Methods of Treating Multiple Myeloma Using Combination Therapy - Patent application

Abstract

Provided herein is a method of using (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin 1-yl)-3-fluorobenzonitrile or an enantiomer, mixture of enantiomers, tautomer, or pharma- ceutically acceptable salt thereof provided herein in combination with a second active agent to treat, prevent, or manage multiple myeloma.

Description

[Technical field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 194,026, filed May 27, 2021, the entirety of which is incorporated herein by reference.

[0002] Provided herein are methods of using (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, mixture of enantiomers, tautomer, or pharma- ceutically acceptable salt thereof, in combination with a second active agent provided herein, to treat, prevent, or manage multiple myeloma. [Background technology]

[0003] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, unregulated proliferation of these cells leads to bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common hematological malignancy, but the exact cause of multiple myeloma remains unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin, except in some patients (estimated 1%-5%) whose myeloma cells do not secrete those proteins (referred to as non-secretory myeloma). M protein, an abbreviation for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by myeloma plasma cells that can be found in the blood or urine of almost all patients with multiple myeloma, except those with non-secretory myeloma or whose myeloma cells produce immunoglobulin light chains with heavy chains.

[0004] Skeletal symptoms, such as bone pain, are one of the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast stimulating factors (including IL-1, IL-6, and TNF), which cause calcium leaching from bone, resulting in lytic lesions; hypercalcemia is another symptom. Osteoclast stimulating factors, also called cytokines, can interfere with apoptosis or death of myeloma cells. Fifty percent of patients have radiologically detectable myeloma-associated bone lesions at the time of diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal failure.

[0005] Current multiple myeloma therapies may include one or more of surgery, stem cell transplantation, chemotherapy, immunotherapy, and / or radiation therapy to eradicate multiple myeloma cells in the patient. All of the current treatment approaches present significant drawbacks for the patient.

[0006] In the past decade, novel therapeutic agents, especially immunomodulatory agents such as lenalidomide and pomalidomide, have significantly increased response rates and prolonged progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma. However, in many patients with multiple myeloma, even after they achieve a complete response (CR), persistent levels of residual disease exist that are below the sensitivity of bone marrow (BM) morphology, protein electrophoresis with immunofixation, and light chain quantification, ultimately causing disease relapse. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and has been explored as a surrogate test endpoint to improve the identification of effective treatments, especially for frontline trials that currently require 5-10 years of follow-up to identify survival differences. Thus, monitoring of minimal residual disease (MRD) in patients with multiple myeloma provides prognostic value for predicting PFS and OS as well as treatment decisions. Detection of minimal residual disease (MRD) in myeloma is based on a threshold of 0.01% (10 -4 10 as a proportion of total bone marrow mononuclear cells. -4Patients with multiple myeloma cells of 10 or fewer are MRD negative, whereas patients with multiple myeloma cells of 10 or fewer are MRD negative. -4 A patient with ≥ 10 cells is considered MRD positive. -4 The MRD threshold was originally based on technical ability, but was increased to 10 by flow cytometry. -5 10 by high-throughput sequencing -6 Quantitative MRD detection is now possible in individuals (Non-Patent Document 1). Methods for measuring MRD include DNA sequencing of VDJ, polymerase chain reaction (PCR) (including allele-specific PCR, ASO PCR), and multiparameter flow cytometry (MPF). For example, an assay for MRD based on clonotype profile measurement is also described in Patent Document 1 to Faham et al., which is incorporated herein by reference.

[0007] By way of example, there is a significant need for safe and effective compounds and methods for treating, preventing and managing multiple myeloma in patients with newly diagnosed or refractory multiple myeloma to standard therapies, while reducing or avoiding the toxicities and / or side effects associated with conventional therapies.

[0008] Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that the reference is prior art to the present application. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] U.S. Pat. No. 8,628,927 [Non-patent literature]

[0010] [Non-Patent Document 1] Rawstron et al.,Blood 2015;125(12):1932-1935 Summary of the Invention [Means for solving the problem]

[0011] Provided herein is a method of using (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, mixture of enantiomers, tautomer, or pharma- ceutically acceptable salt thereof, in combination with a second active agent, for treating, preventing, or managing multiple myeloma. In one embodiment, the second agent is (i) a combination of bortezomib and dexamethasone; (ii) a combination of daratumumab and dexamethasone; (iii) a combination of carfilzomib and dexamethasone; (iv) a combination of elotuzumab and dexamethasone; or (v) a combination of isatuximab and dexamethasone.

[0012] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof, in combination with elotuzumab and dexamethasone.

[0013] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof in combination with isatuximab and dexamethasone.

[0014] In one embodiment, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM). In one embodiment, the multiple myeloma is newly diagnosed multiple myeloma (NDMM).

[0015] In one embodiment, provided herein is a combination of compounds provided herein for use in a method of treating a disease provided herein.

[0016] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] definition Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, the definitions in this section shall prevail unless otherwise stated.

[0018] As used herein, and in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents unless the context clearly indicates otherwise.

[0019] As used herein, the terms "comprise" and "comprise" can be used synonymously. The terms "comprise" and "comprise" should be interpreted to specify the presence of the described feature or component as recited, but do not preclude the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprise" and "comprise" are intended to include examples encompassed by the term "consisting of". As a result, the term "consisting of" can be used in place of the terms "comprise" and "comprise" to provide more specific embodiments of the present invention.

[0020] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98% or 99% of the recited features or components that make it up. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any succeeding recitation, including but not limited to features or components that are not essential to the technical effect to be achieved.

[0021] As used herein, the term "or" should be interpreted as an inclusive "or" meaning any one or any combination. Thus, "A, B or C" means any of "A; B; C; A and B; A and C; B and C; A, B and C." Exceptions to this definition occur only if combinations of elements, features, steps or acts are in some way inherently mutually exclusive.

[0022] As used herein, the term "and / or," when used in phrases such as "A and / or B," is intended to include any of A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or," when used in phrases such as "A, B, and / or C," is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0023] Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as, but not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as, but not limited to, lithium, potassium and and sodium; alkaline earth metal salts, including but not limited to, barium, calcium, and magnesium; transition metal salts, including but not limited to, zinc; and other metal salts, including but not limited to, sodium hydrogen phosphate and disodium phosphate; further including but not limited to, salts of mineral acids, including but not limited to, hydrochlorides and sulfates; and salts of organic acids, including but not limited to, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates, and organic sulfonates.

[0024] Unless specifically stated otherwise, where a compound can assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a compound can have one of two tautomeric forms, both tautomers are intended to be encompassed herein.

[0025] Therefore, the compounds provided herein can be enantiomerically pure or can be stereoisomeric or diastereomeric mixtures.As used herein, unless otherwise indicated, the term "stereoisomerically pure" refers to a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound.For example, a stereoisomerically pure composition of a compound having one chiral center is substantially free of the opposite enantiomer of the compound.A stereoisomerically pure composition of a compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomer of the compound, more preferably more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomer of the compound, even more preferably more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomer of the compound, and most preferably more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomer of the compound. A stereoisomerically pure compound, as used herein, comprises more than about 80% by weight of one stereoisomer of the compound, more preferably more than about 90% by weight of one stereoisomer of the compound, even more preferably more than about 95% by weight of one stereoisomer of the compound, and most preferably more than about 97% by weight of one stereoisomer of the compound. As used herein, unless otherwise indicated, the term "stereoisomerically enriched" refers to a composition that contains more than about 60% by weight of one stereoisomer of a compound, preferably more than about 70% by weight, more preferably more than about 80% by weight of one stereoisomer of a compound. As used herein, unless otherwise indicated, the term "enantiomerically pure" refers to a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "stereoisomerically enriched" refers to a stereoisomerically enriched composition of a compound having one chiral center. As used herein, a stereoisomeric or diastereomeric mixture refers to a composition that contains two or more stereoisomers of a compound.A typical stereoisomeric mixture of the compounds comprises about 50% by weight of one stereoisomer of the compound and about 50% by weight of the other stereoisomer of the compound, or more than about 50% by weight of one stereoisomer of the compound and less than about 50% by weight of the other stereoisomer of the compound, or more than about 45% by weight of one stereoisomer of the compound and less than about 55% by weight of the other stereoisomer of the compound, or more than about 40% by weight of one stereoisomer of the compound and less than about 60% by weight of the other stereoisomer of the compound, or more than about 35% by weight of one stereoisomer of the compound and less than about 65% by weight of the other stereoisomer of the compound.

[0026] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either (R) or (S) configuration, or may be a mixture thereof. It should be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, those skilled in the art will understand that for compounds that undergo epimerization in vivo, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form.

[0027] Optically active (+) and (-), (R) and (S) isomers, or (D) and (L) isomers, may be prepared using chiral synthons or chiral reagents or separated using conventional techniques, such as chromatography on chiral stationary phases.

[0028] "Tautomer" refers to isomeric forms of a compound that are in equilibrium with each other. The concentration of isomeric forms will depend on the environment in which the compound is found, and may vary depending on, for example, whether the compound is a solid or an organic or aqueous solution. For example, in an aqueous solution, pyrazole may exhibit the following isomeric forms, referred to as tautomers of each other: [ka]

[0029] As used herein, an "isotopologue" is an isotope-enriched compound. "Isotopically enriched" refers to an atom having an isotopic composition other than the atom's natural isotopic composition. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the atom's natural isotopic composition. The term "isotopic composition" refers to the amount of each isotope present at a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., multiple myeloma therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments presented herein. In some embodiments, isotopologues of compounds are provided, e.g., isotopologues of compound 1, compound 2, or compound 3 are deuterium-, carbon-13-, or nitrogen-15-enriched compounds. In some embodiments, isotopologues provided herein are deuterium-enriched compounds. In some embodiments, the isotopologues provided herein are deuterium-enriched compounds where deuteration occurs at a chiral center.

[0030] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure shall be given more weight.

[0031] As used herein, "multiple myeloma" refers to a hematological condition characterized by malignant plasma cells, including the following disorders: monoclonal gammopathy of undetermined significance (MGUS); low-, intermediate-, and high-risk multiple myeloma; newly diagnosed multiple myeloma (including low-, intermediate-, and high-risk newly diagnosed multiple myeloma); transplant-eligible and transplant-ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including low-, intermediate-, and high-risk smoldering multiple myeloma); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; nonsecretory myeloma. ; immunoglobulin D myeloma; and immunoglobulin E myeloma; and multiple myeloma characterized by genetic abnormalities such as cyclin D translocations (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20)); MMSET translocations (e.g., t(4;14)(p16;q32)); MAF translocations (e.g., t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal elements (e.g., deletions of chromosome 17p13 or 13; del(17 / 17p), non-hyperdiploidy, and amplification (1q)). In one embodiment, the multiple myeloma is characterized according to the International Staging Classification for Multiple Myeloma (ISS). In one embodiment, the multiple myeloma is stage I multiple myeloma as characterized by the ISS (e.g., serum β2 microglobulin < 3.5 mg / L and serum albumin > 3.5 g / dL). In one embodiment, the multiple myeloma is stage III multiple myeloma as characterized by the ISS (e.g., serum β2 microglobulin > 5.4 mg / L). In one embodiment, the multiple myeloma is stage II multiple myeloma as characterized by the ISS (e.g., not stage I or III).

[0032] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" refer to alleviating or reducing the severity of the symptoms associated with the disease or condition being treated, e.g., multiple myeloma.

[0033] The term "prevention" includes inhibition of symptoms of a particular disease or disorder, e.g., multiple myeloma. In some embodiments, patients with a family history of multiple myeloma are candidates for a preventative regimen. In general, the term "preventing" refers to administration of a drug prior to the onset of symptoms, particularly to patients at risk of multiple myeloma.

[0034] As used herein, and unless otherwise specified, the term "managing" includes preventing recurrence of a particular disease or disorder, e.g., multiple myeloma, in a patient afflicted therewith, extending the time a patient afflicted with a disease or disorder remains in remission, reducing patient mortality, and / or maintaining a reduction in the severity or avoidance of symptoms associated with the disease or condition being managed.

[0035] As used herein, a "subject" or "patient" is an animal, typically a mammal, e.g., a human, e.g., a human patient.

[0036] The term "relapsed" refers to the situation where a patient who has been in remission of multiple myeloma after treatment has return of myeloma cells and / or reduced normal cells in the bone marrow.

[0037] The term "refractory or resistant" refers to the situation where, even after intensive treatment, a patient has residual myeloma cells and / or reduced normal cells in the bone marrow.

[0038] As used herein, "induction therapy" refers to the initial treatment given to a disease or the initial treatment given with the aim of inducing a complete remission of a disease, e.g., cancer. When used by itself, induction therapy is a therapy that is accepted as the best available treatment. If residual cancer is detected, the patient is treated with another therapy called reinduction. If the patient is in complete remission after induction therapy, additional consolidation and / or maintenance therapy is given to extend the remission or potentially cure the patient.

[0039] As used herein, "consolidation therapy" refers to treatment that is given to a disease after remission is first achieved.For example, cancer consolidation therapy is treatment that is given after the cancer disappears after initial treatment.Consolidation therapy can include treatment with radiation therapy, stem cell transplantation, or cancer chemotherapy.Consolidation therapy is also referred to as intensive therapy and post-remission therapy.

[0040] As used herein, "maintenance therapy" refers to treatment given to a disease to prevent or delay recurrence after remission or optimal response has been achieved. Maintenance therapy can include chemotherapy, hormonal therapy, or targeted therapy.

[0041] As used herein, "remission" refers to the reduction or disappearance of signs and symptoms of cancer, such as multiple myeloma. In partial remission, some, but not all, signs and symptoms of cancer have disappeared. In complete remission, all signs and symptoms of cancer have disappeared, although cancer may still be present in the body.

[0042] As used herein, "transplantation" refers to high-dose therapy with stem cell rescue. Hematopoietic (blood) or bone marrow stem cells are used to rescue patients after high-dose therapy, such as high-dose chemotherapy and / or radiation therapy, rather than as a treatment. Transplantation includes "autologous" stem cell transplantation (ASCT), which refers to the use of a patient's own stem cells harvested and used as replacement cells. In some embodiments, transplantation also includes tandem or multiple transplantation.

[0043] As used herein, unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, such as multiple myeloma, or to delay or minimize one or more symptoms associated with the disease or disorder being treated. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or pathogenesis of a disease or disorder, or improves the therapeutic effectiveness of another therapeutic agent.

[0044] The terms "co-administration" and "in combination with" include administration of one or more therapeutic agents (e.g., a compound provided herein and another anti-multiple myeloma agent, anti-cancer agent, or supportive care agent) in parallel, simultaneously, or sequentially with no set time limit. In one embodiment, the agents are present in a cell or in the patient's body at the same time or impart their biological or therapeutic effect simultaneously. In one embodiment, the therapeutic agents are present in the same composition or unit dosage form. In another embodiment, the therapeutic agents are present in separate compositions or unit dosage forms.

[0045] As used herein, unless otherwise specified, the "therapeutic agent" provided herein is not limited to a single therapeutic agent, and in some embodiments, it may be a combination of one or more different therapeutic agents. One or more therapeutic agents may be administered in combination with each other, as described herein. As used herein, unless otherwise specified, the "therapeutic agent" may be used interchangeably with "therapeutic therapy" and is not limited to a therapeutic agent. For example, the therapeutic agent may be a cancer treatment, such as radiation therapy or CAR-T therapy.

[0046] "Cycling therapy" refers to a regimen or treatment that includes periods of administration as described herein and optionally periods of rest as described herein.

[0047] The term "administration period," as used herein, refers to the period during which a compound or composition described herein is continuously or actively administered to a subject.

[0048] The term "drug holiday" as used herein refers to a period of time, often following an administration period, when a compound or composition described herein is not administered to a subject (e.g., treatment is discontinued). In some embodiments, a "drug holiday" refers to a period of time when a single agent is not administered to a subject or when treatment with a particular compound is discontinued. In such embodiments, a second therapeutic agent (e.g., a different agent than the compound or composition administered in the pre-administration period) can be administered to the subject.

[0049] The term "supportive care agent" refers to any substance that treats, prevents, or manages adverse effects from treatment with Compound 1, Compound 2, or Compound 3, or an enantiomer or a mixture of enantiomers, tautomers, isotopologues, or pharma- ceutically acceptable salts thereof.

[0050] The term "biotherapy" refers to the administration of a biotherapeutic agent, such as umbilical cord blood, stem cells, growth factors, and the like.

[0051] With respect to cancer, e.g., multiple myeloma, inhibition can be assessed by, among others, inhibition of disease progression, inhibition of tumor growth, reduction of primary tumors, alleviation of tumor-related symptoms, inhibition of tumor secreted factors, delay in the appearance of primary or secondary tumors, slowing of the development of primary or secondary tumors, reduction in the occurrence of primary or secondary tumors, slowing of the secondary effects of the disease or reducing their severity, cessation of tumor growth and tumor regression, increase in time to progression (TTP), increase in progression-free survival (PFS), increase in overall survival (OS). As used herein, OS refers to the time from the start of treatment to death from any cause. As used herein, TTP refers to the time from the start of treatment to tumor progression; TTP does not include death. In one embodiment, PFS refers to the time from the start of treatment to tumor progression or death. In one embodiment, PFS refers to the time from the first administration of the compound to the first occurrence of disease progression or death from any cause. In one embodiment, the PFS rate is calculated using the Kaplan-Meier estimator. Event-free survival (EFS) refers to the time from initiation of treatment to any treatment failure, e.g., disease progression, treatment discontinuation for any reason, or death. In one embodiment, overall response rate (ORR) refers to the proportion of patients achieving a response. In one embodiment, ORR refers to the sum of the proportion of patients achieving a complete and partial response. In one embodiment, ORR refers to the proportion of patients with a best response >= partial response (PR) according to the IMWG Uniform Response Criteria. In one embodiment, duration of response (DoR) is the time from achievement of response to relapse or disease progression. In one embodiment, DoR is the time from achievement of response >= partial response (PR) to relapse or disease progression. In one embodiment, DoR is the time from first documented response to first documented progression or death. In one embodiment, DoR is the time from first documented response >= partial response (PR) to first documented progression or death. In one embodiment, time to response (TTR) refers to the time from first administration of a compound to first documented response. In one embodiment, TTR refers to the time from the first administration of a compound to the first documented response >= partial response (PR). In extreme cases, complete inhibition is referred to herein as prophylaxis or chemoprevention.In this regard, the term "prevention" includes either preventing the development of clinically evident cancer altogether or preventing the development of cancer at a pre-clinically evident stage. This definition is also intended to encompass the prevention of transformation into malignant cells or the arrest or reversal of the progression of pre-malignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing cancer.

[0052] In one embodiment, treatment of multiple myeloma can be evaluated according to the International Uniform Response Criteria for Multiple Myeloma (IURC) using the response and endpoint definitions set forth below (see Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006;(10)10:1-7).

[0053] [Table 1]

[0054] As used herein, ECOG status refers to the Eastern Cooperative Oncology Group (ECOG) Performance Status (Oken M, et al Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-655), as set forth below.

[0055] [Table 2]

[0056] As used herein, unless otherwise specified, the terms "about" and "approximately," when used in the context of a dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that is recognized by one of ordinary skill in the art as providing a pharmacological effect equivalent to that resulting from the stated dose, amount, or weight percentage. In one embodiment, the terms "about" and "approximately," when used in this context, contemplate a dose, amount, or weight percentage that is within 30%, within 20%, within 15%, within 10%, or within 5% of the stated dose, amount, or weight percentage.

[0057] compound In one embodiment, the compound used in the methods provided herein has the formula: [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof. (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile is also referred to herein as "Compound 1."

[0058] In one embodiment, the compound used in the methods provided herein is [ka] (R)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (referred to herein as “Compound 2”), or a tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof.

[0059] In one embodiment, the compound used in the methods provided herein has the formula: [ka] or a tautomer, isotopologue, or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, Compound 1 (free base) is used in the methods provided herein. In one embodiment, a tautomer of Compound 1 is used in the methods provided herein. In one embodiment, an isotopologue of Compound 1 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of Compound 1 is used in the methods provided herein. In one embodiment, the hydrobromide salt of Compound 1 is used in the methods provided herein. In one embodiment, the monohydrobromide salt of Compound 1 is used in the methods provided herein. Certain salts and polymorphic forms of Compound 1 are described in U.S. Patent Publication No. 2020-0216418, the entirety of which is incorporated herein by reference.

[0061] In one embodiment, Compound 2 is used in the methods provided herein. In one embodiment, a tautomer of Compound 2 is used in the methods provided herein. In one embodiment, an isotopologue of Compound 2 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of Compound 2 is used in the methods provided herein.

[0062] In one embodiment, compound 3 is used in the methods provided herein. In one embodiment, a tautomer of compound 3 is used in the methods provided herein. In one embodiment, an isotopologue of compound 3 is used in the methods provided herein. In one embodiment, a pharma- ceutically acceptable salt of compound 3 is used in the methods provided herein.

[0063] In one embodiment, isotopically enriched analogs of compounds are used in the methods provided herein. In one embodiment, the isotopically enriched analogs of compounds used in the methods provided herein include those described in U.S. Patent No. 10,357,489, the entirety of which is incorporated herein by reference.

[0064] The synthesis and specific uses of the compounds provided herein are described in U.S. Pat. No. 10,357,489 and U.S. Patent Application Publication No. 2020-0215060, each of which is incorporated by reference in its entirety.

[0065] Treatment and prevention methods In one embodiment, provided herein is a method of using (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, mixture of enantiomers, tautomer, or pharma- ceutically acceptable salt thereof, in combination with a second active agent provided herein to treat, prevent, or manage multiple myeloma. In one embodiment, the second agent is (i) a combination of bortezomib and dexamethasone; (ii) a combination of daratumumab and dexamethasone; (iii) a combination of carfilzomib and dexamethasone; (iv) a combination of elotuzumab and dexamethasone; or (v) a combination of isatuximab and dexamethasone. In one embodiment, provided herein is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, mixture of enantiomers, tautomer, or pharma- ceutically acceptable salt thereof, for use in a method of treating, preventing, or managing multiple myeloma, the method comprising the additional administration of a second active agent provided herein. In one embodiment, provided herein is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, mixture of enantiomers, tautomer, or pharma- ceutically acceptable salt thereof, for use in a method of treating multiple myeloma comprising the additional administration of a second active agent provided herein.

[0066] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the second therapeutic agent is (i) a combination of bortezomib and dexamethasone; (ii) a combination of daratumumab and dexamethasone; (iii) a combination of carfilzomib and dexamethasone; (iv) a combination of elotuzumab and dexamethasone; or (v) a combination of isatuximab and dexamethasone. Unless otherwise specified, "compound of formula (I)" and "compound 1" are used interchangeably herein.

[0067] In one embodiment, provided herein is a method of preventing multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the second therapeutic agent is (i) a combination of bortezomib and dexamethasone; (ii) a combination of daratumumab and dexamethasone; (iii) a combination of carfilzomib and dexamethasone; (iv) a combination of elotuzumab and dexamethasone; or (v) a combination of isatuximab and dexamethasone.

[0068] In one embodiment, provided herein is a method of managing multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof, in combination with a second therapeutic agent, wherein the second therapeutic agent is (i) a combination of bortezomib and dexamethasone; (ii) a combination of daratumumab and dexamethasone; (iii) a combination of carfilzomib and dexamethasone; (iv) a combination of elotuzumab and dexamethasone; or (v) a combination of isatuximab and dexamethasone.

[0069] In one embodiment, the multiple myeloma is previously untreated multiple myeloma.

[0070] In one embodiment, the multiple myeloma is newly diagnosed multiple myeloma (NDMM). In one embodiment, the subject is eligible for transplant. In one embodiment, the subject is eligible for autologous stem cell transplant (ASCT).

[0071] In one embodiment, a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)) is administered in combination with a second therapeutic agent provided herein as a first-line treatment for multiple myeloma.

[0072] In one embodiment, a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., hydrobromide salt)) is administered in combination with a second therapeutic agent provided herein as induction therapy. In one embodiment, induction therapy is followed by autologous stem cell transplantation (ASCT), with or without maintenance, as part of standard of care (SOC).

[0073] In one embodiment, the multiple myeloma is relapsed or refractory multiple myeloma (RRMM). In one embodiment, the subject has received at least one first-line therapy. In one embodiment, the subject has received at least two first-line therapies. In one embodiment, the subject has received 1-3 first-line therapies. In one embodiment, the subject has received 2-4 first-line therapies. In one embodiment, the first-line therapy is an anti-myeloma therapy. In one embodiment, the subject has achieved a response (minimal response [MR] or better) to at least one first-line therapy. In one embodiment, the subject has disease progression after achieving at least a partial remission to the first-line therapy (e.g., within 6 months). In one embodiment, the first-line therapy comprises a therapy comprising lenalidomide. In one embodiment, the first-line therapy comprises a proteasome inhibitor. In one embodiment, the proteasome inhibitor is bortezomib. In one embodiment, the proteasome inhibitor is carfilzomib. In one embodiment, the proteasome inhibitor is ixazomib.

[0074] Further provided herein, in one embodiment, is a method of inducing a therapeutic response in a patient as assessed using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006;(10)10:1-7), comprising administering to a patient with multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)) in combination with a second active agent provided herein.

[0075] In another embodiment, provided herein is a method of achieving a stringent complete response, complete response, or best partial response in a patient as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC), comprising administering to the patient with multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutical acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0076] In another embodiment, provided herein is a method for achieving increased overall survival, progression-free survival, event-free survival, progression-free survival, or disease-free survival in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0077] In another embodiment, provided herein is a method for achieving increased overall survival in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0078] In another embodiment, provided herein is a method for achieving increased progression-free survival in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0079] In another embodiment, provided herein is a method for achieving increased event-free survival in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0080] In another embodiment, provided herein is a method for achieving an increase in time to progression in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0081] In another embodiment, provided herein is a method for achieving increased disease-free survival in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt)), in combination with a second active agent provided herein.

[0082] Also provided herein are methods of treating patients who have been previously treated for multiple myeloma but are non-responsive to standard therapy, as well as previously untreated patients.Further encompassed are methods of treating patients who have undergone surgery to treat multiple myeloma, as well as patients who have not.Also provided herein are methods of treating patients who have undergone transplant therapy, as well as patients who have not.

[0083] The methods provided herein include the treatment of relapsed, refractory or resistant multiple myeloma. The methods provided herein include the prevention of relapsed, refractory or resistant multiple myeloma. The methods provided herein include the management of relapsed, refractory or resistant multiple myeloma. In some such embodiments, the myeloma is a first, second, third, fourth or fifth relapsed multiple myeloma. In one embodiment, the methods provided herein reduce, maintain or eliminate minimal residual disease (MRD). In one embodiment, provided herein is a method of increasing the proportion and / or durability of MRD negativity in multiple myeloma patients, comprising administering an effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., hydrobromide salt)) in combination with a second active agent provided herein. In one embodiment, the methods provided herein encompass treating, preventing or managing various types of multiple myeloma, such as monoclonal gammopathy of undetermined significance (MGUS), low-risk, intermediate-risk and high-risk multiple myeloma, newly diagnosed multiple myeloma (including low-risk, intermediate-risk and high-risk newly diagnosed multiple myeloma), transplant eligible and transplant ineligible multiple myeloma, smoldering (low-grade) multiple myeloma (including low-risk, intermediate-risk and high-risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma and immunoglobulin E myeloma, by administering a therapeutically effective amount of a compound disclosed herein.In another embodiment, the methods provided herein include treating, preventing, or managing multiple myeloma characterized by genetic abnormalities, such as cyclin D translocations (e.g., t(11;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20)); MMSET translocations (e.g., t(4;14)(p16;q32)); MAF translocations (e.g., t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (e.g., deletions of chromosome 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy, and amplification (1q)) by administering a therapeutically effective amount of a compound disclosed herein. In one embodiment, the multiple myeloma is characterized according to the International Staging Classification for Multiple Myeloma (ISS). In one embodiment, the multiple myeloma is stage I multiple myeloma characterized by ISS (e.g., serum β2 microglobulin < 3.5 mg / L and serum albumin ≧ 3.5 g / dL). In one embodiment, the multiple myeloma is stage III multiple myeloma characterized by ISS (e.g., serum β2 microglobulin > 5.4 mg / L). In one embodiment, the multiple myeloma is stage II multiple myeloma characterized by ISS (e.g., not stage I or III).

[0084] In some embodiments, the method comprises administering a therapeutically effective amount of Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as induction therapy. In some embodiments, the method comprises administering a therapeutically effective amount of Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as consolidation therapy. In some embodiments, the method comprises administering a therapeutically effective amount of Compound 1, or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, in combination with a second active agent provided herein as maintenance therapy.

[0085] In one embodiment of the method described herein, the multiple myeloma is high-risk multiple myeloma. In some such embodiments, the high-risk multiple myeloma is relapsed or refractory. In one embodiment, the high-risk multiple myeloma is multiple myeloma that relapses within 12 months of initial treatment. In yet another embodiment, the high-risk multiple myeloma is multiple myeloma characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In some such embodiments, the high-risk multiple myeloma is relapsed or refractory to one, two, or three previous treatments.

[0086] In one embodiment, the multiple myeloma is characterized by a p53 mutation. In one embodiment, the p53 mutation is a Q331 mutation. In one embodiment, the p53 mutation is a R273H mutation. In one embodiment, the p53 mutation is a K132 mutation. In one embodiment, the p53 mutation is a K132N mutation. In one embodiment, the p53 mutation is a R337 mutation. In one embodiment, the p53 mutation is a R337L mutation. In one embodiment, the p53 mutation is a W146 mutation. In one embodiment, the p53 mutation is a S261 mutation. In one embodiment, the p53 mutation is a S261T mutation. In one embodiment, the p53 mutation is an E286 mutation. In one embodiment, the p53 mutation is an E286K mutation. In one embodiment, the p53 mutation is a R175 mutation. In one embodiment, the p53 mutation is a R175H mutation. In one embodiment, the p53 mutation is an E258 mutation. In one embodiment, the p53 mutation is an E258K mutation. In one embodiment, the p53 mutation is an A161 mutation. In one embodiment, the p53 mutation is an A161T mutation.

[0087] In one embodiment, the multiple myeloma is characterized by a homozygous deletion of p53. In one embodiment, the multiple myeloma is characterized by a homozygous deletion of wild-type p53.

[0088] In one embodiment, the multiple myeloma is characterized by wild-type p53.

[0089] In one embodiment, the multiple myeloma is characterized by activation of one or more oncogenic drivers. In one embodiment, the one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1 and cyclin D. In one embodiment, the multiple myeloma is characterized by activation of C-MAF. In one embodiment, the multiple myeloma is characterized by activation of MAFB. In one embodiment, the multiple myeloma is characterized by activation of FGFR3 and MMset. In one embodiment, the multiple myeloma is characterized by activation of C-MAF, FGFR3 and MMset. In one embodiment, the multiple myeloma is characterized by activation of cyclin D1. In one embodiment, the multiple myeloma is characterized by activation of MAFB and cyclin D1. In one embodiment, the multiple myeloma is characterized by activation of cyclin D.

[0090] In one embodiment, the multiple myeloma is characterized by one or more chromosomal translocations. In one embodiment, the chromosomal translocation is t(14;16). In one embodiment, the chromosomal translocation is t(14;20). In one embodiment, the chromosomal translocation is t(4;14). In one embodiment, the chromosomal translocation is t(4;14) and t(14;16). In one embodiment, the chromosomal translocation is t(11;14). In one embodiment, the chromosomal translocation is t(6;20). In one embodiment, the chromosomal translocation is t(20;22). In one embodiment, the chromosomal translocation is t(6;20) and t(20;22). In one embodiment, the chromosomal translocation is t(16;22). In one embodiment, the chromosomal translocation is t(14;16) and t(16;22). In one embodiment, the chromosomal translocation is t(14;20) and t(11;14).

[0091] In one embodiment, the multiple myeloma is characterized by a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma is characterized by a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma is characterized by a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In one embodiment, the multiple myeloma is characterized by wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma is characterized by wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In one embodiment, the multiple myeloma is characterized by homozygous deletion of p53, activation of FGFR3, MMset and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In one embodiment, the multiple myeloma is characterized by homozygous deletion of p53, activation of cyclin D1, and chromosomal translocations at t(11;14). In one embodiment, the multiple myeloma is characterized by R337L p53 mutation, activation of cyclin D1, and chromosomal translocations at t(11;14). In one embodiment, the multiple myeloma is characterized by W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocations at t(4;14). In one embodiment, the multiple myeloma is characterized by S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In one embodiment, the multiple myeloma is characterized by E286K p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma is characterized by R175H p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In one embodiment, the multiple myeloma is characterized by E258K p53 mutation, activation of C-MAF, and chromosomal translocation at t(14;16) and t(16;22).In one embodiment, the multiple myeloma is characterized by wild-type p53, MAFB and cyclin D1 activation, and chromosomal translocations at t(14;20) and t(11;14). In one embodiment, the multiple myeloma is characterized by A161T p53 mutation, cyclin D activation, and chromosomal translocations at t(11;14).

[0092] In some embodiments of the methods described herein, the multiple myeloma is transplant eligible newly diagnosed multiple myeloma. In another embodiment, the multiple myeloma is transplant ineligible newly diagnosed multiple myeloma.

[0093] In yet other embodiments, the multiple myeloma is characterized by early progression (e.g., less than 12 months) after initial treatment. In yet other embodiments, the multiple myeloma is characterized by early progression (e.g., less than 12 months) after autologous stem cell transplant. In another embodiment, the multiple myeloma is refractory to lenalidomide. In another embodiment, the multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, the multiple myeloma is relapsed or refractory to three or more therapies and has been exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iverdimide, or avadomide), or is dual refractory to a proteasome inhibitor and an immunomodulatory compound. In yet other embodiments, the multiple myeloma is relapsed or refractory to three or more previous therapies, such as, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iverdimide, or avadomide), or is dual refractory to a proteasome inhibitor or an immunomodulatory compound and a CD38 mAb. In yet other embodiments, the multiple myeloma is triple refractory, for example, the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iverdimide, or avadomide), and one other active agent as described herein.

[0094] In certain embodiments, provided herein is a method for treating, preventing and / or managing multiple myeloma, e.g., relapsed / refractory multiple myeloma, in a patient with renal impairment or a symptom thereof, comprising administering to a patient with relapsed / refractory multiple myeloma with renal impairment a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) in combination with a second active agent provided herein.

[0095] In some embodiments, provided herein is a method for treating, preventing and / or managing multiple myeloma, for example relapsed or refractory multiple myeloma or symptoms thereof, in a frail patient, comprising administering to a frail patient having multiple myeloma a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) in combination with a second active agent provided herein. In some such embodiments, the frail patient is characterized by ineligibility for induction therapy or intolerance to dexamethasone treatment. In some such embodiments, the frail patient is, for example, elderly, over 65 years old.

[0096] In one embodiment, provided herein is a method for treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), in combination with a second active agent provided herein, wherein the multiple myeloma is fourth-line relapsed / refractory multiple myeloma.

[0097] In one embodiment, provided herein is a method for treating, preventing, or managing multiple myeloma, comprising administering to a patient, as induction therapy, a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), in combination with a second active agent provided herein, wherein the multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma.

[0098] In certain embodiments, provided herein is a method for treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) in combination with a second active agent provided herein as a maintenance therapy following other treatment or transplant, wherein the multiple myeloma is newly diagnosed, transplant-eligible multiple myeloma prior to other treatment or transplant.

[0099] In some embodiments, provided herein is a method for treating, preventing or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) in combination with a second active agent provided herein as a maintenance therapy after other treatment or transplantation. In some embodiments, the multiple myeloma is a newly diagnosed transplant-eligible multiple myeloma prior to other treatment and / or transplantation. In some embodiments, the other treatment prior to transplantation is chemotherapy or treatment with a compound provided herein (e.g., Compound 1 or a pharmaceutically acceptable salt thereof).

[0100] In certain embodiments, provided herein is a method of treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), in combination with a second active agent provided herein, wherein the multiple myeloma is high-risk multiple myeloma that is relapsed or refractory to one, two, or three prior treatments.

[0101] In certain embodiments, provided herein is a method for treating, preventing, or managing multiple myeloma, comprising administering to a patient a therapeutically effective amount of a compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof), in combination with a second active agent provided herein, wherein the multiple myeloma is newly diagnosed, transplant-ineligible multiple myeloma.

[0102] In some embodiments, the patient to be treated with one of the methods provided herein has not been treated with multiple myeloma therapy prior to administration of the compound provided herein (e.g., Compound 1 or a pharma- ceutically acceptable salt thereof) in combination with the second active agent provided herein. In some embodiments, the patient to be treated with one of the methods provided herein has developed drug resistance to anti-multiple myeloma therapy. In some such embodiments, the patient has developed resistance to one, two or three anti-multiple myeloma therapies, and the therapy is selected from CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdimide or avadomide).

[0103] The methods provided herein encompass treating patients regardless of the patient's age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is over 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the subject is under 65 years of age. In other embodiments, the subject is over 65 years of age. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject over 65 years of age. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject over 75 years of age.

[0104] In one embodiment, the second therapeutic agent is a combination of elotuzumab and dexamethasone.

[0105] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with elotuzumab and dexamethasone. In one embodiment, provided herein are compounds for use in a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound characterized by formula (I), or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with elotuzumab and dexamethasone.

[0106] Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the signaling lymphocyte activation molecule family member 7 (SLAMF7) protein. In one embodiment, elotuzumab is administered in an amount as determined by a physician. In one embodiment, elotuzumab is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, elotuzumab is administered according to the Empliciti® label. In one embodiment, elotuzumab is administered at a dose of about 10 mg / kg / day. In one embodiment, elotuzumab is administered at a dose of about 20 mg / kg / day. In one embodiment, elotuzumab is administered on days 1, 8, 15, and 22 of the first two 28-day cycles and on day 1 of the subsequent 28-day cycles. In one embodiment, elotuzumab is administered intravenously. In one embodiment, elotuzumab is administered via intravenous injection. In one embodiment, elotuzumab is administered via intravenous infusion.

[0107] In one embodiment, dexamethasone is administered in an amount as determined by a physician. In one embodiment, dexamethasone is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, dexamethasone is administered at a dose of about 40 mg / day. In one embodiment, dexamethasone is administered at a dose of about 36 mg / day. In one embodiment, dexamethasone is administered at a dose of about 28 mg / day. In one embodiment, dexamethasone is administered at a dose of about 20 mg / day. In one embodiment, dexamethasone is administered at a dose of about 16 mg / day. In one embodiment, dexamethasone is administered at a dose of about 8 mg / day. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, dexamethasone is administered orally. In one embodiment, dexamethasone is administered intravenously. In one embodiment, dexamethasone is administered via intravenous injection.In one embodiment, dexamethasone is administered via intravenous infusion.

[0108] In one embodiment, elotuzumab is administered on days 1, 8, 15, and 22 of the first two 28-day cycles and day 1 of each subsequent 28-day cycle; and dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28-day cycles.

[0109] In one embodiment, elotuzumab is administered intravenously and dexamethasone is administered intravenously or orally.

[0110] In one embodiment, elotuzumab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of the first two 28 day cycles and at a dose of about 20 mg / kg on day 1 of each subsequent 28 day cycle; and dexamethasone is administered both orally at a dose of about 28 mg and intravenously at a dose of about 8 mg (for a total of 36 mg) on ​​days 1, 8, 15, and 22 of the first two 28 day cycles and on day 1 of each subsequent 28 day cycle beginning with the third 28 day cycle, and at a dose of about 40 mg orally on days 8, 15, and 22 of each subsequent 28 day cycle beginning with the third 28 day cycle.

[0111] In one embodiment, elotuzumab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of the first two 28 day cycles and at a dose of about 20 mg / kg on day 1 of each subsequent 28 day cycle; and dexamethasone is administered both orally at a dose of about 8 mg and intravenously at a dose of about 8 mg (for a total of 16 mg) on ​​days 1, 8, 15, and 22 of the first two 28 day cycles and on day 1 of each subsequent 28 day cycle beginning with the third 28 day cycle, and at a dose of about 20 mg orally on days 8, 15, and 22 of each subsequent 28 day cycle beginning with the third 28 day cycle.

[0112] In one embodiment, the second therapeutic agent is a combination of isatuximab and dexamethasone.

[0113] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with isatuximab and dexamethasone. In one embodiment, provided herein is a compound for use in a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound characterized by formula (I), or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, in combination with isatuximab and dexamethasone.

[0114] Isatuximab is an immunoglobulin G1 (IgG1) derived monoclonal antibody that binds to CD38 expressed on the surface of hematopoietic and tumor cells, such as MM cells. In one embodiment, isatuximab is administered in an amount as determined by a physician. In one embodiment, isatuximab is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, isatuximab is administered according to the Sarclisa® label. In one embodiment, isatuximab is administered at a dose of about 10 mg / kg / day. In one embodiment, isatuximab is administered on days 1, 8, 15, and 22 of the first 28-day cycle, and days 1 and 15 of the subsequent 28-day cycle. In one embodiment, isatuximab is administered intravenously. In one embodiment, isatuximab is administered via intravenous injection. In one embodiment, isatuximab is administered via intravenous infusion.

[0115] In one embodiment, dexamethasone is administered in an amount as determined by a physician. In one embodiment, dexamethasone is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, dexamethasone is administered at a dose of about 40 mg / day. In one embodiment, dexamethasone is administered at a dose of about 20 mg / day. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, dexamethasone is administered orally. In one embodiment, dexamethasone is administered intravenously. In one embodiment, dexamethasone is administered via intravenous injection. In one embodiment, dexamethasone is administered via intravenous infusion.

[0116] In one embodiment, isatuximab is administered on days 1, 8, 15, and 22 of a first 28 day cycle and days 1 and 15 of each subsequent 28 day cycle; and dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28 day cycles.

[0117] In one embodiment, isatuximab is administered intravenously and dexamethasone is administered intravenously or orally.

[0118] In one embodiment, isatuximab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of a first 28 day cycle and at a dose of about 10 mg / kg on days 1 and 15 of each subsequent 28 day cycle; and dexamethasone is administered intravenously or orally at a dose of about 40 mg on days 1, 8, 15, and 22 of each of the 28 day cycle.

[0119] In one embodiment, isatuximab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of a first 28 day cycle and at a dose of about 10 mg / kg on days 1 and 15 of each subsequent 28 day cycle; and dexamethasone is administered intravenously or orally at a dose of about 20 mg on days 1, 8, 15, and 22 of each of the 28 day cycle.

[0120] In one embodiment, the second therapeutic agent is a combination of bortezomib and dexamethasone.

[0121] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof in combination with bortezomib and dexamethasone.

[0122] Bortezomib is a proteasome inhibitor. In one embodiment, bortezomib is administered in an amount as determined by a physician. In one embodiment, bortezomib is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, bortezomib is administered according to the Velcade® label. In one embodiment, bortezomib is administered at about 1.3 mg / m 2In one embodiment, bortezomib is administered at a dose of 0.1 mg / day. In one embodiment, bortezomib is administered on days 1, 4, 8, and 11 of the first eight 21-day cycles and days 1 and 8 of the subsequent 21-day cycles. In one embodiment, bortezomib is administered on days 1, 4, 8, and 11 of up to six 21-day cycles. In one embodiment, bortezomib is administered on days 1, 4, 8, and 11 of six 21-day cycles. In one embodiment, bortezomib is administered subcutaneously. In one embodiment, bortezomib is administered via subcutaneous infusion.

[0123] In one embodiment, dexamethasone is administered in an amount as determined by a physician. In one embodiment, dexamethasone is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, dexamethasone is administered at a dose of about 20 mg / day. In one embodiment, dexamethasone is administered at a dose of about 10 mg / day. In one embodiment, dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first eight 21-day cycles and days 1, 2, 8, and 9 of the subsequent 21-day cycles. In one embodiment, dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12 of up to six 21-day cycles. In one embodiment, dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12 of six 21-day cycles. In one embodiment, dexamethasone is administered orally.

[0124] In one embodiment, bortezomib is administered on days 1, 4, 8, and 11 of the first eight 21-day cycles, and days 1 and 8 of each subsequent 21-day cycle; and dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first eight 21-day cycles, and days 1, 2, 8, and 9 of each subsequent 21-day cycle.

[0125] In one embodiment, bortezomib is administered on days 1, 4, 8, and 11 of (up to) six 21-day cycles; and dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 21-day cycles.

[0126] In one embodiment, bortezomib is administered subcutaneously and dexamethasone is administered orally.

[0127] In one embodiment, bortezomib is administered at about 1.3 mg / m on days 1, 4, 8, and 11 of the first eight 21-day cycles and days 1 and 8 of each subsequent 21-day cycle. 2 and dexamethasone is administered orally at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first eight 21-day cycles and days 1, 2, 8, and 9 of each subsequent 21-day cycle.

[0128] In one embodiment, bortezomib is administered at about 1.3 mg / m on days 1, 4, 8, and 11 of the first eight 21-day cycles and days 1 and 8 of each subsequent 21-day cycle. 2 and dexamethasone is administered orally at a dose of about 10 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first eight 21-day cycles and days 1, 2, 8, and 9 of each subsequent 21-day cycle.

[0129] In one embodiment, bortezomib is administered at about 1.3 mg / m on days 1, 4, 8, and 11 of (up to) six 21-day cycles. 2 and dexamethasone is administered orally at a dose of about 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of a 21 day cycle.

[0130] In one embodiment, bortezomib is administered at about 1.3 mg / m on days 1, 4, 8, and 11 of (up to) six 21-day cycles. 2and dexamethasone is administered orally at a dose of about 10 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of a 21 day cycle.

[0131] In one embodiment, the second therapeutic agent is a combination of daratumumab and dexamethasone.

[0132] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof, in combination with daratumumab and dexamethasone.

[0133] Daratumumab is a human immunoglobulin G (IgG) kappa monoclonal antibody that targets the cell surface molecule CD38 expressed by malignant plasma cells. In one embodiment, daratumumab is administered in an amount as determined by a physician. In one embodiment, daratumumab is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, daratumumab is administered according to the Darzalex® label. In one embodiment, daratumumab is administered at a dose of about 16 mg / kg / day. In one embodiment, daratumumab is administered at a dose of about 1800 mg / day. In one embodiment, daratumumab is administered on days 1, 8, 15, and 22 of the first two 28-day cycles, days 1 and 15 of the third through sixth 28-day cycles, and day 1 of subsequent 28-day cycles. In one embodiment, daratumumab is administered on days 1, 8, and 15 of the first three 21-day cycles, day 1 of the fourth through eighth 21-day cycles, and day 1 of any subsequent 28-day cycles. In one embodiment, daratumumab is administered intravenously. In one embodiment, daratumumab is administered via intravenous injection. In one embodiment, daratumumab is administered via intravenous infusion. In one embodiment, daratumumab is administered subcutaneously. In one embodiment, daratumumab is administered via subcutaneous infusion.

[0134] In one embodiment, dexamethasone is administered in an amount as determined by a physician. In one embodiment, dexamethasone is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, dexamethasone is administered at a dose of about 40 mg / day. In one embodiment, dexamethasone is administered at a dose of about 20 mg / day. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, dexamethasone is administered on days 1, 8, and 15 of the first eight 21-day cycles and on days 1, 8, 15, and 22 of the subsequent 28-day cycles. In one embodiment, dexamethasone is administered orally. In one embodiment, dexamethasone is administered intravenously. In one embodiment, dexamethasone is administered via intravenous injection. In one embodiment, dexamethasone is administered via intravenous infusion.

[0135] In one embodiment, daratumumab is administered on days 1, 8, 15, and 22 of the first two 28-day cycles, days 1 and 15 of the third through sixth 28-day cycles, and day 1 of each subsequent 28-day cycle; and dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28-day cycles.

[0136] In one embodiment, daratumumab is administered on days 1, 8, and 15 of the first three 21-day cycles, day 1 of the fourth through eighth 21-day cycles, and day 1 of each subsequent 28-day cycle; and dexamethasone is administered on days 1, 8, and 15 of the first eight 21-day cycles, and days 1, 8, 15, and 22 of each subsequent 28-day cycle.

[0137] In one embodiment, daratumumab is administered intravenously or subcutaneously and dexamethasone is administered intravenously or orally.

[0138] In one embodiment, daratumumab is administered intravenously at a dose of about 16 mg / kg or subcutaneously at a dose of about 1800 mg on days 1, 8, 15, and 22 of the first two 28-day cycles, days 1 and 15 of the third through sixth 28-day cycles, and day 1 of each subsequent 28-day cycle; and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, 15, and 22 of each of the 28-day cycles.

[0139] In one embodiment, daratumumab is administered intravenously at a dose of about 16 mg / kg or subcutaneously at a dose of about 1800 mg on days 1, 8, 15, and 22 of the first two 28 day cycles, days 1 and 15 of the third through sixth 28 day cycles, and day 1 of each subsequent 28 day cycle; and dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 8, 15, and 22 of each of the 28 day cycles.

[0140] In one embodiment, daratumumab is administered intravenously at a dose of about 16 mg / kg or subcutaneously at a dose of about 1800 mg on days 1, 8, and 15 of the first three 21-day cycles, day 1 of the fourth through eighth 21-day cycles, and day 1 of each subsequent 28-day cycle; and dexamethasone is administered orally or intravenously at a dose of about 40 mg on days 1, 8, and 15 of the first eight 21-day cycles, and days 1, 8, 15, and 22 of each subsequent 28-day cycle.

[0141] In one embodiment, daratumumab is administered intravenously at a dose of about 16 mg / kg or subcutaneously at a dose of about 1800 mg on days 1, 8, and 15 of the first three 21-day cycles, day 1 of the fourth through eighth 21-day cycles, and day 1 of each subsequent 28-day cycle; and dexamethasone is administered orally or intravenously at a dose of about 20 mg on days 1, 8, and 15 of the first eight 21-day cycles, and days 1, 8, 15, and 22 of each subsequent 28-day cycle.

[0142] In one embodiment, the second therapeutic agent is a combination of carfilzomib and dexamethasone.

[0143] In one embodiment, provided herein is a method of treating multiple myeloma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I): [ka] or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or a pharma- ceutically acceptable salt thereof in combination with carfilzomib and dexamethasone.

[0144] Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active site of the 20S proteasome. In one embodiment, carfilzomib is administered in an amount as determined by a physician. In one embodiment, carfilzomib is administered according to the locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, carfilzomib is administered according to the Kyprolis® label. In one embodiment, carfilzomib is administered at a dose of about 20 mg / m 2 In one embodiment, carfilzomib is administered at a dose of about 56 mg / m 2 / day. In one embodiment, carfilzomib is administered on days 1, 8, and 15 of the first twelve 28-day cycles and days 1 and 15 of each subsequent 28-day cycle. In one embodiment, carfilzomib is administered intravenously. In one embodiment, carfilzomib is administered via intravenous injection. In one embodiment, carfilzomib is administered via intravenous infusion.

[0145] In one embodiment, dexamethasone is administered in an amount as determined by a physician. In one embodiment, dexamethasone is administered according to a locally approved label or pharmaceutical manual for preparation, administration, and storage information. In one embodiment, dexamethasone is administered at a dose of about 40 mg / day. In one embodiment, dexamethasone is administered at a dose of about 20 mg / day. In one embodiment, dexamethasone is administered on days 1, 8, 15, and 22 of a 28-day cycle. In one embodiment, dexamethasone is administered orally. In one embodiment, dexamethasone is administered intravenously. In one embodiment, dexamethasone is administered via intravenous injection. In one embodiment, dexamethasone is administered via intravenous infusion.

[0146] In one embodiment, carfilzomib is administered on days 1, 8, and 15 of the first twelve 28-day cycles and days 1 and 15 of each subsequent 28-day cycle; and dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28-day cycles.

[0147] In one embodiment, carfilzomib is administered intravenously and dexamethasone is administered intravenously or orally.

[0148] In one embodiment, carfilzomib is administered at about 20 mg / m on day 1 of the first 28-day cycle. 2 56 mg / m on days 8 and 15 of the first 28-day cycle 2 of approximately 56 mg / m on days 1, 8, and 15 of 28-day cycles 2 through 12. 2 and about 56 mg / m on days 1 and 15 of subsequent 28-day cycles. 2 and dexamethasone is administered intravenously or orally at a dose of about 40 mg on days 1, 8, 15, and 22 of each of a 28 day cycle.

[0149] In one embodiment, carfilzomib is administered at about 20 mg / m on day 1 of the first 28-day cycle.2 56 mg / m on days 8 and 15 of the first 28-day cycle 2 of approximately 56 mg / m on days 1, 8, and 15 of 28-day cycles 2 through 12. 2 and about 56 mg / m on days 1 and 15 of subsequent 28-day cycles. 2 and dexamethasone is administered intravenously or orally at a dose of about 20 mg on days 1, 8, 15, and 22 of each of a 28 day cycle.

[0150] In one embodiment, a first therapy provided herein (e.g., a prophylactic or therapeutic agent, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof) is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) administration of a second therapeutic agent provided herein to a subject.

[0151] In one embodiment, a first therapy provided herein (e.g., a prophylactic or therapeutic agent, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof) is administered simultaneously with the administration of a second therapy provided herein to a subject.

[0152] In one embodiment, a first therapy provided herein (e.g., a prophylactic or therapeutic agent, e.g., Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharma- ceutically acceptable salt thereof) is administered after administration of a second therapeutic agent provided herein to the subject (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks or more).

[0153] In one embodiment, a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered. In one embodiment, a compound of formula (I) (free base) is administered. In one embodiment, a compound of formula (I) is administered as a hydrobromide salt. In one embodiment, the compound is administered orally.

[0154] In one embodiment, the compound is administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). Additionally, administration can be continuous (i.e., daily or every day for consecutive days), intermittent, such as on a cyclical basis (i.e., including drug-free periods of days, weeks, or months).

[0155] In one embodiment, a compound described herein, for example, Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt of Compound 1), is administered once a day at a dose of about 0.1 mg to about 2 mg. In one embodiment, the compound is administered once a day at a dose of about 0.3 mg to about 0.6 mg. In one embodiment, the compound is administered once a day at a dose of about 0.3 mg to about 0.8 mg. In one embodiment, the compound is administered once a day at a dose of about 0.3 mg to about 1 mg. In one embodiment, the compound is administered once a day at a dose of about 0.6 mg to about 0.8 mg. In one embodiment, the compound is administered once a day at a dose of about 0.6 mg to about 1 mg. In one embodiment, the compound is administered once a day at a dose of about 0.8 mg to about 1 mg.

[0156] In one embodiment, a compound described herein, e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt of Compound 1), is administered once daily at a dose of about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, or about 2 mg. In one embodiment, the compound is administered once daily at a dose of about 0.1 mg. In one embodiment, the compound is administered once daily at a dose of about 0.15 mg. In one embodiment, the compound is administered once daily at a dose of about 0.2 mg. In one embodiment, the compound is administered at a dose of about 0.3 mg once per day. In one embodiment, the compound is administered at a dose of about 0.4 mg once per day. In one embodiment, the compound is administered at a dose of about 0.45 mg once per day. In one embodiment, the compound is administered at a dose of about 0.5 mg once per day. In one embodiment, the compound is administered at a dose of about 0.6 mg once per day. In one embodiment, the compound is administered at a dose of about 0.7 mg once per day. In one embodiment, the compound is administered at a dose of about 0.8 mg once per day. In one embodiment, the compound is administered at a dose of about 0.9 mg once per day. In one embodiment, the compound is administered at a dose of about 1 mg once per day. In one embodiment, the compound is administered at a dose of about 1.1 mg once per day. In one embodiment, the compound is administered at a dose of about 1.2 mg once per day. In one embodiment, the compound is administered at a dose of about 1.3 mg once per day. In one embodiment, the compound is administered at a dose of about 1.4 mg once per day. In one embodiment, the compound is administered at a dose of about 1.5 mg once per day. In one embodiment, the compound is administered at a dose of about 1.6 mg once per day. In one embodiment, the compound is administered at a dose of about 1.7 mg once per day. In one embodiment, the compound is administered at a dose of about 1.8 mg once per day. In one embodiment, the compound is administered at a dose of about 1.9 mg once per day.In one embodiment, the compound is administered at a dosage of about 2 mg once daily.

[0157] In one embodiment, a compound described herein, e.g., Compound 1 or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt of Compound 1), is administered for 7 days followed by a 7-day rest period. In one embodiment, the compound is administered for 14 days followed by a 7-day rest period. In one embodiment, the compound is administered for 21 days followed by a 7-day rest period.

[0158] In one embodiment, a compound described herein, e.g., Compound 1, or a pharma- ceutically acceptable salt thereof (e.g., the hydrobromide salt of Compound 1), is administered on days 1-14 of a 21 day cycle. In one embodiment, the compound is administered on days 1-21 of a 28 day cycle. In one embodiment, the compound is administered on days 1-7 and days 15-21 of a 28 day cycle. The period of compound administration is followed by a holiday of the compound for the remaining days of the cycle.

[0159] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering elotuzumab on days 1, 8, 15, and 22 of the first two 28 day cycles and day 1 of each subsequent 28 day cycle; (ii) administering dexamethasone on days 1, 8, 15, and 22 of each of the 28 day cycles; and (iii) administering a compound on days 1-21 of each of the 28 day cycles.

[0160] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering isatuximab on days 1, 8, 15, and 22 of an initial 28 day cycle, and days 1 and 15 of each subsequent 28 day cycle; (ii) administering dexamethasone on days 1, 8, 15, and 22 of each of the 28 day cycles; and (iii) administering a compound on days 1-21 of each of the 28 day cycles.

[0161] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering isatuximab on days 1, 8, 15, and 22 of an initial 28 day cycle, and days 1 and 15 of each subsequent 28 day cycle; (ii) administering dexamethasone on days 1, 8, 15, and 22 of each of the 28 day cycle; and (iii) administering a compound on days 1-7 and days 15-21 of each of the 28 day cycle.

[0162] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering bortezomib on days 1, 4, 8, and 11 of the first eight 21 day cycles, and days 1 and 8 of each subsequent 21 day cycle; (ii) administering dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first eight 21 day cycles, and days 1, 2, 8, and 9 of each subsequent 21 day cycle; and (iii) administering a compound on days 1 through 14 of each 21 day cycle.

[0163] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering daratumumab on days 1, 8, 15, and 22 of the first two 28 day cycles, days 1 and 15 of the third through sixth 28 day cycles, and day 1 of each subsequent 28 day cycle; (ii) administering dexamethasone on days 1, 8, 15, and 22 of each of the 28 day cycles; and (iii) administering a compound on days 1 through 21 of each of the 28 day cycles.

[0164] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering daratumumab on days 1, 8, and 15 of the first three 21-day cycles, day 1 of the fourth through eighth 21-day cycles, and day 1 of each subsequent 28-day cycle; (ii) administering dexamethasone on days 1, 8, and 15 of the first eight 21-day cycles, and days 1, 8, 15, and 22 of each subsequent 28-day cycle; and (iii) administering a compound on days 1-14 of the first eight 21-day cycles, and days 1-21 of each subsequent 28-day cycle.

[0165] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering daratumumab on days 1, 8, 15, and 22 of the first two 28 day cycles, days 1 and 15 of the third through sixth 28 day cycles, and day 1 of each subsequent 28 day cycle; (ii) administering dexamethasone on days 1, 8, 15, and 22 of each of the 28 day cycles; and (iii) administering a compound on days 1-7 and days 15-21 of the first six 28 day cycles, and days 1-21 of each subsequent 28 day cycle.

[0166] In one embodiment, provided herein is a method for treating relapsed or refractory multiple myeloma, comprising: (i) administering carfilzomib on days 1, 8, and 15 of the first twelve 28-day cycles, and days 1 and 15 of each subsequent 28-day cycle; (ii) administering dexamethasone on days 1, 8, 15, and 22 of each of the 28-day cycles; and (iii) administering a compound on days 1-21 of each of the 28-day cycles.

[0167] In one embodiment, provided herein is a method for treating newly diagnosed multiple myeloma, comprising: (i) administering bortezomib on days 1, 4, 8, and 11 of (up to) six 21-day cycles; (ii) administering dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of each of the 21-day cycles; and (iii) administering a compound on days 1-14 of each of the 21-day cycles.

[0168] Pharmaceutical Compositions Pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more of the compounds provided herein and / or a second active agent provided herein, and optionally a pharma- ceutically acceptable carrier, diluent or excipient.

[0169] Compound can be formulated into suitable pharmaceutical preparation for oral administration, such as liquid, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained release formulation or elixir, or sterile solution or suspension for ocular or parenteral administration, as well as transdermal patch preparation and dry powder inhaler.Typically, the above-mentioned compound is formulated into pharmaceutical composition using well-known technology and procedures in the art (for example, see Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[0170] In the compositions, an effective concentration of one or more compounds or pharma- ceutically acceptable salts are mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective to deliver an amount that, upon administration, treats, prevents, or ameliorates one or more symptoms and / or progression of multiple myeloma.

[0171] Typically, the composition is formulated for single dose administration. To formulate the composition, the weight fraction of the compound is dissolved, suspended, dispersed or otherwise mixed in the selected vehicle at an effective concentration to alleviate or improve the pathology being treated. Pharmaceutical carriers or vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0172] Furthermore, the compound can be formulated as the only pharma- ceutically active ingredient in the composition or can be combined with other active ingredients. Liposomal suspensions, such as tissue-targeted liposomes, such as tumor-targeted liposomes, can also be suitable as pharma- ceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art. For example, liposomal formulations can be prepared according to methods known to those skilled in the art. Briefly, liposomes, such as multilamellar vesicles (MLVs), can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of the compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0173] The active compound is included in a pharma- ceutically acceptable carrier in an amount sufficient to confer a therapeutically beneficial effect in the absence of undesirable side effects on the patient being treated. The therapeutically effective concentration can be empirically determined by testing the compounds in the in vitro and in vivo systems described herein, and then extrapolated therefrom for administration to humans.

[0174] The concentration of the active compound in the pharmaceutical composition depends on the absorption, tissue distribution, inactivation, metabolism and excretion rates of the active compound, the physicochemical characteristics of the compound, the administration schedule and dosage, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of cancer, including solid tumors and blood-borne tumors.

[0175] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain any of the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparaben; antioxidants such as ascorbic acid, sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates, phosphates; and agents for adjusting isotonicity such as sodium chloride or dextrose. Parenteral preparations can be encapsulated in ampoules, pens, disposable syringes, or single- or multiple-dose vials made of glass, plastic, or other suitable material.

[0176] If a compound exhibits insufficient solubility, methods of solubilizing the compound can be used, which are known to those skilled in the art and include, but are not limited to, the use of co-solvents such as dimethylsulfoxide (DMSO), the use of detergents such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[0177] Upon mixing or addition of the compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the dissolution rate of the compound in the selected carrier or vehicle. The effective concentration is a concentration sufficient to ameliorate the symptoms of the disease, disorder, or condition being treated, and can be empirically determined.

[0178] Pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions and oil-in-water emulsions, containing a suitable amount of the compound or its pharma- ceutically acceptable salts. Pharmaceutically therapeutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. Unit dosage forms, as used herein, refer to physically distinct units suitable for human and animal subjects, individually packaged as known in the art. Each unit dosage contains a predetermined amount of therapeutically active compound sufficient to produce the desired therapeutic effect, together with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit dosage form can be administered in portions or multiples thereof. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container to be administered in separate unit dosage forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple dose form is an undivided multiple of a unit dose in packaging.

[0179] Dosage forms or compositions can be prepared containing active ingredients in the range of 0.005% to 100%, with the remainder consisting of non-toxic carriers. For oral administration, pharma- ceutically acceptable non-toxic compositions can be formed by incorporating any of the commonly used excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained release formulations, including, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, and the like. Methods for preparing these compositions are known to those skilled in the art.

[0180] The active compounds or pharma- ceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time-release formulations or coatings.

[0181] The composition may contain other active compounds to obtain a combination of desired properties.The compounds provided herein or their pharmacologic acceptable salts described herein may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be beneficial in treating one or more of the above-mentioned diseases or medical conditions, such as diseases associated with oxidative stress.It should be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

[0182] Certain pharmaceutical compositions and formulations of Compound 1 are described in U.S. Patent Application Publication No. 2020-0215061 and U.S. Patent Application No. 63 / 048,998, the entireties of which are incorporated by reference herein.

[0183] It is understood that the foregoing detailed description and the accompanying examples are merely illustrative and should not be construed as limitations on the scope of the subject matter. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including but not limited to the chemical structures, substituents, derivatives, intermediates, synthesis, formulations and / or methods of use provided herein, can be made without departing from the spirit and scope thereof. The U.S. patents and publications referenced herein are incorporated by reference. EXAMPLES

[0184] Certain embodiments of the present invention are illustrated by the following non-limiting examples.

[0185] Example 1: Phase 1 / 2 Clinical Trial A Phase 1 / 2 multicenter, open-label study will be conducted to determine the recommended dose and regimen and to evaluate the safety and preliminary efficacy of Compound 1 in combination with standard of care in subjects with relapsed or refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM).

[0186] Indications Relapsed or refractory multiple myeloma (RRMM) and newly diagnosed multiple myeloma (NDMM).

[0187] the purpose Primary Objective: To determine the recommended dose and regimen and to evaluate the safety and preliminary efficacy of Compound 1 in combination with standard of care in subjects with RRMM and NDMM.

[0188] Secondary Objective: To evaluate additional measures of efficacy of Compound 1 in combination with standard of care (time to response, duration of response, very good partial response [VGPR] or better complete response rate) in subjects with RRMM and NDMM.

[0189] Purpose of exploration: Evaluate the PK of Compound 1 when administered in combination with standard of care in subjects with RRMM and NDMM. Evaluate the relationship between pharmacokinetic (PK) / pharmacodynamic (PD) biomarkers and clinical outcomes of Compound 1 when administered in combination with standard of care in subjects with RRMM and NDMM. The percentage of subjects achieving minimal residual disease (MRD)-negative status will be assessed by flow cytometry (EuroFlow™). Evaluate additional measures of efficacy (progression-free survival) of Compound 1 in combination with standard of care in subjects with RRMM and NDMM.

[0190] Test Design This is an open-label, multicenter, Phase 1 / 2 study to determine the maximum tolerated dose (MTD) / recommended Phase 2 dose (RP2D) and evaluate the safety and preliminary efficacy of Compound 1 in combination with standard of care.

[0191] Phase 1 (approximately 108 subjects) A modified toxicity probability interval-2 (mTPI-2) design (Ji et al., Clin. Trials. 2010, 7(6):653-63; Ji et al., J. Clin. Oncol. 2013, 31(14):1785-91; Guo et al., Contemp. Clin. Trials. 2017, 58:23-33) will be used to determine the RP2D for compound 1 in combination with standard of care in subjects with RRMM who have received 2-4 prior regimens. Each cohort will operate independently. Cohort A: Compound 1 in combination with bortezomib (BTZ) and dexamethasone (dex) Cohort B: Consists of three subcohorts (B1, B2, and B3) of compound 1 in combination with daratumumab (DARA) and dex; the term Cohort B refers to all subcohorts B1, B2, and B3 Cohort C: Compound 1 in combination with carfilzomib (CFZ) and dex Cohort H: Compound 1 in combination with elotuzumab (ELO) and dex Cohort I: Compound 1 in combination with isatuximab (ISA) and dex

[0192] All subjects in cohort A and subcohort B2 will be observed for 21 days (Cycle 1) after the first dose of Compound 1, while subjects in subcohorts B1, B3 and subjects in cohorts C, H, and I will be observed for 28 days (Cycle 1) after the first dose of Compound 1 before initiating the next dose level. All subjects for these Phase 1 treatment cohorts will continue on study treatment until progressive disease (PD), death, unacceptable toxicity, or withdrawal of consent.

[0193] The target toxicity rate of dose-limiting toxicity (DLT) in the combination of Compound 1 + standard of care is 25% for all schedules (i.e., the target toxicity level [TTL] is 0.25). Subjects are enrolled in cohorts of size ≧3 with a maximum sample size of 9 at each dose level. The dose levels of Compound 1 in the Phase 1 cohorts are 0.3 mg, 0.6 mg, and 1.0 mg. Based on the data from subcohort B1, the initial dose level of Compound 1 (0.3 mg or 0.6 mg) is determined in Phase 1 subcohorts B2 and B3.

[0194] If 1.0 mg of Compound 1 is not tolerated, 0.8 mg will be tested. For Cohort I, the initial dose level is the RP2D-1 level determined in subcohorts B1, B2, or B3. When escalating the dose of Compound 1, the maximum dose increase between two dose levels is 100% and the maximum planned dose is 1.0 mg. Dose escalation / deescalation follows the mTPI-2 algorithm (Ji, 2010; Ji, 2013; Guo, 2017).

[0195] The MTD can be the RP2D, but an RP2D less than the MTD can also be determined by PK, PD data, and safety and preliminary efficacy data, if applicable.

[0196] Phase 2 The safety and preliminary efficacy of Compound 1 in combination with standard of care in subjects with RRMM and NDMM will be further evaluated in the Phase 2 part.

[0197] Part 1 (Approximately 231 participants) Once the RP2D is confirmed for each Compound 1 triplet regimen, the following cohorts will be enrolled at the RP2D (each cohort will act independently): Cohort D: Compound 1 in combination with BTZ and dex in subjects with RRMM who have received 1-3 prior regimens. This cohort will enroll approximately 47 subjects. Cohort E: Cohort E includes up to three subcohorts (E1, E2, and E3) of compound 1 in combination with DARA and dex in subjects with RRMM who have received 1-3 prior regimens. Each subcohort will begin once the MTD / RP2D in the corresponding subcohort B has been demonstrated and further study of that subcohort is deemed warranted. Cohort E will enroll approximately 49 subjects overall, and the number of subjects enrolled in each subcohort will be determined by review of available safety, efficacy, and PK and PD data, if applicable. The term Cohort E refers to all subcohorts E1, E2, and E3. Cohort F: Compound 1 in combination with CFZ and dex in subjects with RRMM who have received 1-3 prior regimens. This cohort will enroll approximately 37 subjects. Cohort J: Compound 1 in combination with ELO and dex in subjects with RRMM receiving ≧2 prior regimens. This cohort will enroll approximately 50 subjects. Cohort K: Compound 1 in combination with ISA and dex in subjects with RRMM receiving ≧2 prior regimens. This cohort will enroll approximately 48 subjects.

[0198] Part 2 (Approximately 69 subjects) If the minimum threshold ≥ VGPR rate in Cohort D is met, additional cohorts will be open-blinded in enrollment: Cohort G: Compound 1 in combination with BTZ and dex for 4-6 cycles as induction followed by autologous stem cell transplant (ASCT) with or without maintenance as part of standard of care (SOC). This cohort will enroll up to 69 transplant-eligible (TE) NDMM subjects.

[0199] The study will be conducted in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP).

[0200] Study population The study population consists of subjects with RRMM (Cohorts A, B, C, D, E, F, H, I, J, and K). Cohort G subjects include subjects with NDMM who are eligible for ASCT.

[0201] Exam duration The study consists of the following consecutive periods: Screening, Treatment, and Follow-up. The Screening Period will not exceed a 28-day window prior to the start of study treatment (Day 1 of Cycle 1). The Treatment Period will consist of 21-day cycles in Cohort A, sub-cohorts B2, E2 (Cycles 1-8), Cohorts D and G, and 28-day cycles in sub-cohorts B1, E1, B2 (Cycles 9 onwards), B3, E3 and Cohorts C, F, H, I, J, and K. Treatment will continue until progressive disease (PD), death, unacceptable toxicity, or withdrawal of consent in all cohorts except Cohort G, where treatment will continue for up to 6 cycles or until PD, death, unacceptable toxicity, or withdrawal of consent prior to 6 cycles. All subjects will have an End of Treatment (EOT) visit to collect safety and efficacy assessments. For subjects in cohort G, the EOT visit will be considered either 3 months (± 7 days) after ASCT (prior to any maintenance therapy, if applicable), or any other time point for treatment interruption. Another visit will be conducted 28 (± 3) days after the EOT visit to collect safety assessments.

[0202] Subjects who discontinue study treatment for any reason other than PD or withdrawal of consent will be followed for response assessments every 21 days (for Cohorts A and D) or every 28 days (for Cohorts B, C, E, F, H, I, J, and K) until PD or until a subsequent anti-myeloma regimen is initiated whereby a progression-free survival (PFS) stop-off visit is performed. In addition, subjects in Cohort G following ASCT with or without induction, maintenance will be followed for response assessments during PFS follow-up every 3 months until PD or until a subsequent anti-myeloma regimen is initiated whereby a PFS stop-off visit is performed.

[0203] The end of the study will be defined as the later of the date of the last visit of the last subject to complete post-treatment follow-up as pre-specified in the protocol or the date of receipt of the last data point from the last subject required for the primary, secondary and / or exploratory analyses.

[0204] Study treatment For subjects enrolled in Cohorts A, D, and G (Compound 1+BTZ+dex): Oral Compound 1 at the specified cohort dose (for Cohort A) or RP2D (for Cohorts D and G) on days 1-14 of a 21-day cycle · below: Days 1, 4, 8, and 11 of a 21-day cycle, cycles 1 to 8 (up to cycle 6 for cohort G) Days 1 and 8 of a 21-day cycle and cycle ≥ 9 (excluding cohort G) at 1.3 mg / m 2 BTZ administered subcutaneously (SC) at a starting dose of: · below: Days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle, cycles 1 to 8 (up to cycle 6 for cohort G) Days 1, 2, 8, and 9 of a 21-day cycle and cycle ≥ 9 (excluding cohort G) Oral dexamethasone administered at 20 mg / day (≤75 years) or 10 mg / day (>75 years) in

[0205] For subjects enrolled in subcohort B1 and subcohort E1 (Compound 1+DARA+dex): Oral compound 1 at the specific cohort dose (for subcohort B1) or RP2D (for subcohort E1) on days 1-21 of a 28-day cycle · Either intravenous (IV) DARA given at a dose of 16 mg / kg or subcutaneous (SC) DARA given at a dose of 1800 mg over 3 to 5 minutes. Days 1, 8, 15, and 22 of a 28-day cycle in cycles 1 and 2 ○ Days 1 and 15 of a 28-day cycle, cycles 3 to 6 ○ Day 1 of a 28-day cycle and cycle ≥ 7 Oral / IV dex administered at a total dose of 40 mg every week on days -1, 8, 15, and 22. For subjects over 75 years of age or who are underweight (body mass index [BMI] < 18.5), dex administration can be at a dose of 20 mg administered weekly. On the day that the subject is to receive an infusion of DARA, dex is administered at the site rather than self-administered. In this situation, dex serves as the therapeutic dose of steroid on that particular day and as a required premedication prior to the DARA infusion. · Calculate each subject's dose based on the subject's body weight rounded to the nearest kilogram. There is no upper limit on the absolute dose permitted unless the dose exceeds 16 mg / kg. Recalculate the DARA dose if the subject's body weight changes by more than 10% from baseline.

[0206] For subjects enrolled in subcohort B2 and subcohort E2: Oral Compound 1 at the specified cohort dose (for subcohort B2) or RP2D (for subcohort E2) on days 1-14 of 21-day cycles over cycles 1-8 and on days 1-21 of 28-day cycles over cycles 9 and onward Either IV DARA given at a dose of 16 mg / kg or SC DARA given at a dose of 1800 mg over 3 to 5 minutes: ○ Days 1, 8, and 15 of a 21-day cycle for cycles 1 to 3 ○ Day 1 of a 21-day cycle, cycles 4-8 ○ Day 1 of a 28-day cycle and cycle ≥ 9 Oral / IV dex administered weekly at a total dose of 40 mg Days 1, 8, and 15 of a 21-day cycle, cycles 1-8 Cycle ≥ 9 on days 1, 8, 15, and 22 of a 28-day cycle For subjects over 75 years of age or who are underweight (BMI<18.5), dex doses can be administered weekly at a dose of 20 mg. On the day that the subject is to receive an infusion of DARA, dex is administered at the site rather than self-administered. In this situation, dex serves as the therapeutic dose of steroid on that particular day and as a required premedication prior to the DARA infusion. · Calculate each subject's dose based on the subject's body weight rounded to the nearest kilogram. There is no upper limit on the absolute dose permitted unless the dose exceeds 16 mg / kg. Recalculate the DARA dose if the subject's body weight changes by more than 10% from baseline.

[0207] For subjects enrolled in subcohort B3 and subcohort E3: Oral Compound 1 at the specified cohort dose (for sub-cohort B3) or RP2D (for sub-cohort E3) on days 1-7 and 15-21 of 28-day cycles over Cycles 1 through 6, and on days 1-21 of 28-day cycles over Cycles 7 and beyond. Either IV DARA given at a dose of 16 mg / kg or SC DARA given at a dose of 1800 mg over 3 to 5 minutes. Days 1, 8, 15, and 22 of a 28-day cycle in cycles 1 and 2 ○ Days 1 and 15 of a 28-day cycle, cycles 3 to 6 ○ Day 1 of a 28-day cycle and cycle ≥ 7 · Oral / IV dex is administered weekly on days 1, 8, 15, and 22 at a total dose of 40 mg. For subjects over 75 years of age or who are underweight (BMI<18.5), dex doses can be administered weekly at a dose of 20 mg. On the day that the subject is to receive an infusion of DARA, dex is administered at the site rather than self-administered. In this situation, dex serves as the therapeutic dose of steroid on that particular day and as a required premedication prior to the DARA infusion. · Calculate each subject's dose based on the subject's body weight rounded to the nearest kilogram. There is no upper limit on the absolute dose permitted unless the dose exceeds 16 mg / kg. Recalculate the DARA dose if the subject's body weight changes by more than 10% from baseline.

[0208] For subjects enrolled in Cohorts C and F (Compound 1+CFZ+dex): Oral Compound 1 at the specified cohort dose (for Cohort C) or RP2D (for Cohort F) on days 1-21 of a 28-day cycle Intravenous CFZ given over 30 minutes: Day 1 of cycle 1 (20 mg / m 2 ) Cycle 1 (56 mg / m) on days 8 and 15 of a 28-day cycle (Cycle 1) 2 ) Days 1, 8, and 15 of a 28-day cycle were administered in cycles 2 to 12 (56 mg / m 2 ) 〇 Cycle ≥ 13 (56 mg / m2) on days 1 and 15 of a 28-day cycle 2 ) Oral / IV dexamethasone administered at 40 mg / day (20 mg / day if >75 years old) on days 1, 8, 15, and 22 of a 28-day cycle

[0209] For subjects enrolled in Cohorts H and J (Compound 1+ELO+dex): Oral Compound 1 at the specified cohort dose (for Cohort H) or RP2D (for Cohort J) on days 1-21 of a 28-day cycle Intravenous ELO Days 1, 8, 15, and 22 of a 28-day cycle, cycles 1-2 (10 mg / kg) Day 1 of a 28-day cycle and cycle ≥ 3 (20 mg / kg) Oral / IV dexamethasone 〇 ELO administration day: Oral (28 mg) / IV (8 mg) dex is administered 36 mg / day in total (for subjects >75 years old, oral [8 mg] / IV [8 mg]) dex is administered 16 mg / day in total) ■ Days 1, 8, 15, and 22 of a 28-day cycle for cycles 1-2 ■ Day 1 of a 28-day cycle and cycle ≥ 3 On non-ELO days: oral dexamethasone is administered at 40 mg / day (20 mg / day if subject is >75 years old) ■ Days 8, 15, and 22 of a 28-day cycle and cycle ≥3

[0210] For subjects enrolled in cohorts I and K (Compound 1+ISA+dex): The dose and schedule of Compound 1 in cohorts I and K will be determined based on data from subcohorts B1, B2, and B3, assuming that both DARA and ISA are CD38-specific cytolytic antibodies. Oral Compound 1 at the specific cohort dose (for Cohort I) or RP2D (for Cohort K) on days 1-21 of a 28-day cycle (21 / 28 dosing schedule) or days 1-7 and 15-21 of a 28-day cycle (14 / 28 dosing schedule). IV ISA Cycle 1 (10 mg / kg) on ​​days 1, 8, 15, and 22 of a 28-day cycle Days 1 and 15 of a 28-day cycle for cycles ≥ 2 (10 mg / kg) · Oral / IV dex is administered weekly on days 1, 8, 15, and 22 at a total dose of 40 mg. For subjects over 75 years of age, dex doses can be administered weekly at a dose of 20 mg. On the day that the subject is to receive an ISA injection, dex is administered at the site instead of being self-administered. In this situation, dex serves as the therapeutic dose of steroid on that particular day and as a required premedication prior to the ISA injection.

[0211] Inclusion criteria Subjects must meet the following criteria to be enrolled in the study: 1. Subjects are ≥ 18 years of age at the time of signing the Informed Consent Form (ICF). 2. Subject must understand and voluntarily sign the ICF before any study-related assessments / procedures are performed. 3. Subject is willing and able to comply with the study visit schedule and other protocol requirements. 4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. 5. Women of childbearing potential (FCBP) require: a. Have two negative pregnancy tests prior to the start of study therapy, as verified by the investigator. She must consent to ongoing pregnancy testing during the course of the study and after completion of study treatment. The subject must be truly abstinent from contact with the opposite sex. * This applies even if the b. True abstinence from contact with the opposite sex * either commit to using and being able to use 2 reliable forms of contraception as defined in the Pregnancy Prevention Plan (PPP) without interruption (must be reviewed on a monthly basis and source documented) during study treatment (including any interruptions) 28 days prior to starting Compound 1 and for 28 days after the last dose of Compound 1, 7 months after the last dose of BTZ (for Cohorts A, D, and G), 90 days after the last dose of DARA (for Cohorts B and E), 6 months after the last dose of CFZ or ELO (for Cohorts C and F and Cohorts H and J), or 5 months after the last dose of ISA (for Cohorts I and K), whichever occurs later. Note: Females of childbearing potential (FCBP) are those who 1) have had menarche at any time and 2) have not had a hysterectomy or bilateral oophorectomy, or 3) have not been postmenopausal for at least 24 consecutive months (amenorrhea after cancer therapy does not exclude childbearing potential) (i.e., have had menses at any time in the preceding 24 consecutive months). 6. Male subjects require: a. True Asceticism * (which must be reviewed on a monthly basis) or agrees to use condoms during sexual contact with pregnant women or women of childbearing potential while participating in the study (even during treatment interruptions) and for at least 3 months after the last dose of Compound 1, DARA (for Cohorts B and E), CFZ (for Cohorts C and F) and ISA (for Cohorts I and K), for at least 4 months after the last dose of BTZ (for Cohorts A, D and G), or for 6 months after the last dose of elotuzumab, even if he has undergone a successful vasectomy. * True abstinence is acceptable if it is consistent with the subject's preferred, usual lifestyle. Periodic abstinence (e.g., calendar, ovulation, basal body temperature, postovulation methods) and coitus interruptus (withdrawal) are not acceptable methods of contraception. 7. Men must agree to refrain from donating sperm or semen during study treatment and for at least 3 months after the last dose of Compound 1, DARA, CFZ, and ISA, 4 months after the last dose of BTZ, or 6 months after the last dose of elotuzumab. Women must refrain from donating egg cells (ova) during study treatment and for 28 days after the last dose of Compound 1. 8. All subjects must agree to refrain from donating blood during study treatment and for 28 days after the last dose of study treatment. 9. All male and female subjects must comply with all requirements defined in the Pregnancy Prevention Program (PPP). For subjects in cohorts A, B, C, D, E, F, H, I, J, and K, the following inclusion also applies: 10. Subject has a documented diagnosis of MM and measurable disease defined as follows: aM protein ≥ 0.5 g / dL (by serum protein electrophoresis (sPEP)) or ≥ 200 mg (by urinary protein electrophoresis (uPEP) in a 24-hour urine collection) and / or b. Serum free light chain (FLC) levels >100 mg / L (10 mg / dL) and abnormal kappa / lambda (κ / λ) ratios involving light chains in subjects without measurable disease in serum or urine 11. Subject has previously received 2-4 (for Cohorts A, B, C, H, and I) or 1-3 (for Cohorts D, E, and F) or ≥ 2 (for Cohorts J and K) anti-myeloma regimens. Note: Induction with or without hematopoietic stem cell transplantation and with or without maintenance therapy is considered one regimen. 12. Subject has received prior treatment with a lenalidomide-containing regimen for at least two consecutive cycles. 13. Subject has achieved a response (minimal response [MR] or better) to at least one prior treatment regimen. 14. Subjects must have documented disease progression during or after their last anti-myeloma regimen. 15. For Cohorts J and K: a. Subject has also received prior treatment with a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) administered alone or in combination for at least two consecutive cycles. b. Subjects have failed treatment with lenalidomide and a proteasome inhibitor administered alone or in combination, defined as disease progression on or within 60 days of treatment, or disease progression within 6 months after achievement of at least a partial remission. c. Subject is refractory to their last treatment (progressed on or within 60 days of treatment). 16. Cohort F: Prior therapy with a proteasome inhibitor (PI), excluding carfilzomib, is permitted as long as the subject had at least a PR to prior PI therapy, was not excluded from PI therapy due to toxicity, but will have a PI treatment-free period of at least 6 months from the last dose received prior to first study treatment (subjects may receive maintenance therapy with an agent not in the PI class during this 6-month treatment-free period). For subjects in Cohort G, the following inclusion also applies: 17. Considered eligible for high-dose chemotherapy and autologous stem cell transplantation (ASCT) by the investigator according to institutional criteria based on age, medical history, cardiac and pulmonary status, overall health and condition, comorbid conditions, physical exam, and laboratory. 18. Subjects must have a documented diagnosis of previously untreated symptomatic MM as defined by the following criteria (Rajkumar et al., Mayo Clinic Proc. 2016, 91(1):101-19): · MM diagnostic criteria; Clonal bone marrow plasma cells ≥ 10% or biopsy-proven osseous or extramedullary plasmacytoma (clonality must be established by demonstrating kappa / lambda light chain restriction by flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be assessed from a core biopsy specimen; if there is discrepancy between aspirate and core biopsy, the highest value should be used.) Any one or more of the following myeloma-defining events: ■ One or more of the following myeloma-related organ failures (at least one of the following): [C] Calcium elevation (serum calcium >0.25 mmol / L [>1 mg / dL] (higher than the upper limit of normal) or >2.75 mmol / L (>11 mg / dL) [R] Renal insufficiency (serum creatinine > 2 mg / dl) [> 177 μmol / L] or creatinine clearance < 40 ml / min [A] Anemia (hemoglobin <10g / dl or >2g / dL (lower than the lower limit of normal)) [B] Bone lesions (lytic or osteopenic), one or more bone lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET) / CT ■ One or more of the following biomarkers of malignancy: Clonal bone marrow plasma cell percentage * ≧60% Abnormal serum free light chain ratio must be ≥ 100 (kappa-involved) or < 0.01 (lambda-involved) and tumor-involved FLC level must be ≥ 100 mg / L >1 focal lesion (at least 5 mm in size) detected by magnetic resonance imaging (MRI) and have measurable disease as defined by one of the following, as assessed by a central laboratory: Immunoglobulin (Ig) G myeloma: serum M protein level ≥ 1.0 g / dL or urine M protein level ≥ 200 mg / 24 hours; or IgA, IgM, IgD, or IgE multiple myeloma: serum M protein level ≥ 0.5 g / dL or urinary M protein level ≥ 200 mg / 24 hours; or Light-chain multiple myeloma without measurable disease in serum or urine: serum FLC ≥ 100 mg / L and abnormal kappa-lambda (κ / λ) ratio

[0212] Exclusion criteria Any of the following will result in a subject being removed from registration: 1. The subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 2. The subject has any medical condition, including the presence of laboratory abnormalities, that places the subject at unacceptable risk if he / she is to participate in the study. 3. Subject has any medical condition that confounds the ability to interpret data from the study. 4. Subject has any of the following laboratory abnormalities: Absolute neutrophil count (ANC) < 1,000 / μL (for Phase 1 without growth factor support for ≥ 7 days [≥ 14 days for pegfilgrastim]) b. Platelet count: <75,000 / μL (it is not acceptable to infuse subjects to reach this level) C. Hemoglobin <8 g / dL (<4.9 mmol / L) d. Creatinine clearance (CrCl) <45 mL / min (<30 mL / min for Cohort G) e. Corrected serum calcium >13.5 mg / dL (>3.4 mmol / L) f. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN g. For subjects with documented Gilbert syndrome, serum total bilirubin >1.5 x ULN or >3.0 mg / dL h. Prothrombin time (PT) / international normalized ratio (INR) > 1.5 x ULN or partial thromboplastin time (PTT) > 1.5 x ULN (for subjects not receiving therapeutic anticoagulation) NOTE: Subjects receiving treatment for a thromboembolic event occurring >3 months prior to enrollment are eligible as long as they are receiving a stable regimen of anticoagulation with warfarin, low molecular weight heparin, or other approved therapeutic anticoagulation regimens. 5. Subject has peripheral neuropathy ≥ grade 2 6. Subjects with gastrointestinal disease that may significantly alter the absorption of Compound 1. 7. Subject has a prior history of malignancy other than MM, provided that the subject has not been disease-free for ≥ 5 years with the exception of the following non-invasive malignancies: Basal cell carcinoma of the skin Squamous cell carcinoma of the skin In situ carcinoma of the cervix In situ carcinoma of the breast Prostate cancer (T1a or T1b using the TNM [Tumor, Node, Metastasis] clinical staging system) or incidental histological findings of definitive prostate cancer 8. Subject has plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly, endocrine abnormalities, monoclonal proteins, and skin changes) or clinically significant amyloidosis. 9. Subject with a known central nervous system (CNS) disorder associated with myeloma. 10. Subject is taking immunosuppressant medication within 14 days prior to starting study treatment. The following are exceptions to this criterion: Intranasal, inhaled, topical or local corticosteroid injections (e.g. intra-articular injections). Systemic corticosteroids in doses not to exceed 10 mg / day of prednisone or equivalent. Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication). 11. Subject has cardiac dysfunction or clinically significant cardiac disease, including any of the following: Left ventricular ejection fraction (LVEF) <45% as measured by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan at screening. Complete left bundle branch block, bifascicular block, or other clinically significant abnormal electrocardiogram (ECG) findings at screening Prolongation of the QT interval on the screening ECG, as defined by repeated demonstration of a QTc interval >470 milliseconds (msec) using the Fridericia QT formula; history or current risk factors for polymorphic ventricular tachycardia (e.g., heart failure, hypokalemia, or family history of long QT syndrome); and concomitant administration of medications that prolong the QT / QTc interval. Congestive heart failure (New York Heart Association class III or IV). - Myocardial infarction within 12 months prior to starting study treatment. Unstable or uncontrolled angina, including Prinzmetal variant angina History of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, pericardial disease, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities (if the subject does not have a pacemaker) 12. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment. 13. Concomitant administration of a strong CYP3A modulator; concomitant administration of a proton pump inhibitor (e.g., omeprazole, esomeprazole, lansoprazole, pantoprazole) within 2 weeks prior to starting Compound 1. 14. Subject is a female who is pregnant, nursing, or breastfeeding, or intends to become pregnant during participation in the study. 15. Subject is positive for Human Immunodeficiency Virus (HIV), chronic or active Hepatitis B, or active Hepatitis A or C. 16. Subject has a history of anaphylaxis or hypersensitivity to thalidomide, lenalidomide, pomalidomide, BTZ (in Cohorts A, D, and G), DARA (in Cohorts B and E), CFZ (in Cohorts C and F), ELO (in Cohorts H and J), ISA (in Cohorts I and K), or dexamethasone. 17. Subject has known or suspected hypersensitivity to any excipient contained in Compound 1 formulations, BTZ (for Cohorts A, D, and G), DARA (for Cohorts B and E), CFZ (for Cohorts C and F), ELO (for Cohorts H and J), ISA (for Cohorts I and K), or dexamethasone. 18. Contraindications to standard treatment regimens per local prescribing information. 19. Subject is unable or unwilling to undergo protocol-required thromboembolic prophylaxis. For subjects in Cohorts A, B, C, D, E, F, H, I, J, and K, the following exclusions also apply: 20.Subject has received any of the following within 14 days prior to starting study treatment: a. Plasma exchange b. Major surgery (as defined by the investigator) Non-local radiation therapy for bone lesions associated with cc myeloma dd Use of any systemic antimyeloma drug therapy 21. Cohorts A and D: Subjects who had progression on treatment or within 60 days of the last dose of BTZ or discontinued BTZ due to toxicity. 22. Cohorts B and I: Subjects who have progression on treatment or within 60 days of the last dose of DARA / ISA or who discontinued DARA / ISA due to toxicity. 23. Cohort C: Subjects who have progression on treatment or within 60 days of the last dose of CFZ or who discontinued CFZ due to toxicity. 24. Cohorts D, E, F, J, and K: prior treatment with pomalidomide (POM). 25. Cohorts E and K: prior treatment with DARA or ISA. 26. Cohort F: prior treatment with CFZ. 27. Subject has used any investigational drug within 28 days or 5 half-lives (whichever is longer) of starting study treatment. · Study participation for subjects receiving an investigational vaccine (e.g., an investigational severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] vaccine) will be determined by discussion between the investigator and the sponsor medical monitor. 28. Subject has already undergone an allogeneic stem cell transplant or has undergone an autologous stem cell transplant within 12 weeks prior to starting study treatment. 29. Cohorts B, E, I, and K: Subjects have known chronic obstructive pulmonary disease (COPD) and a forced expiratory volume in 1 second (FEV1) of 50% of predicted normal. Note that subjects suspected of having COPD are required to have a forced expiratory volume test (FEV1) and must be excluded if FEV1 is <50% of predicted normal. 30. Cohorts B, E, I, and K: Subjects have known moderate or severe persistent asthma or currently have uncontrolled asthma of any classification. 31. Cohorts C and F: Subjects have mild liver impairment defined as elevated bilirubin >1.0 but <1.5 x ULN or normal bilirubin and some elevation of AST. 32. Cohort H: Subjects who have progression on treatment or within 60 days of the last dose of ELO or who discontinued ELO due to toxicity 33. Cohort J: Prior treatment with ELO For subjects in Cohort G, the following exclusion criteria also apply: 34. Previous treatment with anti-myeloma therapy (radiation therapy, bisphosphonates, or a single short-term steroid [i.e., the equivalent of ≤ 40 mg / day dexamethasone over 4 days; such short-term steroid treatment should not be given within 14 days of starting study treatment]). For subjects in all cohorts 35. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection prior to enrollment, within 14 days for mild or asymptomatic infection or within 28 days for severe / critical illness. Acute symptoms must have resolved and there must be no sequelae that would place the subject at higher risk of clinically significant complications from receiving the study treatment based on the Investigator's assessment in consultation with the Sponsor Medical Monitor.

[0213] Summary of Key Efficacy Evaluations Myeloma paraprotein (serum and 24-hour urine) · Serum immunofixation method Serum immunoglobulins Serum free light chains Bone marrow aspiration / biopsy Percent plasma cells in bone marrow Radiographic evaluation of lytic bone lesions Extramedullary plasmacytoma (EMP) evaluation Minimal Residual Disease Assessment Response according to International Myeloma Working Group (IMWG) criteria

[0214] Summary of major safety evaluations Adverse Events (AEs) Complete physical exam including vital signs and VTE monitoring Clinical laboratory evaluation (hematology, serum chemistry, urinalysis) Renal function assessment Electrocardiogram (ECG) Pregnancy testing / counseling Concomitant medications and surgery

[0215] Overview of Pharmacokinetic Evaluation PK samples will be collected in a low density sampling scheme for Compound 1 and its R-enantiomer. Exposure response analysis will be performed as needed to help identify the RP2D of Compound 1.

[0216] The above embodiments are intended to be merely illustrative; those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the invention and are covered by the appended claims.

Claims

1. A pharmaceutical composition for treating multiple myeloma in a subject in need of treatment, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I): 【Chemical 1】 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and the compound of formula (I), or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is used to be administered in combination with elotuzumab and dexamethasone. A pharmaceutical composition characterized by this.

2. The pharmaceutical composition according to claim 1, wherein elotuzumab is administered on days 1, 8, 15, and 22 of the first two 28-day cycles, and on day 1 of each subsequent 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of each of said 28-day cycles.

3. The pharmaceutical composition according to claim 1, wherein elotuzumab is administered intravenously and dexamethasone is administered intravenously or orally.

4. Elotuzumab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of the first two 28-day cycles, and at a dose of about 20 mg / kg on day 1 of each subsequent 28-day cycle, and dexamethasone is administered orally at a dose of about 28 mg and intravenously at a dose of about 8 mg on days 1, 8, 15, and 22 of the first two 28-day cycles, and on day 1 of each subsequent 28-day cycle starting from the third 28-day cycle, and orally at a dose of about 40 mg on days 8, 15, and 22 of each subsequent 28-day cycle starting from the third 28-day cycle. The pharmaceutical composition according to claim 1.

5. Elotuzumab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of the first two 28-day cycles, and at a dose of about 20 mg / kg on day 1 of each subsequent 28-day cycle; dexamethasone is administered orally at a dose of about 8 mg and intravenously at a dose of about 8 mg on days 1, 8, 15, and 22 of the first two 28-day cycles, and on day 1 of each subsequent 28-day cycle starting from the third 28-day cycle, and orally at a dose of about 20 mg on days 8, 15, and 22 of each subsequent 28-day cycle starting from the third 28-day cycle. The pharmaceutical composition according to claim 1.

6. A pharmaceutical composition for treating multiple myeloma in a subject in need of treatment, wherein said pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I): 【Chemical Formula 2】 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and the compound of formula (I), or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof is used to be administered in combination with isatuximab and dexamethasone. A pharmaceutical composition characterized by this.

7. The pharmaceutical composition according to claim 6, wherein isatuximab is administered on days 1, 8, 15, and 22 of the first 28-day cycle, and on days 1 and 15 of each subsequent 28-day cycle, and dexamethasone is administered on days 1, 8, 15, and 22 of each of said 28-day cycles.

8. The pharmaceutical composition according to claim 6, wherein isatuximab is administered intravenously and dexamethasone is administered intravenously or orally.

9. The pharmaceutical composition according to claim 6, wherein isatuximab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle, and on days 1 and 15 of each subsequent 28-day cycle, and dexamethasone is administered intravenously or orally at a dose of about 40 mg on days 1, 8, 15, and 22 of each of said 28-day cycles.

10. The pharmaceutical composition according to claim 6, wherein isatuximab is administered intravenously at a dose of about 10 mg / kg on days 1, 8, 15, and 22 of the first 28-day cycle, and on days 1 and 15 of each subsequent 28-day cycle, and dexamethasone is administered intravenously or orally at a dose of about 20 mg on days 1, 8, 15, and 22 of each of said 28-day cycles.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein said multiple myeloma is relapsed or refractory multiple myeloma (RRMM).

12. The pharmaceutical composition according to claim 11, wherein said subject has received at least two first-choice treatment methods.

13. The pharmaceutical composition according to claim 11, wherein said subject has received 1 to 3 first-choice treatment methods.

14. The pharmaceutical composition according to claim 11, wherein said subject has received 2 to 4 first-choice treatment methods.

15. The pharmaceutical composition according to claim 11, wherein the subject has received at least two first-choice treatment methods, the subject has received 1 to 3 first-choice treatment methods, or the subject has received 2 to 4 first-choice treatment methods, and the first-choice treatment method includes a treatment method including lenalidomide.

16. The pharmaceutical composition according to claim 11, wherein the subject has received at least two first-choice treatment methods, the subject has received 1 to 3 first-choice treatment methods, or the subject has received 2 to 4 first-choice treatment methods, and the first-choice treatment method includes a proteasome inhibitor.

17. The pharmaceutical composition according to claim 16, wherein the proteasome inhibitor is bortezomib, carfilzomib, or ixazomib.

18. The pharmaceutical composition according to any one of claims 1 to 10, wherein the multiple myeloma is newly diagnosed multiple myeloma (NDMM).

19. The pharmaceutical composition according to claim 18, wherein the subject is eligible for transplantation.

20. The pharmaceutical composition according to claim 19, wherein the subject is eligible for autologous stem cell transplantation (ASCT).

21. The pharmaceutical composition according to any one of claims 1 to 10, which is used such that a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered.

22. The pharmaceutical composition according to claim 21, which is used such that a compound of formula (I) is administered.

23. The pharmaceutical composition according to claim 21, which is used such that a hydrobromide salt of a compound of formula (I) is administered.

24. The pharmaceutical composition according to any one of claims 1 to 10, wherein the compound is used to be administered orally.

25. The pharmaceutical composition according to any one of claims 1 to 10, wherein the compound is used to be administered at a dose of about 0.1 mg to about 2 mg once a day.

26. The pharmaceutical composition according to claim 25, wherein the compound is used to be administered at a dose of about 0.3 mg to about 1 mg once a day.

27. The pharmaceutical composition according to claim 25, wherein the compound is used to be administered at a dose of about 0.3 mg, about 0.6 mg, about 0.8 mg, or about 1 mg once a day.

28. The pharmaceutical composition according to any one of claims 1 to 10, wherein the compound is administered for 7 days and then withdrawn for 7 days, or administered for 14 days and then withdrawn for 7 days, or administered for 21 days and then withdrawn for 7 days.

29. For treating relapsed or refractory multiple myeloma, (i) elotuzumab is administered on days 1, 8, 15, and 22 of the first two 28-day cycles and on day 1 of each subsequent 28-day cycle; (ii) dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28-day cycles; and then (iii) the compound is administered from day 1 to day 21 of each of the 28-day cycles, the pharmaceutical composition according to claim 1.

30. For treating relapsed or refractory multiple myeloma, (i) isatuximab is administered on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent 28-day cycle; (ii) dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28-day cycles; and then (iii) the compound is administered from day 1 to day 21 of each of the 28-day cycles, the pharmaceutical composition according to claim 6.

31. For treating relapsed or refractory multiple myeloma, (i) isatuximab is administered on days 1, 8, 15, and 22 of the first 28-day cycle and on days 1 and 15 of each subsequent 28-day cycle; (ii) dexamethasone is administered on days 1, 8, 15, and 22 of each of the 28-day cycles; and then (iii) the compound is administered from day 1 to day 7 and from day 15 to day 21 of each of the 28-day cycles, the pharmaceutical composition according to claim 6.

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