wherein the pharmaceutically acceptable form of Compound 1 is not administered to the subject in combination with TAK-079.

[00173] Embodiment 58: The method of any one of embodiments 1 to 57, 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.

[00174] Embodiment 59: The method of any one of embodiments 1 to 58, wherein the multiple myeloma in the subject has been determined to be refractory according to IMWG criteria prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00175] Embodiment 60: The method of any one of embodiments 1 to 59, wherein the multiple myeloma in the subject has been determined to be refractory to one or more agents selected from (a) immunomodulatory agents, (b) proteasome inhibitors and (c) monoclonal antibody treatments prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00176] Embodiment 61 : The method of any one of embodiments 1 to 60, wherein the multiple myeloma in the subject has been determined to be refractory to one or more immunomodulatory agents prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. [00177] Embodiment 62: The method of embodiment 61, wherein the one or more immunomodulatory agents is selected from thalidomide, lenalidomide, and pomalidomide.

[00178] Embodiment 63: The method of any one of embodiments 1 to 60, wherein the multiple myeloma in the subject has been determined to be refractory to one or more proteasome inhibitors prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00179] Embodiment 64: The method of embodiment 63, wherein the one or more proteasome inhibitors is selected from bortezomib, carfilzomib, and ixazomib.

[00180] Embodiment 65: The method of any one of embodiments 1 to 60, wherein the multiple myeloma in the subject has been determined to be refractory to one or more monoclonal antibody treatments prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00181] Embodiment 66: The method of embodiment 65, wherein the one or more monoclonal antibody treatments are selected from elotuzumab and belantamab.

[00182] Embodiment 67: The method of any one of embodiments 1 to 66, wherein the multiple myeloma in the subject has been determined to be refractory to one or more anti-CD38 agents prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00183] Embodiment 68: The method of embodiment 67, wherein the one or more anti-CD38 agents is selected from daratumumab, isatuximab, MOR202, and TAK-079.

[00184] Embodiment 69: The method of any one of embodiments 1 to 59, wherein the multiple myeloma in the subject has been determined to be triple-class refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00185] Embodiment 70: The method of any one of embodiments 1 to 59, wherein the multiple myeloma in the subject has been determined to be penta- refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1 .

[00186] Embodiment 71 : The method of any one of embodiments 1 to 60, wherein the multiple myeloma in the subject has been determined to be refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab or isatuximab prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00187] Embodiment 72: The method of any one of embodiments 1 to 60, wherein the multiple myeloma in the subject has been determined to be refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00188] Embodiment 73: The method of any one of embodiments 1 to 60, wherein the multiple myeloma in the subject has been determined to be refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and isatuximab prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1. [00189] Embodiment 74: The method of any one of embodiments 1 to 73, wherein the subject has received CAR-T therapy prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00190] Embodiment 75 : The method of any one of embodiments 1 to 74, wherein the subject has received therapy with one or more anti-BCMA/CD3 bispecific antibodies prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00191] Embodiment 76: The method of embodiment 75, wherein the one or more anti-BCMA/CD3 bispecific antibodies is selected from teclistamab and elranatamab

[00192] Embodiment 77: The method of any one of embodiments 1 to 76, wherein the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 400 mg QD to about 5000 mg QD of the free base of Compound 1.

[00193] Embodiment 78: The method of any one of embodiments 1 to 77, wherein the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 750 nM for about 8 hours following administration.

[00194] Embodiment 79: The method of any one of embodiments 1 to 78, wherein the subject does not experience any Grade 2 or Grade 3 treatment-related adverse events following the administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00195] Embodiment 80: The method of any one of embodiments 1 to 79, wherein the soluble CD73 activity in the serum of the subject is decreased following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the soluble CD73 activity in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[00196] Embodiment 81 : The method of any one of embodiments 1 to 80, wherein the cell-surface CD73 activity in the bone marrow of the subject is decreased following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the cell-surface CD73 activity in the bone marrow of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[00197] Embodiment 82: The method of any one of embodiments 1 to 81, wherein the subject exhibits an increase in the amount of CD8-positive T cells in the blood of the subject following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the amount of CD8- positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[00198] Embodiment 83: The method of any one of embodiments 1 to 82, wherein the subject exhibits an increase in the amount of CD25 -expressing CD8-positive T cells in the blood of the subject following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the amount of CD25 -expressing CD8-positive T cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[00199] Embodiment 84: The method of any one of embodiments 1 to 83, wherein the subject exhibits an increase in the amount of NK cells in the blood of the subject following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the amount of NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1. [00200] Embodiment 85: The method of any one of embodiments 1 to 84, wherein the subject exhibits an increase in the amount of CD69-expressing NK cells in the blood of the subject following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the amount of CD69-expressing NK cells in the blood of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1.

[00201] Embodiment 86: The method of any one of embodiments 1 to 85, wherein the subject exhibits a decrease in the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject following the administration to the subject of the pharmaceutically acceptable form of Compound 1 as compared to the amount of soluble B-cell maturation antigen (sBCMA) in the serum of the subject prior to the administration of the pharmaceutically acceptable form of Compound 1 .

[00202] Embodiment 87: The method of any one of embodiments 1 to 86, 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 pharmaceutically acceptable form of Compound 1.

[00203] Embodiment 88: The method of any one of embodiments 1 to 87, wherein the subject experiences overall survival (OS) of at least 6 months following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00204] Embodiment 89: The method of any one of embodiments 1 to 88, wherein the subject achieves minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

[00205] Embodiment 90: The method of any one of embodiments 1 to 89, 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 pharmaceutically acceptable form of Compound 1.

[00206] Embodiment 91: The method of any one of embodiments 1 to 90, 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 pharmaceutically acceptable form of Compound 1.

[00207] Embodiment 92: The method of any one of embodiments 1 to 91, 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 pharmaceutically acceptable form of Compound 1.

[00208] Embodiment 93: The method of any one of embodiments 1 to 92, 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 pharmaceutically acceptable form of Compound 1.

[00209] Embodiment 94: The method of any one of embodiments 1 to 93, wherein the subject achieves sustained minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

EXAMPLES

Example 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 acid

Step 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)

[00210] -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 SnCL (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)

[00211]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)

[00212]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 Na2SC>4, 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)

[00213]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)

[00214]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 TsOHEhO (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 Na2SOr, 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)

[00215]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)

[00216] 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 (Na2SOr), 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)

[00217]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 sodium borohydride (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)

[00218] 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 mL) 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)

[00219] 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)

[00220]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 mL) and the resulting mixture was stirred at rt for 10 min. sat. aq. NaHCCh (7.2 mL) 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)

[00221]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%). ^XH NMR (400 MHz, methanol-d₄) 5 8.08 (d, J= 0.8 Hz, IH), 6.25-6.20 (m, IH), 4.96 (s, 2H), 4.72-4.69 (m, IH), 4.57-4.47 (m, 2H), 4.19-4.16 (m, IH), 4.08 (dd, J= 10.4, 4.0 Hz, IH), 4.01- 3.92 (m, 4H), 3.84 (dd, J= 12.4, 7.6Hz, IH), 2.13-2.06 (m, 2H), 1.84-1.57 (m, 6H); m/z (ESI, +ve ion)= 606.1 [M+H]+.

[00222] 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)

[00223] 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)

[00224]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 (Na2SO₄), 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)

[00225] 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 mb, 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 layer was 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) 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, 7.6 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 succinate form of Compound 1

[00226] A slurry was prepared comprising an amount of Compound 1 (20 mg, free base) and an equimolar amount of succinic acid in tetrahydrofuran/water (about 0.2 mL, 9: 1, v/v) and the resulting slurry was stirred at room temperature for 3 days and then at 5 °C for an additional 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 a succinate form of Compound 1.

Example 3: Preparation of Form 1 of gentisate form of Compound 1

[00227] 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 4: Preparation of Form 2 of gentisate form of Compound 1

[00228] 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 5: Preparation of Form 2 of gentisate form of Compound 1

[00229] 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 6: X-ray powder diffraction (XRPD) analysis of polymorphic forms of a gentisate form of Compound 1

[00230] 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

[00231] 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

[00232] 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 4

Example 7: Thermal gravimetric analyses and differential scanning calorimetry analyses of a gentisate form of Compound 1.

[00233] 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 5

Example 8: Solubility of polymorphic forms of a gentisate form of Compound 1

[00234] 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.

[00235] 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.

[00236] A FaSSIF buffer was prepared by weighing 340.8 mg of NaH2PO4, 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. [00237] 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.

[00238]An Agilent 1260 high performance liquid chromatography (HPLC) instrument equipped with a DAD 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

[00239] 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 mb 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 7

Example 9: Tablets comprising a gentisate form of Compound 1

[00240] 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

[00241] 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 added to 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.

[00242] 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

[00243]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.

[00244] 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 10

Table 11

Example 10: Preparation of Form 2 of a gentisate form of Compound 1

[00245] 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 11: X-ray powder diffraction (XRPD) analysis of Form 2 of a gentisate form of Compound 1

[00246] A sample of Form 2 of a gentisate form of Compound 1 that was prepared using a method analogous to that described in Example 10 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 12

Example 12: Stability of Form 2 of a gentisate form of Compound 1

[00247] 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 13

Table 14

[00248] 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

[00249] 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 13: Clinical evaluation of a gentisate form of Compound 1 in human subjects having relapsed/refractory multiple myeloma.

[00250] A clinical study of a gentisate form of Compound 1 in human subjects having relapsed/refractory multiple myeloma was undertaken. Enrolled subjects were administered a gentisate form of Compound 1 in the form of immediate release tablets comprising an amount of the gentisate form of Compound 1 equivalent to 200 mg of the free base of Compound 1.

[00251] Subjects were eligible to be enrolled in the clinical study if they met at least the following criteria

(a) had a diagnosis of multiple myeloma with relapsed or refractory disease according to IMWG criteria,

(b) determined to be refractory to or not eligible for multiple myeloma treatment regimens that were known to provide clinical benefit, (c) had measurable multiple myeloma disease, (d) had an Eastern Cooperative Oncology Group (ECOG) (now the ECOG-ACRIN Cancer Research Group) status of 0-2, and (e) were determined to have adequate bone marrow, renal, hepatic, pulmonary, and cardiac function. [00252] As of the date of data cutoff of November 2, 2023, a total of 22 subjects were enrolled across the

5 dose levels set forth in Table 16.

Table 16

[00253] The demographics of the subjects enrolled in the clinical study are shown in Table 17. Table 17

[00254] As of the data cut-off date of November 2, 2023, (a) all doses of the gentisate form of Compound 1 were well -tolerated with all treatment-related adverse events being Grade 1 or Grade 2, (b) no Grade 3 treatment-related toxicities were observed, and (c) there were no dose-limiting toxicities (DLTs), dose reductions, or treatment-related serious adverse events (SAEs) observed. The list of Grade 1/Grade 2 treatment-related adverse events observed per dose level in the enrolled subjects are set forth in Table 18 and Table 19.

Table 18

Table 19

[00255] The measured soluble CD73 activity in serum from subjects treated with a gentisate form of Compound 1 that provided doses of the free base of Compound 1 of (from left to right) about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD are shown in FIG. 1. In FIG. 1: “C1D1” means treatment cycle 1, day 1; “C1D8” means treatment cycle 1, day 8; “C1D15” means treatment cycle 1, day 15; “C2D1” means treatment cycle 2, day 1; and “C3D1” means treatment cycle 3, day 1.

[00256] The absolute change in the number of CD8-positive T cells from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the blood of subjects treated with a gentisate form of Compound 1 that provided doses of the free base of Compound 1 of about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD are shown in FIG. 2.

[00257]The percent change in number of CD25 -expressing CD8-positive T cells from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the blood of subjects treated with a gentisate form of Compound 1 that provided doses of the free base of Compound 1 of about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD are shown in FIG. 3.

[00258] The absolute change in the number of NK cells from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the blood of subjects treated with a gentisate form of Compound 1 that provided doses of the free base of Compound 1 of about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD are shown in FIG. 4.

[00259] The percent change in the number of CD69-expressing NK cells from pre-treatment to treatment cycle 2 or 3, day 1, or end of treatment in case preceding treatment cycle 2, day 1, in the blood of subjects treated with a gentisate form of Compound 1 that provided doses of the free base of Compound 1 of about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, or about 3200 mg QD are shown in FIG. 5. [00260] The mean unbound concentration in the plasma of subjects over time receiving doses of a gentisate form of Compound 1 in an amount that provided a dose of the free base of Compound 1 of about 400 mg QD, about 800 mg QD, about 1200 mg QD, or about 1600 mg QD is shown in FIG. 6.

[00261] The best percent change in soluble BCMA levels from pre-treatment to any on-treatment timepoint in serum of subjects that were treated with a gentisate form of Compound 1 at doses that provided about 400 mg QD, about 800 mg QD, about 1200 mg QD, or about 1600 mg QD of the free base of Compound 1 are shown in FIG. 7. In FIG. 7, the doses of the Compound 1 were, from left to right, about 400 mg QD, about 800 mg QD, about 1200 mg QD, about 1600 mg QD, about 2400 mg QD, and about 3200 mg QD.

Example 14: Clinical treatment of a 74-year old male with extramedullary multiple myeloma by administration of a gentisate form of Compound 1

[00262] A 74-year old male subject with extramedullary multiple myeloma having an initial diagnosis in 2015 was enrolled in the clinical study. The subject had received four prior lines of therapy, including two proteosome inhibitors, two immunomodulatory drugs, an anti-CD38 agent, and an autologous transplant. The subject received about 1200 mg QD of the free base of Compound 1 in the form of a tablet comprising a gentisate form of Compound 1 . As of the cutoff date of November 2, 2023, the subject exhibited (a) non-secretory myeloma (i.e., no measurable serum or urine paraprotein), (b) FDG-PT/CT of extramedullary plasmacytomas showed stable disease per RECIST 1.1, and (c) a decrease in standardized uptake values (SUV) ranging from 37% to 73% across 3 lesions (precaval mass, a L5 lytic mass, and T10 lytic mass) as shown in FIG. 8. As of the cutoff date of November 2, 2023, the subject completed 7 treatment cycles (6.5 months) followed by progressive disease, and experienced Grade 2 hypophosphatemia. In FIG. 8,”Baseline” means the time prior to the subject being administered

Compound 1; “C2D1” means cycle 2, day 1; “C4D1” means cycle 4, day 1; and “C6D1” means cycle 6, day 1.

Example 15: Clinical treatment of a 55-year old female with multiple myeloma by administration of a gentisate form of Compound 1

[00263] A 55-year old female subject with multiple myeloma having an initial diagnosis in 2021 was enrolled in the clinical study. The subject had received four prior lines of therapy, including two proteosome inhibitors, two immunomodulatory drugs, an anti-CD38 agent, an autologous transplant, and an anti-BCMA/CD38 agent (most recent prior therapy). The subject received about 1600 mg QD of the free base of Compound 1 in the form of a tablet comprising a gentisate form of Compound 1 . As of the cutoff date of November 2, 2023, the subject exhibited (a) a 41% decrease in serum paraprotein by treatment cycle 3, day 1 as shown in FIG. 9, (b) improvement in baseline thrombocytopenia, and (c) an 80% decrease in soluble B-cell maturation antigen (sBCMA) as shown in FIG. 7. As of the cutoff date of November 2, 2023, the subject had completed 3 treatment cycles (2.8 months), followed by progressive disease, and did not report any Grade 2 or higher treatment-related adverse events. In FIG. 9, “Baseline” means the time prior to the subject being administered Compound 1; “C2D1” means cycle 2, day 1; “C3D1” means cycle 3, day 1; and “C4D1” means cycle 4, day 1.

[00264] 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

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating a subject having multiple myeloma, comprising administering to the subject a pharmaceutically acceptable form of Compound 1 :

2. The method of claim 1, wherein pharmaceutically acceptable form of Compound 1 is a gentisate form.

3. The method of claim 1 or 2, 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.

4. The method of any one of claims 1 to 3, wherein the multiple myeloma in the subject has been determined to be refractory according to IMWG criteria prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

5. The method of any one of claims 1 to 4, wherein the multiple myeloma in the subject has been determined to be refractory to one or more agents selected from (a) immunomodulatory agents, (b) proteasome inhibitors and (c) monoclonal antibody treatments prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

6. The method of any one of claims 1 to 5, wherein the multiple myeloma in the subject has been determined to be refractory to one or more immunomodulatory agents prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

7. The method of claim 6, wherein the one or more immunomodulatory agents is selected from thalidomide, lenalidomide, and pomalidomide.

8. The method of any one of claims 1 to 7, wherein the multiple myeloma in the subject has been determined to be refractory to one or more proteasome inhibitors prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

9. The method of claim 8, wherein the one or more proteasome inhibitors is selected from bortezomib, carfilzomib, and ixazomib.

10. The method of any one of claims 1 to 9, wherein the multiple myeloma in the subject has been determined to be refractory to one or more monoclonal antibody treatments prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

11. The method of claim 10, wherein the one or more monoclonal antibody treatments are selected from elotuzumab and belantamab.

12. The method of any one of claims 1 to 11, wherein the multiple myeloma in the subject has been determined to be refractory to one or more anti-CD38 agents prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

13. The method of claim 12, wherein the one or more anti-CD38 agents is selected from daratumumab, isatuximab, MOR202, and TAK-079.

14. The method of any one of claims 1 to 4, wherein the multiple myeloma in the subject has been determined to be triple-class refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1.

15. The method of any one of claims 1 to 4, wherein the multiple myeloma in the subject has been determined to be penta-refractory prior to the administration to the subject of the pharmaceutically acceptable form of Compound 1 .

16. The method of any one of claims 1 to 15, wherein the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides from about 400 mg QD to about 5000 mg QD of the free base of Compound 1.

17. The method of any one of claims 1 to 16, wherein the subject is administered an amount of the pharmaceutically acceptable form of Compound 1 that provides an unbound concentration of Compound 1 in the plasma of the subject of from about 50 nM to about 750 nM for about 8 hours following administration.

18. The method of any one of claims 1 to 17, 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 pharmaceutically acceptable form of Compound 1.

19. The method of any one of claims 1 to 17, wherein the subject experiences overall survival (OS) of at least 6 months following administration to the subject of the pharmaceutically acceptable form of Compound 1.

20. The method of any one of claims 1 to 19, wherein the subject achieves minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

21. The method of any one of claims 1 to 19, wherein the subj ect achieves flow minimum residual disease (MRD) negative status based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.

22. The method of any one of claims 1 to 19, 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 pharmaceutically acceptable form of Compound 1.

23. The method of any one of claims 1 to 19, 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 pharmaceutically acceptable form of Compound 1.

24. The method of any one of claims 1 to 19, 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 pharmaceutically acceptable form of Compound 1.

25. The method of any one of claims 1 to 19, wherein the subject achieves sustained minimum residual disease (MRD) based on International Myeloma Working Group (IMWG) criteria following administration to the subject of the pharmaceutically acceptable form of Compound 1.