Therapy for treating multiple myeloma

Abstract

The present invention provides a method for treating and / or controlling multiple myeloma, comprising administering to a patient a combination of 3-(4-((4-((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (“Compound A”) or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds or polymorphs with a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3).

Description

Technical Field

[0001] This article provides a therapy for the treatment and / or control of multiple myeloma, which involves administering a cereblon E3 ligase modulator and a BCMA×CD3 bispecific antibody to the patient. Existing technology

[0002] Multiple myeloma, especially relapsed refractory multiple myeloma (RRMM), remains challenging to treat, though outcomes have improved with the use of proteasome inhibitors, immunomodulatory compounds, and differentiation cluster 38-targeted antibodies. Nevertheless, relapse rates remain high, and relapsed multiple myeloma (MM) cells often acquire a more aggressive phenotype, leading to shorter duration of response and reduced survival. This underscores the need for novel agents and combinations that offer synergistic anti-myeloma activity, overcome resistance to prior therapies, and represent novel treatment options with good tolerability (Leow CC, Low MSY. Targeted Therapies for Multiple Myeloma. J Pers Med. 2021;11(5)).

[0003] Optimizing treatment outcomes for patients with multiple myeloma (MM) may require a multi-faceted approach to address the heterogeneous biological aspects of the disease, including immune dysfunction. Long-term disease control can be optimally achieved by combining therapies with different mechanisms of action, particularly those targeting key components of the immune system and capable of restoring its function. The combinations presented in this article may offer additional enhanced clinical benefits to patients with recurrent partial myeloma (RRMM). Summary of the Invention

[0004] This article provides methods for treating or controlling multiple myeloma. In one aspect, this article provides a method for treating or controlling multiple myeloma comprising administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of a compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

[0005] This article also provides compounds used in methods for treating multiple myeloma. In one aspect, this article provides compounds used in methods for treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of the compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

[0006] This article also provides a bispecific antibody for a method of treating multiple myeloma. In one aspect, this article provides a bispecific antibody for a method of treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of the bispecific antibody, wherein the bispecific antibody comprises a first binding portion binding to B-cell maturation antigen (BCMA) and a second binding portion binding to differentiation cluster 3 (CD3), wherein the first binding portion binding to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; VHCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region comprising VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22. CDR3; and wherein the second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45; and (b) A therapeutically effective amount of the compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds or polymorphs.

[0007] This article also provides compounds and bispecific antibodies used in methods for treating multiple myeloma. In one aspect, this article provides compounds and bispecific antibodies used in methods for treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of the compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of the bispecific antibody, which comprises a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

[0008] In some embodiments, the first bonding portion to BCMA includes: (a) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 3, VH CDR2 containing the amino acid sequence of SEQ ID NO: 4, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 5; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 6, VL CDR2 containing the amino acid sequence of SEQ ID NO: 7, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (b) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 9, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VLCDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (c) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 14, VH CDR2 containing the amino acid sequence of SEQ ID NO: 15, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (d) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (e) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 17, VH CDR2 containing the amino acid sequence of SEQ ID NO: 18, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 19; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 20, VL CDR2 containing the amino acid sequence of SEQ ID NO: 21, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 22; or (f) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 23, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8.

[0009] In some embodiments, the second binding portion to CD3 includes: (a) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 26, VH CDR2 containing the amino acid sequence of SEQ ID NO: 27, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 28; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 29, VL CDR2 containing the amino acid sequence of SEQ ID NO: 30, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (b) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 32, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (c) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 37, VH CDR2 containing the amino acid sequence of SEQ ID NO: 38, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (d) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (e) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 40, VH CDR2 containing the amino acid sequence of SEQ ID NO: 41, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 42; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 43, VL CDR2 containing the amino acid sequence of SEQ ID NO: 44, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 45; or (f) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 46, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31.

[0010] In some embodiments, the first binding portion to BCMA comprises a VH region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1 and a VL region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2, and the second binding portion to CD3 comprises a VH region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24 and a VL region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25.

[0011] In some embodiments, the first binding portion to BCMA comprises a heavy chain and a light chain; and the second binding portion to CD3 comprises a heavy chain and a light chain. In some embodiments, the heavy chain of the first binding portion to BCMA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 47, and the light chain of the first binding portion to BCMA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 48; and the heavy chain of the second binding portion to CD3 comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49, and the light chain of the second binding portion to CD3 comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the heavy chain bound to the first binding portion of BCMA contains the amino acid sequence of SEQ ID NO: 47 and the light chain bound to the first binding portion of BCMA contains the amino acid sequence of SEQ ID NO: 48, and the heavy chain bound to the second binding portion of CD3 contains the amino acid sequence of SEQ ID NO: 49 and the light chain bound to the second binding portion of CD3 contains the amino acid sequence of SEQ ID NO: 50.

[0012] In some embodiments, the bispecific antibody is an IgG2κ antibody.

[0013] In some embodiments, the compound is compound AS Compound AS Or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, cage compound, or polymorph thereof. In some embodiments, the compound is the hydrochloride salt of compound AS.

[0014] In some embodiments, the multiple myeloma is relapsed, refractory, or drug-resistant. In some embodiments, the multiple myeloma is relapsed or refractory. In some embodiments, the multiple myeloma is relapsed or refractory to at least two prior therapies, wherein these prior therapies are selected from lenalidomide, pomalidomide, and proteasome inhibitors. In some embodiments, the multiple myeloma is a newly diagnosed multiple myeloma.

[0015] In some embodiments, the compound is administered orally. In some embodiments, the compound is administered at doses of about 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, or 1.6 mg daily. In some embodiments, the compound is administered once daily for 21 days, followed by a 7-day break.

[0016] In some embodiments, the bispecific antibody is administered subcutaneously. In some embodiments, the bispecific antibody is administered in amounts of about 12 mg, about 32 mg, or about 76 mg. In some embodiments, the bispecific antibody is administered once weekly, once every two weeks, or once every four weeks. In some embodiments, the bispecific antibody is administered on days 1, 4, and 8 of a 14-day priming dose cycle prior to the administration of the compound, and subsequently once weekly, once every two weeks, or once every four weeks in a 28-day cycle, while the compound is administered daily from day 1 to day 21 of that 28-day cycle. In some embodiments, during the 14-day priming dose cycle prior to the administration of the compound, the bispecific antibody is administered in amounts of 12 mg on day 1, 32 mg on day 4, and 76 mg on day 8. In some embodiments, after the initial dosing cycle, the bispecific antibody is administered weekly, every two weeks, or every four weeks at a dose of 76 mg during a 28-day cycle, while the compound is administered daily at a dose of 1.0 mg, 1.3 mg, or 1.6 mg from day 1 to day 21 of the 28-day cycle. In some embodiments, after the initial dosing cycle, the bispecific antibody is administered weekly, every two weeks, or every four weeks at a dose of 76 mg during a 28-day cycle, while the compound is administered daily at a dose of 0.75 mg from day 1 to day 21 of the 28-day cycle. In some embodiments, after the initial dosing cycle and the subsequent six 28-day cycles, if the patient has been treated for at least 6 months and the disease response shows at least a partial response or better and the response lasts for at least 2 months, the bispecific antibody is administered every two weeks at a dose of 76 mg. In some embodiments, after the initial dosing cycle and subsequent twelve 28-day cycles, if the disease response shows at least a partial response or better and the response lasts for at least 2 months, the bispecific antibody is administered at a dose of 76 mg every four weeks. In some embodiments, after the initial dosing cycle and subsequent three 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every two weeks during 28-day cycles. In some embodiments, after three 28-day cycles in which the bispecific antibody is administered at a dose of 76 mg every two weeks, the bispecific antibody is administered at a dose of 76 mg every four weeks during 28-day cycles. In some embodiments, the compound is administered once daily at a dose of 1.0 mg from day 1 to day 21 of each 28-day cycle. In some embodiments, after the initial dosing cycle and subsequent seven or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every two weeks for three 28-day cycles. In some embodiments, after the initial dosing cycle and subsequent ten or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every four weeks.

[0017] In some embodiments, after the initial dosing cycle, the bispecific antibody is administered every two weeks at a dose of 76 mg over a 28-day cycle. In some embodiments, after the initial dosing cycle and three subsequent 28-day cycles in which the bispecific antibody is administered every two weeks at a dose of 76 mg, the bispecific antibody is administered every four weeks over a 28-day cycle. In some embodiments, the compound is administered once daily at a dose of 0.75 mg, 1.0 mg, or 1.3 mg on days 1 through 21 of each 28-day cycle. Attached Figure Description

[0018] Figure 1 An exemplary form of the bispecific antibody used in this application is shown.

[0019] Figure 2 The study design in Example 1 is shown (C1. Overall Design 1). An exemplary elranatamab dosing regimen includes: initial C0: 12 / 32 / 76 mg; 76 mg QW for cycles 1 through 6; 76 mg Q2W for cycles 7 through 12; 76 mg Q4W for cycles 13+. “DL A” refers to dose level A of iberdomide; “DL B” refers to dose level B of iberdomide.

[0020] Figure 3 An exemplary dosing schedule for enostatumab and ibelidomine is shown under overall design 1.

[0021] Figure 4 The study design in Example 1 is shown (C2. Overall Design 2). In Part 1, the exemplary enatumab dosing regimen includes: Initial C0 (14 days): 12 / 32 / 76 mg; 76 mg QW for cycles 1 through 3; 76 mg Q2W for cycles 4 through 6; 76 mg Q4W for cycle 7+. In dose escalation, the exemplary enatumab dosing regimen includes: Initial C0 (14 days): 12 / 32 / 76 mg; 76 mg Q2W for cycles 1 through 3; 76 mg Q4W for cycle 4+.

[0022] Figure 5 An exemplary dosing schedule for enatumab and ibelidomide at dose level 1 (DL1) is shown under overall design 2.

[0023] Figure 6 Exemplary dosing schedules for enoatumab and ibelidomide at dose level 2 (DL2), dose level-1 (DL-1), or dose level-2 (DL-2) are shown under overall design 2. Detailed Implementation

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, publications, and other disclosures are incorporated herein by reference in their entirety. Unless otherwise stated, in the event of multiple definitions of terms herein, the definitions in this section shall prevail.

[0025] When used in conjunction with the term “comprising” in the claims and / or this specification, the word “a” or “an” may mean “one”, but it is also consistent with the meanings of “one or more”, “at least one” and “one or more”.

[0026] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be interpreted as specifying the presence of the stated features or components mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. Additionally, the terms “comprising” and “including” are intended to include instances covered by the term “consisting of”. Therefore, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide more specific embodiments of the invention.

[0027] The term "composed of" means that the target object has at least 90%, 95%, 97%, 98%, or 99% of the stated features or components that constitute it. In another embodiment, the term "composed of" excludes any other features or components from any of the following categories, except those that are not essential to the technical effect to be achieved.

[0028] As used herein, the term “or” should be interpreted as inclusive “or,” meaning any one or any combination. Therefore, “A, B, or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B, and C.” Exceptions to this definition will only occur when the combination of elements, functions, steps, or actions is inherently mutually exclusive in some way.

[0029] As used herein, and unless otherwise stated, the terms “about” or “approximately” mean an acceptable error in the measurement of a particular value by a person skilled in the art or of ordinary skill in the art, depending in part on the manner in which the value is measured or determined. In some embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms “about” or “approximately” for numerical values ​​or ranges of values ​​may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the listed values ​​or ranges of values. In one embodiment, the term “about” refers to a value that is no more than 10% higher or lower than the value modified by the term. For example, the term “about 10 mg / m³”... 2 "This means 9 mg / m 2 Up to 11 mg / m 2 The range.

[0030] The terms “optional” or “optionally” mean that the situation described below may or may not occur, and therefore this specification includes both the scenario in which the situation occurs and the scenario in which the situation does not occur.

[0031] Unless otherwise specifically stated, where a compound may be in the form of substitutional tautomerism, regio-isomerism, and / or stereo-isomerism, all substitutional isomers are intended to be included within the scope of the claimed target. For example, where a compound may have one of two tautomer forms, it is desirable that both tautomers be included herein.

[0032] Therefore, the compounds provided herein may be enantiomerically pure or a mixture of stereoisomers or diastereomers. As used herein and unless otherwise indicated, the term "stereoisomerically pure" means a composition containing one stereoisomer of the compound and substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure composition of a compound having one chiral center should substantially free of the opposite enantiomers of the compound. A stereoisomerically pure composition of a compound having two chiral centers will substantially free of other diastereomers of the compound. Typical stereoisomeric pure compounds comprise more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound; in one embodiment, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound; in one embodiment, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound; and in one embodiment, more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Stereoisomeric pure compounds A, AS, or AR used herein comprise more than about 80% by weight of one stereoisomer of the compound; in one embodiment, more than about 90% by weight of one stereoisomer of the compound; in one embodiment, more than about 95% by weight of one stereoisomer of the compound; and in one embodiment, more than about 97% by weight of one stereoisomer of the compound. As used herein and unless otherwise indicated, the term "stereoisomerically enriched" means a composition comprising more than about 60% by weight of one stereoisomer of the compound, more than about 70% by weight in one embodiment, and more than about 80% by weight in another embodiment. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having a chiral center. Similarly, the term "stereoisomerically enriched" means a stereoisomerically enriched composition of a compound having a chiral center. As used herein, a stereoisomer or non-stereoisomer mixture means a composition comprising more than one stereoisomer of the compound. A typical stereoisomer mixture of the compound comprises about 50% by weight of one stereoisomer of the compound and about 50% by weight of other stereoisomers of the compound, or comprises more than about 50% by weight of one stereoisomer of the compound and less than about 50% by weight of other stereoisomers of the compound, or comprises more than about 45% by weight of one stereoisomer of the compound and less than about 55% by weight of other stereoisomers of the compound, or comprises more than about 40% by weight of one stereoisomer of the compound and less than about 60% by weight of other stereoisomers of the compound, or comprises more than about 35% by weight of one stereoisomer of the compound and less than about 65% by weight of other stereoisomers of the compound.

[0033] It should be understood that the compounds provided herein may contain a chiral center. Such a chiral center may have an (R) or (S) conformation, or may be a mixture thereof. It should be understood that the chiral center of the compounds provided herein may undergo in vivo epimerization. Therefore, those skilled in the art will recognize that, for compounds undergoing in vivo epimerization, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form.

[0034] Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chiral stationary phase chromatography.

[0035] As used herein, an "isotope" is an isotopically enriched compound. The term "isotopically enriched" means that an atom has an isotopic composition other than that of its natural atom. "Isotopically enriched" may also mean that at least one atom in a compound has an isotopic composition other than that of its natural atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds are suitable as therapeutic agents, such as those for multiple myeloma; as research reagents, such as those for binding analysis; and as diagnostic agents, such as those for in vivo contrast agents. All isotopic variants of the compounds described herein, whether or not radioactive, are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopes of compounds are provided. In some embodiments, the isotopes provided herein are deuterium-enriched compounds. In some embodiments, the isotopes provided herein are deuterium-enriched compounds in which deuteration occurs at the chiral center.

[0036] In the descriptions herein, if there is any difference between chemical names and chemical structures, the structure shall prevail.

[0037] As used herein and unless otherwise indicated, the term "solvent" means the compound or salt thereof provided herein, which further includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. In the case of water as the solvent, the solvate is a hydrate.

[0038] As used herein and unless otherwise indicated, the term "stereoisomerically pure" means a composition containing one stereoisomer of a compound and substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure composition of a compound having one chiral center substantially free of its opposite enantiomers. A stereoisomerically pure composition of a compound having two chiral centers substantially free of other diastereomers of the compound. In some embodiments, the stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. As used herein and unless otherwise indicated, the term "stereoisomerically enriched" means a composition comprising more than about 60% by weight of one stereoisomer of the compound, more than about 70% by weight, or more than about 80% by weight of one stereoisomer of the compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having a chiral center. Similarly, the term "stereoisomerically enriched" means a stereoisomerically enriched composition of a compound having a chiral center.

[0039] As used herein, the term "human BCMA" refers to human B-cell maturation antigen, TR17_HUMAN, TNFRSF17 (UniProt Q02223), a member of the tumor necrosis receptor superfamily preferentially expressed in differentiated plasma cells. The extracellular domain of BCMA is composed of UniProt amino acids 1-54 (or 5-51). As used herein, the terms "antibody against BCMA" or "anti-BCMA antibody" refer to antibodies that specifically bind to BCMA.

[0040] The term "antibody against CD3" or "anti-CD3 antibody" refers to an antibody that specifically binds to CD3. In one embodiment, the antibody specifically binds to CD3ε. As used herein, the term "CD3ɛ" refers to human CD3ɛ (CD3E_HUMAN) as described in UniProt P07766.

[0041] As used herein, the term "antibody" refers to a monoclonal antibody. An antibody consists of two pairs of "light chains" (LC) and "heavy chains" (HC) (these light chain (LC) / heavy chain pairs are abbreviated as LC / HC in this document). The light and heavy chains of such antibodies are polypeptides composed of several domains. Each heavy chain contains a heavy chain variable region (abbreviated as HCVR or VH in this document) and a heavy chain constant region. The heavy chain constant region contains heavy chain constant domains CH1, CH2, and CH3 (antibody classes IgA, IgD, and IgG) and optionally, a heavy chain constant domain CH4 (antibody classes IgE and IgM). Each light chain contains a light chain variable domain VL and a light chain constant domain CL. The variable domains VH and VL can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The "constant domains" of the heavy and light chains do not directly bind the antibody to the target but exhibit various effector functions. If the antibody moiety is included in the bispecific antibody according to the invention, the antibody (or the antibody moiety) may be a Fab fragment in one embodiment. The antibody according to the invention may also be Fab', F(ab')2, scFV, bis-scFv, or a bispecific T-cell conjugate (BiTE). ® ).

[0042] The terms “antibody,” “immunoglobulin,” and “Ig” are used interchangeably herein and in the broadest sense, and specifically encompass, for example, polyclonal antibodies, monoclonal antibodies (including agonists, antagonists, neutralizing antibodies, and full-length monoclonal antibodies), antibody compositions having multi-epitope or single-epitope specificity, recombinant antibodies, single-domain (e.g., VHH) antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, or human forms of antibodies having full-length heavy chains and / or light chains. As used herein, VHH refers to a domain antibody derived only from the variable region of the antibody heavy chain. Exemplary single-domain antibodies include, but are not limited to, antibodies naturally lacking the light chain, such as antibodies from camelid species (e.g., llamas); single-domain antibodies derived from conventional 4-chain antibodies; engineered antibodies; and single-domain backbones other than those derived from the antibody backbone. Single-domain antibodies can be derived from any species, including but not limited to mice, humans, camels, llamas, goats, rabbits, and cattle. VHHs can also be derived from other species besides camelids that produce heavy chain antibodies naturally lacking the light chain. Antibodies also include antibody fragments (and / or polypeptides containing antibody fragments) that maintain antigen-binding characteristics. Non-limiting examples of antibody fragments include antigen-binding regions and / or effector regions of antibodies, such as Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, single-chain antibody molecules, bivariate-domain antibodies, monovariate-domain antibodies, linear antibodies, V regions, multispecific antibodies formed from antibody fragments, F(ab)2, Fd, Fc, bifunctional antibodies, di-bifunctional antibodies, disulfide-linked Fv (dsFv), monovariate antibodies (e.g., nanobodies), or other fragments (e.g., fragments consisting of variable regions of non-covalently coupled heavy and light chains). Generally, the variable (V) region can be any suitable arrangement of immunoglobulin heavy chain (VH) and / or light chain (VL) variable domains. For example, antibodies also include tetrameric antibodies containing two heavy chain and two light chain molecules, antibody light chain monomers, and antibody heavy chain monomers. Therefore, for example, the V region can be a dimer containing antigen-binding VHH-VHH, VH-VH, VH-VL, or VL-VL dimers. Where necessary, VH and VL can be covalently coupled directly or through a linker to form a single-chain Fv (scFv). For ease of reference, scFv proteins mentioned herein are included in the category of “antibody fragments.” Another form of antibody fragment is a peptide containing one or more complementarity-determining regions (CDRs) of the antibody. CDRs (also known as “minimum recognition units” or “hypervariates”) can be obtained by constructing polynucleotides encoding one or more CDRs of interest.Such polynucleotides are prepared, for example, by using polymerase chain reaction to synthesize variable regions using mRNA from antibody-producing cells as templates (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, “Genetic Manipulation of Monoclonal Antibodies”, Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), p. 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies”, Monoclonal Antibodies: Principles and Applications, Birch et al. (eds.), p. 137, Wiley-Liss, Inc. (1995)). Antibody fragments may be incorporated, for example, into single-domain antibodies, maximal antibodies, micro antibodies, intracellular antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, variable domains (v-NAR) of neoantigen receptors, and double single-chain Fv regions (see, for example, Hollinger and Hudson, Nature Biotechnology, 23(9):1126-1136, 2005). In some embodiments, antibodies containing VH and / or VL contain light chain and / or heavy chain constant regions, such as one or more constant regions, including one or more IgG1, IgG2, IgG3, and / or IgG4 constant regions. In some embodiments, antibodies may include epitope-binding fragments of any of the above. The antibodies described herein may belong to any class of immunoglobulin molecules (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or any subclass (e.g., IgG2a or IgG2b). In some embodiments, the antibody described herein is an IgG antibody (e.g., human IgG) or its class (e.g., human IgG1, IgG2, IgG3, or IgG4) or subclass.

[0043] Bispecific antibody forms are well known in the current state of the art and are described, for example, in Kontermann RE, mAbs 4:2 1-16 (2012); Holliger P., Hudson PJ, Nature Biotech. 23 (2005) 1126-1136; Chan AC, Carter PJ Nature Reviews Immunology 10, 301-316 (2010); and Cuesta AM et al., Trends Biotech 28 (2011) 355-362. In one embodiment, the term “bispecific antibody” as used herein refers to an antibody in which one of two pairs of heavy and light chains (HC / LC) specifically binds to CD3 and the other pair specifically binds to BCMA. The term also refers to other forms of bispecific antibodies according to the current state of the art. In one embodiment, the term “bispecific antibody” includes bispecific single-chain antibodies, such as those exhibiting BiTE. ® Types of antibodies, DART antibodies, bifunctional antibodies, tandem scFvs, and antibody mimics such as DARPin.

[0044] The term "identity" or "identity percentage" in the case of two or more nucleic acids or peptides refers to two or more sequences or subsequences being identical or having a specified percentage of identical nucleotide or amino acid residues when compared and aligned according to maximum correspondence (optionally introducing gaps), without considering any conserved amino acid substitutions as part of sequence identity. The identity percentage can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software available for obtaining amino acid or nucleotide sequence alignments are well known in the art. These algorithms and software include (but are not limited to) BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variations thereof. In some embodiments, the two nucleic acids or peptides of the present invention are substantially identical, meaning that when compared and aligned according to maximum correspondence, they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, or 99% nucleotide or amino acid residue identity, as measured using sequence comparison algorithms or by visual inspection. In some embodiments, consistency is present in a region of an amino acid sequence whose length is at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues, or any integer value between these lengths. In some embodiments, consistency is present in a region longer than 60-80 residues (e.g., at least about 80-100 residues), and in some embodiments, the sequences are substantially consistent across the full length of the compared sequences (e.g., the coding region of a target protein or antibody). In some embodiments, consistency is present in a region of a nucleotide sequence whose length is at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues, or any integer value between these lengths. In some embodiments, consistency is present in a region longer than 60-80 residues (e.g., at least about 80-1000 residues or more), and in some embodiments, the sequences are substantially consistent across the full length of the compared sequences (e.g., the nucleotide sequence encoding the protein of interest). As used herein, “antigen” is a portion or molecule containing an epitope that a binding agent (e.g., an antibody) can bind to. Therefore, antigens can be bound by antibodies. In some embodiments, the antigen bound by the binding agent (e.g., antibody) described herein is BCMA (e.g., human BCMA) or a fragment thereof, including fragments containing one or more domains of BCMA. In some embodiments, the antigen bound by the binding agent (e.g., antibody) described herein is CD3 (e.g., human CD3) or a fragment thereof, including fragments containing one or more domains of CD3.

[0045] As used herein, the terms “specific binding,” “specific recognition,” “immunospecific binding,” “selective binding,” “immunospecific recognition,” and “immunospecific” are similar terms in the context of antibodies and refer to molecules that bind to antigens (e.g., epitopes), as such binding is understood by those skilled in the art. In some embodiments, “specific binding” means, for example, that the interaction between a peptide or molecule and an epitope, protein, or target molecule is more frequent, faster, longer-lasting, more affinity, or a combination thereof than that of alternative substances (including related and unrelated proteins). For example, molecules that specifically bind to antigens may generally bind to other peptides or polypeptides with lower affinity, as determined by, for example, immunoassays, BIACORE™, KinExA 3000 instruments (Sapidyne Instruments, Boise, ID), OctetQK384 systems (ForteBio, Menlo Park, CA), or other analytical assays known in this art. In some embodiments, an antibody or antigen-binding domain binds to or specifically binds to an antigen when its affinity for that antigen is higher than that for any cross-reactive antigen, as determined using experimental techniques such as radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA). Typically, a specific or selective reaction will be at least twice the background signal or noise and may exceed 10 times the background. For a discussion of binding specificity, see, for example, Fundamental Immunology 332-36 (Paul, ed., 2nd ed., 1989). In some embodiments, the antibody or antigen-binding domain binds to less than about 10% of its binding to a specific target antigen, as determined, for example, by fluorescence activated cell sorting (FACS) analysis or RIA. In some embodiments, the Ka of a molecule specifically bound to an antigen is at least 2 log, 2.5 log, 3 log, 4 log, or greater than the Ka of the molecule bound to another antigen. In some embodiments, a molecule specifically bound to an antigen does not cross-react with other proteins. In another specific embodiment, a molecule specifically bound to an antigen does not cross-react with other proteins. In some embodiments, "specific binding" means, for example, a peptide or molecule binding at a K+ level of about 0.1 mM or less, but more typically less than about 1 µM. D Binding to a protein or target. In some embodiments, "specific binding" means that the peptide or molecule binds at a concentration of at least about 0.1 µM or less, at least about 0.01 µM or less, or at least about 1 nM or less. DTarget binding. Due to sequence consistency among homologous proteins of different species, specific binding may include a peptide or molecule recognizing proteins or targets of more than one species. Similarly, due to homology in certain regions of peptide sequences of different proteins, specific binding may include a peptide or molecule recognizing more than one protein or target. It should be understood that in some embodiments, a peptide or molecule that specifically binds to a first target may or may not specifically bind to a second target. Therefore, “specific binding” does not necessarily require (although it may include) exclusive binding, such as binding to a single target. Thus, in some embodiments, a peptide or molecule may specifically bind to more than one target. In some embodiments, multiple targets may be bound by the same antigen-binding site on the peptide or molecule. For example, in some cases, an antibody may contain two identical antigen-binding sites, each specifically binding to the same epitope on two or more proteins. In some alternative embodiments, the antibody may be bispecific and contain at least two antigen-binding sites with different specificities. Generally, but not necessarily, the term “binding” means “specific binding.”

[0046] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a binder, such as an antibody) and its binding complex (e.g., an antigen, such as NKG2A). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding complex Y can generally be determined by the dissociation constant (K). D The term "K" indicates that affinity can be measured using common methods known in the art, including those described herein. Low-affinity antibodies generally bind to antigens slowly and tend to dissociate easily, while high-affinity antibodies generally bind to antigens quickly and tend to remain bound for a longer period. Various methods for measuring binding affinity are known in the art, any of which may be used for the purposes of this invention. In one embodiment, "K" indicates that affinity can be measured using common methods known in the art, including those described herein. D "or "K D The "value" can be measured via biolayer interferometry (BLI) using, for example, the Octet QK384 system (ForteBio, Menlo Park, CA). Alternatively, K... DIt can also be performed in radiolabeled antigen-binding assays (RIA) using, for example, the Fab form of the antibody of interest and its antigen (Chen et al., (1999) J. Mol Biol 293:865-881), or using surface plasmon resonance (SPR) assays via BIACORE™, using, for example, BIACORE™-2000 or BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ). "On-rate" or "rate of association" or "association rate" or "k on "and "off-rate" or "rate of dissociation" or "dissociation rate" or "k off "The same SPR or BLI techniques described above can also be used, for example, with the Octet QK384 system (ForteBio, Menlo Park, CA) or BIACORE™-2000 or BIACORE™-3000 (BIACORE™, Inc., Piscataway, NJ) for determination."

[0047] In this paper, the term "Fc region" is used to define the C-terminal region of the immunoglobulin heavy chain, including, for example, the native sequence Fc region, the recombinant Fc region, and the variant Fc region. Although the boundaries of the Fc region of the immunoglobulin heavy chain can vary, the human IgG heavy chain Fc region is generally defined as an amino acid residue extending from position Cys226 (according to the EU numbering system) or from Pro230 (according to the EU numbering system) to its C-terminus. The C-terminal lysine (residue 447, according to the EU numbering system) of the Fc region can be removed, for example, during antibody preparation or purification, or by recombinantly engineering the nucleic acid encoding the heavy chain of the antibody.

[0048] As used herein, the term "heavy chain," when used in relation to antibodies, refers to a polypeptide chain of approximately 50 to 70 kDa, wherein the amino-terminal portion comprises a variable region of approximately 120 to 130 or more amino acids, and the carboxyl-terminal portion comprises one or more constant regions. "Heavy chain" can refer to any different type, such as alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (µ), based on the amino acid sequence of the constant domain, which respectively generate the IgA, IgD, IgE, IgG, and IgM classes of antibodies, including subclasses of IgG such as IgG1, IgG2, IgG3, and IgG4.

[0049] As used herein, when referring to antibody use, the term "light chain" may refer to a polypeptide chain of approximately 25 kDa, wherein the amino-terminal portion comprises a variable region of approximately 100 to approximately 110 or more amino acids, and the carboxyl-terminal portion comprises a constant region. The approximate length of a light chain is 211 to 217 amino acids. Based on the amino acid sequence of the constant domain, there are two distinct types, referred to as kappa (κ) or lambda (λ). The amino acid sequence of a light chain is well known in this art.

[0050] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” “antigen-binding portion,” and similar terms refer to portions of an antibody that contain amino acid residues (e.g., CDRs) that interact with an antigen and confer specificity and affinity to the antigen on the binding fragment, domain, region, or portion. As used herein, “antigen-binding fragment” includes “antibody fragment”, which contains portions of an antibody that include one or more CDRs, such as antigen-binding regions or variable regions of an antibody.

[0051] A universal numbering system has been developed and is widely used: ImMunoGeneTics (IMGT) ® The information system (Lafranc et al., Dev. Comp. Immunol. 27(1):55-77(2003)). IMGT is an integrated information system specifically for immunoglobulins (IG), T cell receptors (TR), and major tissue-compatible complexes (MHC) in humans and other vertebrates. In this paper, CDRs are referred to based on their amino acid sequence and position within the light or heavy chain. Since the “position” of CDRs within the structure of immunoglobulin variable domains is conserved across species and exists in structures called loops, it is easy to identify CDRs and framework residues by using a numbering system that compares variable domain sequences based on structural features. This information can be used to transplant and replace CDR residues from immunoglobulins of one species into receptor frameworks typically derived from human antibodies. Honegger and Plückthun, J. Mol. Biol. 309: 657-670(2001) have developed another numbering system (AHon). The correspondence between numbering systems (including, for example, the Kabat numbering system and the IMGT unique numbering system) is well known to those skilled in the art (see, for example, Kabat, ibid.; Chothia and Lesk, ibid.; Martin, ibid.; Lefranc et al., ibid.) and is also described below. The various systems known in this art or described herein represent different methods of defining CDRs, and are generally considered equivalent when used to define the same antibody. Exemplary system combinations Kabat and Chothia are shown herein. Residues from each of these hypervariable regions or CDRs are illustrated in Table 1 below. Table 1: Exemplary CDRs based on different numbering systems

[0052] The high-variability region may include the following “extended high-variability regions”: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2), and 93-102, 94-102, or 95-102 (H3) in VH. As used herein, the terms “high-variability region,” “HVR,” “HV,” “complementary determinant region,” and “CDR” are used interchangeably.

[0053] As used herein, “multiple myeloma” refers to a hematologic disorder characterized by malignant plasma cells and includes the following conditions: monoclonal gammopathy of undetermined significance (MGUS); relapsed, refractory, or drug-resistant multiple myeloma; 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-suitable and transplant-unsuitable multiple myeloma; stagnant (indolent) multiple myeloma (including low-risk, intermediate-risk, and high-risk stagnant multiple myeloma); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; and central nervous system polycythemia. Multiple myeloma; light chain myeloma; non-secretory 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 factors (e.g., deletion of 17p13 or chromosome 13; deletion (17 / 17p), non-hyperdiploidy, and addition (1q)).

[0054] As used herein and unless otherwise specified, the terms “individual” or “patient” refer to an animal, including but not limited to mammals, including primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. Referring to, for example, an individual mammal (such as a human individual), the terms “individual” and “patient” are used interchangeably herein.

[0055] As used herein and unless otherwise specified, the terms “treat,” “treating,” and “treatment” mean the eradication or improvement of a disease or condition or one or more symptoms associated with a disease or condition. In some embodiments, these terms mean minimizing the spread or worsening of a disease or condition resulting from the administration of one or more preventative or therapeutic agents to a patient suffering from such a disease or condition. In some embodiments, these terms mean the administration of the compounds provided herein, with or without other additional active agents, after the onset of symptoms of a particular disease.

[0056] As used herein and unless otherwise specified, the terms “prevent,” “preventing,” and “prevention” mean the prevention of the onset, recurrence, or spread of a disease or condition or one or more symptoms thereof. In some embodiments, these terms refer to the treatment with or without other additional active compounds of the compounds provided herein, prior to the onset of symptoms, particularly for patients at risk of the disease or condition described herein. These terms cover the suppression or reduction of symptoms of a particular disease. In some embodiments, patients with a family history of the disease are particularly candidates for preventative treatment. Additionally, patients with a history of recurrent symptoms are also potential candidates for prevention. In this regard, the term “prevention” may be used interchangeably with the term “preventative treatment.”

[0057] As used herein and unless otherwise specified, the terms “manage,” “managing,” and “management” mean the prevention or mitigation of the progression, spread, or worsening of a disease or condition or one or more symptoms thereof. Generally, the beneficial effects on patients derived from preventative and / or therapeutic agents do not cure the disease or condition. In this regard, the term “management” encompasses treating patients with a particular disease in an attempt to prevent or minimize disease recurrence, or to prolong the period of remission.

[0058] As used herein and unless otherwise specified, the term "therapeuticly effective amount" for a compound or antibody is an amount sufficient to provide therapeutic benefit in the treatment or control of a disease or condition, or sufficient to delay or minimize one or more symptoms associated with that disease or condition. A therapeutically effective amount of a compound or antibody means the amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment or control of a disease or condition. The term "therapeuticly effective amount" may also encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of another therapeutic agent.

[0059] Combination therapy or “in combination with” refers to the use of more than one therapeutic agent to treat a specific condition or symptom. “In combination with” is not intended to imply that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, but such delivery methods are within the scope of this invention. The therapeutic agent may be administered simultaneously with, before (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, 12 weeks, or 16 weeks prior to) or after (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, 12 weeks, or 16 weeks after) a different therapeutic agent. Therapeutic agents in combination therapy may also be administered on an alternating dosing schedule, with or without a withdrawal period (e.g., not administered on certain days of the schedule). Administration of a therapeutic agent "in combination with another therapeutic agent" includes, but is not limited to, sequential and simultaneous administration of two agents. Generally, each therapeutic agent will be administered at a dose and / or schedule determined according to that particular agent.

[0060] As used herein and unless otherwise specified, a “preventively effective amount” of a compound or antibody is an amount sufficient to prevent disease or symptom or its recurrence. A preventively effective amount of a compound or antibody means the amount of a therapeutic agent, alone or in combination with other agents, that provides preventive benefit in the prevention of disease. The term “preventively effective amount” may also encompass amounts that improve overall prevention or enhance the preventive efficacy of another preventive agent.

[0061] As used herein and unless otherwise specified, the terms “pharmaceuticalally acceptable carrier,” “pharmaceuticalally acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” mean a pharmaceutically acceptable substance, composition, or mediator, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating substance. In one embodiment, a component is “pharmaceuticalally acceptable” in the sense that it is compatible with other components of a pharmaceutical formulation and suitable for contact with human and animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and that matches a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th edition; Rowe et al., eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd edition; Ash and Ash, eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson, ed., CRC Press LLC: BocaRaton, FL, 2004.

[0062] As used herein and unless otherwise specified, the term "relapse" refers to a recurrence of disease after a period of improvement. In some embodiments, the term "relapse" refers to a recurrence of cancer cells in an individual or mammal that has achieved cancer remission following treatment. As used herein and unless otherwise specified, the terms "refractory" or "resistant" refer to a disease or condition that does not respond to treatment. In some embodiments, the terms "refractory" or "resistant" refer to a situation where an individual or mammal still has residual cancer cells in their body even after intensive treatment.

[0063] As used in this article, "induction therapy" refers to the first treatment given for a disease, or the first treatment intended to induce complete remission of a disease (such as cancer). When used alone, induction therapy is a recognized best-of-breed treatment. If residual cancer is detected, the patient is treated with another therapy called re-induction. If the patient achieves complete remission after induction therapy, additional consolidation and / or maintenance therapy is given to prolong remission or potentially cure the patient.

[0064] As used in this article, "consolidation therapy" refers to treatment given after the initial achievement of remission. For example, consolidation therapy for cancer is treatment given after the cancer has disappeared following initial therapy. Consolidation therapy may include radiation therapy, stem cell transplantation, or treatment with cancer drugs. Consolidation therapy is also known as enhancement therapy or post-remission therapy.

[0065] As used in this article, "maintenance therapy" refers to treatment given to the disease after remission or optimal response has been achieved, in order to prevent or delay relapse. Maintenance therapy may include chemotherapy, hormone therapy, or targeted therapy.

[0066] As used herein and unless otherwise specified, “effective patient tumor response” means any increase in the therapeutic benefit to a patient. An “effective patient tumor response” can be, for example, a reduction in the rate of tumor progression of 5%, 10%, 25%, 50%, or 100%. An “effective patient tumor response” can be, for example, a reduction in the physical symptoms of cancer of 5%, 10%, 25%, 50%, or 100%. An “effective patient tumor response” can also be, for example, an increase in patient response of 5%, 10%, 25%, 50%, 100%, 200%, or more as measured by any suitable means, such as gene expression, cell count, analytical results, etc.

[0067] As used herein and unless otherwise specified, the term “probability” generally refers to an increased probability of an event. When used to refer to the effectiveness of a patient’s tumor response, the term “probability” generally encompasses an increased probability that the rate of tumor progression or the rate of tumor cell growth will decrease. When used to refer to the effectiveness of a patient’s tumor response, the term “probability” may also generally refer to an increase in indicators such as mRNA or protein expression, which can demonstrate increased progress in the treatment of the tumor.

[0068] As used herein and unless otherwise specified, the term “prediction” generally means a prior determination or notification. For example, when used to “predict” the effectiveness of cancer treatment, the term “prediction” may mean that the likelihood of a treatment outcome can be determined at the start, before treatment begins, or before substantial progress is made during treatment.

[0069] As used herein and unless otherwise specified, the term “monitoring” generally refers to the regulation, oversight, control, observation, follow-up, or surveillance of an activity. For example, the term “monitoring the effectiveness of a compound” refers to following up on the effectiveness of treatment of a patient or cancer in a tumor cell culture. Similarly, when used alone or in conjunction with patient compliance in a clinical trial, “monitoring” refers to following up on or confirming that a patient is actually taking the immunomodulatory compound being tested as prescribed. Monitoring may be performed, for example, by tracking the expression of mRNA or protein biomarkers.

[0070] Improvement in cancer or cancer-related disease can be characterized as a complete or partial response. A “complete response” is defined as the absence of clinically detectable disease, with normalization of any previously abnormal radiographic studies, bone marrow and cerebrospinal fluid (CSF) measurements, or abnormal monoclonal protein values. A “partial response” is defined as a reduction of at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in all measurable tumor burden (i.e., the number of malignant cells present in the individual, or the measured volume of the tumor mass, or the amount of abnormal monoclonal protein), with no new lesions. The term “treatment” encompasses both complete and partial responses.

[0071] As used herein and unless otherwise specified, the term "drug resistance" refers to a condition in which a disease does not respond to treatment with one or more drugs. Drug resistance can be endogenous (meaning that the disease has never responded to one or more drugs) or acquired (meaning that the disease has ceased to respond to one or more drugs to which the disease previously responded). In some embodiments, drug resistance is endogenous. In some embodiments, drug resistance is acquired.

[0072] As used herein and unless otherwise specified, when referring to treatment with a compound, the terms “sensitivity” and “sensitive” are relative terms referring to the degree of effectiveness of the compound in reducing or decreasing the progression of a tumor or the disease being treated. For example, when used to refer to the treatment of cells or tumors, the term “increased sensitivity” in conjunction with a compound means an increase in the effectiveness of tumor treatment by at least 5% or more.

[0073] As used herein and unless otherwise specified, the terms “determination,” “measurement,” “evaluation,” “assessment,” and “analysis” as used herein generally refer to any form of measurement, including the determination of the presence or absence of an element. These terms include both quantitative and / or qualitative determinations. Assessments can be relative or absolute. “Assessing the presence of…” can include determining the quantity of something present as well as determining its presence or absence.

[0074] As used herein and unless otherwise specified, the term "pharmaceutically acceptable salt" encompasses non-toxic acid addition salts and base addition salts of the compounds referred to by the term. Acceptable non-toxic acid addition salts include salts derived from organic acids and inorganic acids or bases known in the art, including, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, heptanoic acid, and similar acids.

[0075] Essentially acidic compounds can form salts with a variety of pharmaceutically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are bases that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as (but not limited to) alkali metal or alkaline earth metal salts, and specifically, calcium, magnesium, sodium, or potassium salts. Suitable organic bases include, but are not limited to, N,N-diphenylmethylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, lysine, and procaine. Clinical trial endpoints

[0076] In the case of cancer, inhibition can be assessed by suppressing disease progression, inhibiting tumor growth, reducing primary tumor size, alleviating tumor-related symptoms, inhibiting tumor-secreting factors, delaying the onset of primary or secondary tumors, slowing the development of primary or secondary tumors, reducing the onset of primary or secondary tumors, slowing or reducing the severity of disease side effects, tumor growth arrest and tumor regression, prolonging time to onset of progression (TTP), increasing progression-free survival (PFS), increasing overall survival (OS), and others. As used herein, OS means the time from the start of treatment until death from any cause. As used herein, TTP means the time from the start of treatment until tumor progression; TTP does not include death. In one embodiment, PFS means the time from the start of treatment until tumor progression or death. In one embodiment, PFS means 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 ratio will be calculated using Kaplan-Meier estimation. Event-free survival (EFS) means the time from the start of treatment until any treatment failure (including disease progression, treatment cessation for any cause, or death). In one embodiment, the overall response rate (ORR) refers to the percentage of patients who achieve a response. In one embodiment, ORR refers to the sum of the percentages of patients who achieve a complete and partial response. In one embodiment, ORR refers to the percentage of patients who, according to the IMWG Uniform Response Criteria, have an optimal response ≥ a partial response (PR). In one embodiment, the duration of response (DoR) is the time from achieving a response until relapse or disease progression. In one embodiment, DoR is the time from achieving a response ≥ a partial response (PR) until relapse or disease progression. In one embodiment, DoR is the time from the first recorded response until the first recorded progressive disease or death. In one embodiment, DoR is the time from the first recorded response ≥ a partial response (PR) until the first recorded progressive disease or death. In one embodiment, the time to response (TTR) refers to the time from the first administration of the compound to the first recorded response. In one embodiment, TTR refers to the time from the first administration of the compound to the first recorded response ≥ a partial response (PR). In extreme cases, complete inhibition is referred to herein as prophylaxis or chemoprevention. In this context, the term "prevention" includes the complete prevention of the onset of clinically apparent cancer or the prevention of the onset of cancer in its preclinical, apparent stages. This definition also aims to cover the prevention of pre-malignant cells from transforming into malignant cells or to halt or reverse the progression of pre-malignant cells to malignant cells. This includes preventative treatments for those at risk of developing cancer.

[0077] In the context of multiple myeloma, the International Myeloma Working Group (IMWG) Common Response Criteria and the Minimal Residual Disease Assessment (Rajkumar et al., Blood, 2011, 117(18): 4691-5; Kumar et al., Lancet Oncol., 2016, 17(8): e328-e346) can be used to assess response. The criteria can be summarized below (further details are available in Lancet Oncol., 2016, 17(8): e328-e346). RD = Trace Residual Disease. NGF = Next-Generation Flow Cytometry. NGS = Next-Generation Sequencing. FLC = Free Light Chains. M Protein = Myeloma Protein. SPD = Sum of the products of the largest vertical diameters of the measured lesions. CRAB Characteristics = Elevated calcium, renal failure, anemia, osteolytic lesions. FCM = Flow Cytometry. SUVmax = Maximum Normalized Uptake Value. 18 F-FDG PET = 18 F-fluorodeoxyglucose PET.

[0078] In some embodiments, treatment for multiple myeloma may also be 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), using the response and endpoint definitions shown below: Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, strictly complete response; VGPR, excellent partial response. a All response categories require two consecutive evaluations at any time before any new therapy is established; if a radiographic study is conducted, no evidence of known progressive or new bone lesions is required for any category. Radiographic studies are not required to meet these response requirements. b No need for confirmation with repeated bone marrow biopsies. cThe presence / absence of asexual cells is based on the κ / λ ratio. An abnormal κ / λ ratio, as determined by immunohistochemistry and / or immunofluorescence, requires a minimum of 100 plasma cells for analysis. An abnormal ratio reflecting the presence of abnormal progeny is κ / λ > 4:1 or < 1:2. d Measurable disease is defined by at least one of the following measurements: bone marrow plasma cells ≥ 30%; serum M-protein ≥ 1 g / dl (≥ 10 gm / l) [10 g / l]; urinary M-protein ≥ 200 mg / 24 h; serum FLC analysis: FLC content involved ≥ 10 mg / dl (≥ 100 mg / l); the limiting condition is an abnormal serum FLC ratio.

[0079] As used in this article, ECOG status refers to the functional status of the Eastern Cooperative Oncology Group (ECOG) (Oken M et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-655), as shown below:

[0080] In some embodiments, the primary endpoint is dose-limiting toxicity (DLT). In some embodiments, adverse events are characterized by type, frequency, severity (e.g., graded by NCI CTCAE v5.0), timing, severity, and relationship to the drug used. In some embodiments, laboratory abnormalities are characterized by type, frequency, severity (e.g., graded by NCI CTCAE v5.0), and timing. In some embodiments, AEs (other than CRS and ICANS) are graded by the investigator according to NCI CTCAE v5.0 and coded using MedDRA. In some embodiments, CRS and ICANS are assessed according to the ASTCT guidelines (Appendix 13) and coded using MedDRA. In some embodiments, AEs may be presented based on the investigator's judgment, with and without causation. In some embodiments, the frequency of overall toxicities classified according to toxicity grades 1 to 5 is described. In some embodiments, clinical laboratory data are graded according to NCI CTCAE v5.0 and will be analyzed using generalized statistics. The worst treatment period grade during treatment is summarized as a numerical value and percentage.

[0081] In some embodiments, the Best Overall Response (BOR) is assessed based on the reported overall response (according to the IMWG response criteria) recorded from the date of first dosing until the first recorded confirmed PD, death, or initiation of a new anticancer therapy (whichever comes first). An objective response is defined as a BOR with a confirmed sCR, CR, VGPR, or PR.

[0082] In some embodiments, the Objective Response Rate (ORR) is defined as the proportion of participants who have an objective response according to the IMWG response criteria, as determined by the researcher. Point estimates of the ORR are calculated using the Clopper-Pearson method along with a two-sided 95% precision CI.

[0083] In some embodiments, the Complete Response Rate (CRR) is defined as the proportion of participants who have a CR / sCR according to the IMWG response criteria, as determined by the investigator. Point estimates of the CRR are calculated using the Clopper-Pearson method along with a two-sided 95% precision CI.

[0084] In some embodiments, for participants who have an objective response according to IMWG criteria, the time to response (TTR) is defined as the time from the first dose to the first recorded and subsequently confirmed objective response. TTR is summarized using the mean, standard deviation, minimum, median, and maximum values.

[0085] In some embodiments, for participants with an objective response according to IMWG criteria, the Duration of Response (DOR) is defined as the time from the first recorded subsequently confirmed objective response until the first recorded PD or death from any cause (whichever comes first) confirmed according to IMWG criteria. For participants who did not experience an event (confirmed PD or death from any cause), the DOR may be reviewed; for participants who started a new cancer therapy before the event occurred, the review may be conducted on the date of the last adequate disease assessment prior to the new cancer therapy; or for participants who experienced an event after two or more missing disease assessments, the review may be conducted on the date of the last adequate disease assessment prior to the two or more missing disease assessments. The DOR is summarized using the Kaplan-Meier method and displayed graphically.

[0086] In some embodiments, for participants with CR / sCR according to IMWG guidelines, the Duration of Complete Response (DOCR) is defined as the time from the first recorded subsequently confirmed CR / sCR until the first recorded confirmed PD according to IMWG guidelines or death from any cause (whichever comes first). DOCR is reviewed for participants who did not experience an event (confirmed PD or death from any cause); for participants who started a new cancer therapy before an event occurred, it is reviewed on the date of the last adequate disease assessment prior to the new cancer therapy; or for participants who experienced an event after two or more missing disease assessments, it is reviewed on the date of the last adequate disease assessment prior to the two or more missing disease assessments. DOCR is summarized using the Kaplan-Mayer method and displayed graphically.

[0087] In some embodiments, progression-free survival (PFS) is defined as the time from the first dosing date to the first recorded PD confirmed according to IMWG guidelines or death from any cause (whichever comes first). In some embodiments, PFS is reviewed as follows: (1) for participants who did not experience an event (PD confirmed according to IMWG guidelines or death from any cause), the review is conducted on the last adequate disease assessment date; (2) for participants who started a new anticancer therapy before the event occurred, the review is conducted on the last adequate disease assessment date prior to the new anticancer therapy; (3) for participants who experienced an event after an interval of two or more missing disease assessments, the review is conducted on the last adequate disease assessment date prior to that interval; (4) for participants who did not undergo an adequate post-baseline disease assessment, the review is conducted on the first dosing date of the study intervention, unless death occurred at or before the second planned disease assessment (i.e., ≤ 70 days after the first dosing date), in which case death is considered an event. PFS is summarized using the Kaplan-Mayer method and displayed graphically.

[0088] In some embodiments, overall survival (OS) is defined as the time from the date of first administration until death from any cause. Survival status is expected to be collected regardless of interruption of the study intervention or participant request to discontinue the study. Survival of all participants who have not withdrawn their consent to further participation in the study is followed up until the end of the study. OS of participants whose death is not yet known is reviewed at their last known date of survival. OS is summarized using the Kaplan-Mayer method and displayed graphically.

[0089] In some embodiments, the MRD negativity rate is the proportion of participants in the safety analysis set who were MRD negative according to IMWG sequencing guidelines from the date of first dosing until the first recorded confirmed PD, death, or initiation of a new anticancer therapy. A point estimate of the MRD negativity rate was calculated using the Clopper-Pearson method with an exact two-sided 95% CI.

[0090] In some embodiments, the methods provided herein can be used to achieve one or more of these clinical trial endpoints in patients. In some embodiments, the methods provided herein can be used to improve one or more of these clinical trial endpoints in patients. compound

[0091] In some embodiments, the compound used in the compositions and methods provided herein is 3-(4-((4-((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione (compound A), which has the following structure: Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds or polymorphs.

[0092] In one embodiment, the compound is 3-(4-((4-((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione. In one embodiment, the compound is a pharmaceutically acceptable salt of compound A. In one embodiment, the compound is 3-(4-(4-(((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione hydrochloride.

[0093] In one embodiment, the compound is (S)-3-(4-((4-((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (compound AS), which has the following structure: Compound AS

[0094] In one embodiment, the compound is a pharmaceutically acceptable salt of compound AS. In one embodiment, the compound is the hydrochloride salt of compound AS. In one embodiment, the compound is ibedoamine (CC-220).

[0095] In one embodiment, the compound is (R)-3-(4-((4-((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidin-2,6-dione (compound AR), which has the following structure: Compound AR

[0096] In one embodiment, the compound is a pharmaceutically acceptable salt of compound AR. In one embodiment, the compound is (R)-3-(4-((4-((N-morpholinyl)methyl)benzyl)oxy)-1-oxoisoindololin-2-yl)piperidine-2,6-dione hydrochloride.

[0097] Compound A, AS, or AR can be prepared according to the methods described in U.S. Application Publications No. 2011-0196150 and No. 2014-0045843, the entire contents of which are incorporated herein by reference. Based on the teachings of these disclosures, the compound can also be synthesized according to other methods that are obvious to those skilled in the art.

[0098] The compounds presented in this paper significantly inhibit TNF-α, IL-1β, and other inflammatory cytokines in LPS-stimulated hPBMCs and human whole blood. TNF-α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-α is responsible for various intracellular signaling events. TNF-α can play a pathological role in cancer. Without being limited by theoretical constraints, one of the biological effects of the immunomodulatory compounds presented in this paper is the reduction of TNF-α synthesis. The immunomodulatory compounds presented in this paper enhance the degradation of TNF-α mRNA. The compounds presented in this paper also strongly inhibit IL-1β and stimulate IL-10 under these conditions.

[0099] Furthermore, without being constrained by any particular theory, the compounds presented in this paper are potent co-stimulators of T cells and increase cell proliferation in a dose-dependent manner under appropriate conditions.

[0100] In some embodiments, without being limited by theory, the biological effects exerted by the immunomodulatory compounds provided herein include, but are not limited to, anti-angiogenic and immunomodulatory effects.

[0101] Compound A, as described herein, contains a chiral center and can exist in the form of mixtures of enantiomers (e.g., racemic mixtures). This invention covers the use of the stereoisomerically pure forms of such compounds, as well as the use of mixtures of these forms. For example, mixtures containing equal or unequal amounts of enantiomers of compound A, as described herein, can be used in the methods and compositions disclosed herein. These isomers can be resolved via asymmetric synthesis or using standard techniques such as chiral columns or chiral eluents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, EL., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH., Tables of Resolving Agents and Optical Resolutions, p. 268 (EL Eliel, ed., Univ. of Notre Dame Press, NotreDame, IN, 1972). Bispecific antibodies

[0102] In some embodiments, the bispecific antibodies provided herein for use in compositions and methods are described. Overview

[0103] In some embodiments, the bispecific antibody is a heterodimeric antibody. In some embodiments, the bispecific antibody is a chimeric, human, or humanized antibody. In some embodiments, the bispecific antibody is a full-length antibody. In some embodiments, the bispecific antibody is an immunoglobulin (IgG) antibody. In some embodiments, the bispecific antibody is an immunoglobulin 2 (IgG2) κ antibody, for example, an immunoglobulin 2-alanine (IgG2Δa) κ antibody. In some embodiments, the bispecific antibody comprises an antibody fragment binding to BCMA and an antibody fragment binding to CD3. In some embodiments, the antibody fragment binding to BCMA or CD3 is selected from Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, single-chain antibody molecules, bivariate domain antibodies, monovariate domain antibodies, linear antibodies, V region, F(ab)2, Fd, Fc, bifunctional antibodies, di-bifunctional antibodies, disulfide-linked Fvs(dsFv), and monodomain antibodies. In some embodiments, the bispecific antibody is selected from BiTEs. ®DART antibodies, bispecific antibodies, tandem scFvs, and antibody mimics such as DARPin are used. In some embodiments, the bispecific antibody is derived from two monoclonal antibody (mAb) anti-BCMA mAb and anti-CD3 mAb. In some embodiments, the anti-BCMA mAb facilitates the binding of a first binding moiety to the B cell maturation antigen (BCMA) in the bispecific antibody. In some embodiments, the anti-CD3 mAb facilitates the binding of a second binding moiety to CD3 in the bispecific antibody. In some embodiments, each of these mAbs contributes a different heavy (H) chain and a different light (L) chain to the bispecific antibody, thereby generating four chains in the bispecific antibody. In some embodiments, the four chains in the bispecific antibody are covalently linked via five interchain disulfide bonds. In some embodiments, the bispecific antibody causes targeted T cell-mediated cytotoxicity after the epitope on a CD3-expressing T cell binds to a second epitope on a BCMA-expressing MM cell. In some embodiments, the bispecific antibody is enastatumab (PF-06863135).

[0104] In some embodiments, the bispecific antibody comprises a first binding portion binding to B cell maturation antigen (BCMA) and a second binding portion binding to differentiation cluster 3 (CD3). In some embodiments, the bispecific antibody comprises a first binding portion binding to human B cell maturation antigen (BCMA) and a second binding portion binding to human differentiation cluster 3 (CD3). In some embodiments, the bispecific antibody comprises, as... Figure 1 The structures shown are illustrated in Tables 2 and 3. Tables 2 and 3 list exemplary amino acid sequences of the first binding moiety to B cell maturation antigen (BCMA) and the second binding moiety to differentiation cluster 3 (CD3). Table 2: Amino acid sequence of the first binding site to BCMA Table 3: Amino acid sequence of the second binding site to CD3 Binds to the first binding site of B cell maturation antigen (BCMA)

[0105] In some embodiments, the first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22. In some embodiments, the first binding portion to BCMA comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 3, VH CDR2 containing the amino acid sequence of SEQ ID NO: 4, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 5; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 6, VL CDR2 containing the amino acid sequence of SEQ ID NO: 7, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first binding portion to BCMA comprises a VH region containing VHCDR1 containing the amino acid sequence of SEQ ID NO: 9, VHCDR2 containing the amino acid sequence of SEQ ID NO: 10, and VHCDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first binding portion to BCMA comprises a VH region containing VHCDR1 containing the amino acid sequence of SEQ ID NO: 14, VH CDR2 containing the amino acid sequence of SEQ ID NO: 15, and VHCDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8.In some embodiments, the first binding portion to BCMA comprises a VH region containing VHCDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VHCDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first binding portion to BCMA comprises a VH region containing VHCDR1 containing the amino acid sequence of SEQ ID NO: 17, VH CDR2 containing the amino acid sequence of SEQ ID NO: 18, and VHCDR3 containing the amino acid sequence of SEQ ID NO: 19; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 20, VL CDR2 containing the amino acid sequence of SEQ ID NO: 21, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 22. In some embodiments, the first binding portion to BCMA comprises a VH region containing VHCDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 23, and VHCDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8.

[0106] In some embodiments, the first binding portion to BCMA includes a VH region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first binding portion to BCMA includes a VH region comprising an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first binding portion to BCMA includes a VH region comprising an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first binding portion to BCMA includes a VH region comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first binding portion to BCMA includes a VH region comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first binding portion to BCMA includes a VL region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the first binding portion to BCMA includes a VL region comprising an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the first binding portion to BCMA includes a VL region comprising an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the first binding portion to BCMA includes a VL region comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the first binding portion to BCMA includes a VL region comprising the amino acid sequence of SEQ ID NO: 2.

[0107] In some embodiments, the first binding portion to the BCMA comprises a heavy chain and a light chain ( Figure 1 In some embodiments, the heavy chain bound to the first binding portion of the BCMA includes a VH region, a CH1 region, and an Fc region from the N-terminus to the C-terminus. Figure 1 In some embodiments, the Fc region includes the CH2 region and the CH3 region. Figure 1In some embodiments, the heavy chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the heavy chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the heavy chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the heavy chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 47. In some embodiments, the heavy chain bound to the first binding portion of BCMA comprises an amino acid sequence of SEQ ID NO: 47. In some embodiments, the heavy chain bound to the first binding portion of BCMA comprises the amino acid sequence of SEQ ID NO: 47. Heavy chains that bind to the first binding portion of BCMA EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAIGGGSGGSLPYADIVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARYWPMDIWGQGTLV TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCEVECP ECPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKT KGQPREPQVYTLPPSREEMTKNQVSLTCEVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ IDNO:47)

[0108] In some embodiments, the light chain bound to the first binding portion of the BCMA includes a VL region and a CL region from the N-terminus to the C-terminus. Figure 1In some embodiments, the light chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the light chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the light chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the light chain bound to the first binding portion of BCMA comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the light chain bound to the first binding portion of BCMA comprises an amino acid sequence of SEQ ID NO: 48. In some embodiments, the light chain bound to the first binding portion of BCMA comprises the amino acid sequence of SEQ ID NO: 48. Light chain bonded to the first bonding portion of BCMA

[0109] EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWY QQKPGQAPRLLMYDASIRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYQSWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 48) Binding to the second binding portion of differentiation cluster 3 (CD3)

[0110] In some embodiments, the second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45. In some embodiments, the second binding portion to CD3 comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 26, VH CDR2 containing the amino acid sequence of SEQ ID NO: 27, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 28; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 29, VL CDR2 containing the amino acid sequence of SEQ ID NO: 30, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31. In some embodiments, the second binding portion to CD3 comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 32, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31. In some embodiments, the second binding portion to CD3 comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 37, VH CDR2 containing the amino acid sequence of SEQ ID NO: 38, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31.In some embodiments, the second binding portion to CD3 comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31. In some embodiments, the second binding portion to CD3 comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 40, VH CDR2 containing the amino acid sequence of SEQ ID NO: 41, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 42; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 43, VL CDR2 containing the amino acid sequence of SEQ ID NO: 44, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 45. In some embodiments, the second binding portion to CD3 comprises a VH region containing VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 46, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region containing VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31.

[0111] In some embodiments, the second binding portion to CD3 includes a VH region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the second binding portion to CD3 includes a VH region comprising an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the second binding portion to CD3 includes a VH region comprising an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the second binding portion to CD3 includes a VH region comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 24. In some embodiments, the second binding portion to CD3 includes a VH region comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the second binding portion to CD3 includes a VL region comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the second binding portion to CD3 includes a VL region comprising an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the second binding portion to CD3 includes a VL region comprising an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the second binding portion to CD3 includes a VL region comprising an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the second binding portion to CD3 includes a VL region comprising the amino acid sequence of SEQ ID NO: 25.

[0112] In some embodiments, the second binding portion to CD3 comprises a heavy chain and a light chain ( Figure 1 In some embodiments, the heavy chain bound to the second binding portion of CD3 includes a VH region, a CH1 region, and an Fc region from the N-terminus to the C-terminus. Figure 1 In some embodiments, the Fc region includes the CH2 region and the CH3 region. Figure 1In some embodiments, the heavy chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the heavy chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the heavy chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the heavy chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 49. In some embodiments, the heavy chain binding to the second binding portion of CD3 comprises the amino acid sequence of SEQ ID NO: 49. Heavy chain bound to the second binding portion of CD3 EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMTWVRQAPGKGLEWVAFIRNRARGYTSDHNPSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRPSYYVLDYWG QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCRV RCPRCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISK TKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSRLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:49).

[0113] In some embodiments, the light chain bound to the second binding portion of CD3 includes a VL region and a CL region from the N-terminus to the C-terminus. Figure 1In some embodiments, the light chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the light chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 96% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the light chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the light chain binding to the second binding portion of CD3 comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the light chain binding to the second binding portion of CD3 comprises the amino acid sequence of SEQ ID NO: 50. Light chain that binds to the second binding portion of CD3 DIVMTQSPDSLAVSLGERATINCKSSQSLFNVRSRKNYLAWYQQKPGQPPKLLISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCKQSYDLFTFGSGTKLEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:50)

[0114] In some embodiments, the heavy chain binding to the first binding portion of BCMA may lack the C-terminal lysine residue present in SEQ ID NO: 47. In some embodiments, the heavy chain binding to the second binding portion of CD3 may lack the C-terminal lysine residue present in SEQ ID NO: 49. In some embodiments, the heavy chain binding to the first binding portion of BCMA may lack the C-terminal lysine residue present in SEQ ID NO: 47, and the heavy chain binding to the first binding portion of CD3 may lack the C-terminal lysine residue present in SEQ ID NO: 49. Treatment methods and compositions for such methods

[0115] The compounds described herein, in combination with the bispecific antibodies that bind to BCMA and CD3 described herein, can be used in all the therapeutic methods described herein.

[0116] In some embodiments, this document provides a method for treating or controlling multiple myeloma, the method comprising administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of a compound provided herein and (b) a therapeutically effective amount of a bispecific antibody provided herein comprising a first binding portion to BCMA and a second binding portion to CD3. Treatment

[0117] In some embodiments, this document provides a method for treating or controlling multiple myeloma, the method comprising administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of a compound, wherein the compound is compound A, AS, or AR. (a) or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds or polymorphs; and (b) a therapeutically effective amount of the bispecific antibody provided herein, which comprises a first binding moiety to BCMA and a second binding moiety to CD3.

[0118] In some embodiments, this document provides a method for treating or controlling multiple myeloma, the method comprising administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the compound provided herein and (b) a therapeutically effective amount of a bispecific antibody comprising a first binding moiety to BCMA and a second binding moiety to CD3, wherein the first binding moiety to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 9, 14, 16 and 17; VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 10, 15, 18 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 11 and 19; and (ii) a VL region comprising VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 12 and 20; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 13 and 21. CDR2; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; wherein the second binding portion to CD3 comprises (i) a VH region having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and VHCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

[0119] In some embodiments, this document provides a method for treating or controlling multiple myeloma, the method comprising administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of a compound, wherein the compound is compound A, AS, or AR. Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45. Compounds for use

[0120] In some embodiments, this document provides compounds for a method of treating multiple myeloma, wherein the compound is the compound provided herein, and wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the compound provided herein and (b) a therapeutically effective amount of a bispecific antibody provided herein, the bispecific antibody comprising a first binding portion to BCMA and a second binding portion to CD3.

[0121] In some embodiments, this document provides compounds for a method of treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the compound, wherein the compound is compound A, AS, or AR. (a) or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds or polymorphs; and (b) a therapeutically effective amount of the bispecific antibody provided herein, which comprises a first binding moiety to BCMA and a second binding moiety to CD3.

[0122] In some embodiments, this document provides a compound for a method of treating multiple myeloma, wherein the compound is the compound provided herein, and wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the compound provided herein and (b) a therapeutically effective amount of a bispecific antibody comprising a first binding portion to BCMA and a second binding portion to CD3, wherein the first binding portion to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region comprising VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; and VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 11 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20 ... The second binding portion to CD3 comprises (i) a VH region comprising a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39, and 40; a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41, and 46; a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34, and 42; and (ii) a VL region comprising a VL CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35, and 43; a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36, and 44; and a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

[0123] In some embodiments, this document provides compounds for a method of treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of a compound, wherein the compound is compound A, AS, or AR. Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45. Bispecific antibodies for use

[0124] In some embodiments, this document provides a bispecific antibody for a method of treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the bispecific antibody provided herein, wherein the bispecific antibody comprises a first binding portion binding to BCMA and a second binding portion binding to CD3; and (b) a therapeutically effective amount of the compound provided herein.

[0125] In some embodiments, this document provides a bispecific antibody for a method of treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the bispecific antibody provided herein, wherein the bispecific antibody comprises a first binding moiety binding to BCMA and a second binding moiety binding to CD3; and (b) a therapeutically effective amount of a compound, wherein the compound is compound A, AS, or AR. Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds or polymorphs.

[0126] In some embodiments, this document provides a bispecific antibody for a method of treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the bispecific antibody comprising a first binding portion to BCMA and a second binding portion to CD3, wherein the first binding portion to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and VHCDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region comprising VLCDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and VLC CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; and VLC CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and VLC CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; and VLC CDR2 ...3 and 21; and VLC CDR2 having an amino The second binding portion to CD3 comprises (i) a VH region having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45; and (b) a therapeutically effective amount of the compound provided herein.

[0127] In some embodiments, this document provides a bispecific antibody for a method of treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient with multiple myeloma: (a) A therapeutically effective amount of the bispecific antibody, wherein the bispecific antibody comprises a first binding portion binding to B-cell maturation antigen (BCMA) and a second binding portion binding to differentiation cluster 3 (CD3); wherein the first binding portion binding to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; VHCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region comprising VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45. (b) A therapeutically effective amount of the compound, wherein the compound is compound A, AS, or AR. Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds or polymorphs. Compounds and bispecific antibodies for use

[0128] In some embodiments, this document provides compounds and bispecific antibodies in a method for treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of a compound (e.g., a compound provided herein) and (b) a therapeutically effective amount of a bispecific antibody (e.g., a bispecific antibody provided herein).

[0129] In some embodiments, this document provides compounds and bispecific antibodies for a method of treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the compound, wherein the compound is compound A, AS, or AR. (a) or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds or polymorphs; and (b) a therapeutically effective amount of the bispecific antibody provided herein, wherein the bispecific antibody comprises a first binding moiety binding to BCMA and a second binding moiety binding to CD3.

[0130] In some embodiments, this document provides compounds and bispecific antibodies for a method of treating multiple myeloma, wherein the method comprises administering to a patient with multiple myeloma a combination of: (a) a therapeutically effective amount of the compound and (b) a therapeutically effective amount of the bispecific antibody comprising a first binding moiety to BCMA and a second binding moiety to CD3, wherein the first binding moiety to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 3, 9, 14, 16 and 17; VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 10, 15, 18 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 11 and 19; and (ii) a VL region comprising VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 12 and 20; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 13 and 21. CDR2; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; wherein the second binding portion to CD3 comprises (i) a VH region having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

[0131] In some embodiments, this document provides compounds and bispecific antibodies for a method of treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of a compound, wherein the compound is compound A, AS, or AR. Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45. Multiple myeloma

[0132] In some embodiments, multiple myeloma is condensed myeloma, indolent myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of bone, light chain myeloma, or nonsecretory myeloma. In some embodiments, methods are provided herein for treating or controlling condensed myeloma, indolent myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of bone, light chain myeloma, or nonsecretory myeloma.

[0133] In some embodiments, the multiple myeloma is relapsed, refractory, or drug-resistant multiple myeloma. In some embodiments, the multiple myeloma is both relapsed and refractory multiple myeloma. In some embodiments, the multiple myeloma is either relapsed or refractory multiple myeloma. In some embodiments, the multiple myeloma is relapsed or refractory to at least two prior therapies, wherein these prior therapies are selected from lenalidomide, pomalidomide, and proteasome inhibitors. In some embodiments, the proteasome inhibitor is selected from carfilzomib, bortezomib, and ixazomib.

[0134] In some embodiments, this document provides methods for treating or controlling relapsed, refractory, or drug-resistant multiple myeloma. In some embodiments, this document provides methods for treating or controlling relapsed and refractory multiple myeloma. In some embodiments, this document provides methods for treating or controlling relapsed or refractory multiple myeloma. In some embodiments, this document provides methods for treating or controlling relapsed or refractory multiple myeloma, wherein the multiple myeloma is relapsed or refractory to at least two prior therapies, wherein these prior therapies are selected from lenalidomide, pomalidomide, and proteasome inhibitors. In some embodiments, the proteasome inhibitor is selected from carfilzomib, bortezomib, and ixazomib.

[0135] In some embodiments, the methods for treating and / or controlling multiple myeloma provided herein can be used in patients who are unresponsive to standard therapy. In some embodiments, prior multiple myeloma therapies comprise at least one drug selected from the group consisting of a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. In some embodiments, the methods for treating and / or controlling multiple myeloma provided herein can be used in patients who have received at least two prior therapies. In some embodiments, the methods for treating and / or controlling multiple myeloma provided herein can be used in patients who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. In some embodiments, the proteasome inhibitor is selected from carfilzomib, bortezomib, and ixazomib.

[0136] In some embodiments, the cancer is a three-category refractory multiple myeloma. In some embodiments, an individual's multiple myeloma is refractory to all three types of the following multiple myeloma therapies: (1) prior multiple myeloma therapy containing a proteasome inhibitor, (2) prior multiple myeloma therapy containing an immunomodulatory agent, and (3) prior multiple myeloma therapy containing an anti-CD38 antibody.

[0137] In some embodiments, multiple myeloma is a newly diagnosed multiple myeloma. In some embodiments, methods for treating or controlling newly diagnosed multiple myeloma are provided herein. In some embodiments, the methods for treating and / or controlling multiple myeloma provided herein are used in untreated patients, i.e., patients who have not yet received treatment.

[0138] In some embodiments, this invention provides methods for treating patients who have previously been treated for multiple myeloma but have not responded to standard therapy, as well as for such patients who have not previously received treatment. The invention also covers methods for treating patients regardless of their age, although some diseases or conditions are more common in certain age groups. The invention further covers methods for treating patients who have undergone surgery to attempt treatment for a controversial disease or condition, as well as for such patients who have not undergone surgery. Because patients with multiple myeloma exhibit heterogeneous clinical expression and varying clinical outcomes, the treatment given to patients can vary depending on their prognosis. Experienced clinicians will be able to readily determine specific second agents, surgical procedures, and types of non-drug-based standard therapies that may be effective in treating individual cancer patients without excessive experimentation. Application of combination therapy

[0139] Compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, in combination with bispecific antibodies, may be administered orally, via non-enteric routes (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous administration or implantation), inhalation, nasal administration, vaginal administration, rectal administration, sublingual administration, or topical administration (e.g., percutaneous or local). Compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, may be formulated alone or with pharmaceutically acceptable excipients, carriers, adjuvants, and mediators to appropriate dose units suitable for each route of administration. In one embodiment, the combination of compound A, AS, or AR or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs with a bispecific antibody is administered orally.

[0140] The bispecific antibody in combination with the compounds provided herein can be administered via oral, non-enteric (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous administration or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical administration (e.g., percutaneous or local). The bispecific antibody can be formulated alone or with pharmaceutically acceptable excipients, carriers, adjuvants, and mediators to a suitable dose unit for each route of administration. In one embodiment, the bispecific antibody in combination with the compounds provided herein is administered subcutaneously. Amount of compound

[0141] This article provides a method for treating and / or controlling multiple myeloma in patients using a compound A, AS, or AR, or an enantiomer or mixture of enantiomers thereof, tautomer, isotope, pharmaceutically acceptable salt, solvate, hydrate, cocrystal, cage compound, or polymorph.

[0142] In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.01 mg to about 50 mg daily, about 0.1 mg to about 50 mg daily, about 0.5 mg to about 50 mg daily, about 1 mg to about 50 mg daily, about 0.02 mg to about 25 mg daily, about 0.05 mg to about 10 mg daily, or about 0.1 mg to about 5 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.01 mg to about 50 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.1 mg to about 50 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.5 mg to about 50 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1 mg to about 50 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR is about 0.02 mg to about 25 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is from about 0.05 mg to about 10 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is from about 0.1 mg to about 5 mg daily.In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is from about 0.1 mg to about 1.3 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is from about 0.6 mg to about 1.3 mg daily.

[0143] In some embodiments, the effective therapeutic or preventative dose of compound A, AS, or AR is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg, about 1.3 mg, about 1.35 mg, about 1.4 mg, about 1.45 mg, about 1.5 mg, about 1.55 mg, about 1.6 mg, about 1.65 mg, about 1.7 mg, about 1.75 mg, or about 1.8 mg daily. mg, approximately 1.85 mg, approximately 1.9 mg, approximately 1.95 mg, approximately 2 mg, approximately 2.05 mg, approximately 2.1 mg, approximately 2.15 mg, approximately 2.2 mg, approximately 2.25 mg, approximately 2.3 mg, approximately 2.35 mg, approximately 2.4 mg, approximately 2.45 mg, approximately 2.5 mg, approximately 2.55 mg, approximately 2.6 mg, approximately 2.65 mg, approximately 2.7 mg, approximately 2.75 mg, approximately 2.8 mg, approximately 2.85 mg, approximately 2.9 mg, approximately 2.95 mg, approximately 3 mg, approximately 3.05 mg, approximately 3.1 mg, approximately 3.15 mg, approximately 3.2 mg, approximately 3.25 mg, approximately 3.3 mg, approximately 3.35 mg, approximately 3.4 mg, approximately 3.45 mg, approximately 3.5 mg, approximately 3.55 mg, approximately 3.6 mg, approximately 3.65 mg, approximately 3.7 mg. mg, approximately 3.75 mg, approximately 3.8 mg, approximately 3.85 mg, approximately 3.9 mg, approximately 3.95 mg, approximately 4 mg, approximately 4.05 mg, approximately 4.1 mg, approximately 4.15 mg, approximately 4.2 mg, approximately 4.25 mg, approximately 4.3 mg, approximately 4.35 mg, approximately 4.4 mg, approximately 4.45 mg, approximately 4.5 mg, approximately 4.55 mg, approximately 4.6 mg, approximately 4.65 mg, approximately 4.7 mg, approximately 4.75 mg, approximately 4.8 mg, approximately 4.85 mg, approximately 4.9 mg, approximately 4.95 mg, or approximately 5 mg.In some embodiments, the therapeutic or preventative effective amount of compound A, AS, or AR is about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1 mg, about 1.05 mg, about 1.1 mg, about 1.15 mg, about 1.2 mg, about 1.25 mg, or about 1.3 mg. In some embodiments, the therapeutic or preventative effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.6 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.65 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.7 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.75 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.8 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.85 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 0.9 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS or AR or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds or polymorphs is about 0.95 mg per day.In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.2 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.25 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.3 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.35 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.4 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.45 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.5 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.55 mg daily.In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.6 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.65 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.7 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.75 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.8 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.85 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.9 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 1.95 mg daily. In some embodiments, the therapeutic or preventive effective amount of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is about 2 mg daily.

[0144] In one embodiment, the recommended daily dose range for compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs for the symptoms described herein is from about 0.1 mg to about 5 mg per day, preferably administered as a single dose once daily or in divided doses throughout the day. In some embodiments, the dose range is from about 1 mg to about 50 mg per day. In other embodiments, the dose range is from about 0.5 mg to about 5 mg per day. In other embodiments, the dose range is from about 0.6 mg to about 1.3 mg per day. Specific daily doses include 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, 1.25 mg, 1.3 mg, 1.35 mg, 1.4 mg, 1.45 mg, 1.5 mg, 1.55 mg, 1.6 mg, 1.65 mg, 1.7 mg, 1.75 mg, 1.8 mg, 1.85 mg, 1.9 mg, 1.95 mg, 2 mg, 2.05 mg, 2.1 mg, 2.15 mg, 2.2 mg, and 2.25 mg daily. mg, 2.3 mg, 2.35mg, 2.4 mg, 2.45 mg, 2.5 mg, 2.55 mg, 2.6 mg, 2.65 mg, 2.7 mg, 2.75 mg, 2.8 mg, 2.85mg, 2.9 mg, 2.95 mg, 3 mg, 3.05 mg, 3.1 mg, 3.15 mg, 3.2 mg, 3.25 mg, 3.3 mg, 3.35 mg, 3.4 mg, 3.45 mg, 3.5 mg, 3.55 mg, 3.6 mg, 3.65 mg, 3.7 mg, 3.75 mg, 3.8 mg, 3.85 mg, 3.9 mg, 3.95 mg, 4 mg, 4.05 mg, 4.1 mg, 4.15 mg, 4.2 mg, 4.25 mg, 4.3 mg, 4.35 mg, 4.4mg, 4.45 mg, 4.5 mg, 4.55 mg, 4.6 mg, 4.65 mg, 4.7 mg, 4.75 mg, 4.8 mg, 4.85 mg, 4.9mg, 4.95 mg or 5 mg.In some embodiments, the compound is administered in amounts of about 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, or 1.6 mg per day. In some embodiments, the compound is administered in amounts of about 0.75 mg, about 1.0 mg, or about 1.3 mg per day.

[0145] In some embodiments, compound A, AS or AR or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds or polymorphs are administered according to a locally approved label or pharmaceutical manual for information on preparation, administration and storage. Amount of bispecific antibodies

[0146] This article provides bispecific antibodies for use in treating and / or controlling multiple myeloma in patients.

[0147] In some embodiments, the bispecific antibody is administered at a therapeutically effective amount. In some embodiments, the bispecific antibody is administered according to a locally approved label or a pharmacy manual containing information on its preparation, administration, and storage.

[0148] In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 1 mg to about 250 mg, about 5 mg to about 250 mg, about 7.5 mg to about 250 mg, about 10 mg to about 250 mg, about 1 mg to about 100 mg, about 1 mg to about 80 mg, about 10 mg to about 80 mg, or about 12 mg to about 76 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 1 mg to about 250 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 5 mg to about 250 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 7.5 mg to about 250 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 10 mg to about 250 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 1 mg to about 100 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 1 mg to about 80 mg. In some embodiments, the therapeutic or prophylactic effective amount of the bispecific antibody is about 10 mg to about 80 mg. In some embodiments, the effective dose of the bispecific antibody for treatment or prevention is from about 12 mg to about 76 mg. In some embodiments, the effective dose of the bispecific antibody for treatment or prevention is from about 40 mg to about 160 mg.

[0149] In some embodiments, the therapeutic or preventative effective amount of the bispecific antibody is about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 32 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 76 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 116 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 152 mg, about 155 mg, or about 160 mg. In some embodiments, the therapeutic or preventative effective amount of the bispecific antibody is about 12 mg. In some embodiments, the effective dose of the bispecific antibody for treatment or prevention is about 32 mg. In some embodiments, the effective dose of the bispecific antibody for treatment or prevention is about 76 mg.

[0150] In one embodiment, the recommended dose range for the bispecific antibody used for the symptoms described herein is from about 0.5 mg to about 100 mg. In some embodiments, the dose range is from about 1 mg to about 100 mg. In other embodiments, the dose range is from about 12 mg to about 76 mg. Specific doses include 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 60 mg, 76 mg, 80 mg, 90 mg, or 100 mg. In one embodiment, the bispecific antibody is administered in an amount of approximately 12 mg. In one embodiment, the bispecific antibody is administered in an amount of approximately 32 mg. In one embodiment, the bispecific antibody is administered in an amount of approximately 76 mg.

[0151] The combination of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, with the bispecific antibody described herein, may be delivered in a single dose (such as a single-dose bolus injection or oral tablets or pills); or over time (such as continuous infusion over time or fractionated bolus doses over time). The combination of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, with the bispecific antibody described herein, may be repeatedly administered as necessary, for example until the patient experiences stable disease or remission, or until the patient experiences disease progression or unacceptable toxicity. Combinations of bispecific antibodies with the compounds provided herein can be delivered in a single dose (e.g., a single injection or oral tablet or pill); or over time (e.g., continuous infusion over time or fractionated injections over time). Combinations of bispecific antibodies with the compounds provided herein can be repeated as needed, for example until the patient experiences stable disease or remission, or until the patient experiences disease progression or unacceptable toxicity.

[0152] Compound A, AS, or AR, or their enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, in combination with the bispecific antibody provided herein, may be administered once daily (QD) or divided into multiple daily doses (such as twice daily (BID), three times daily (TID), and four times daily (QID). Combinations of bispecific antibodies with the compounds provided herein may be administered once daily (QD), once weekly (Q1W or QW), twice weekly (Q2W), or four times weekly (Q4W). Furthermore, administration may be continuous (i.e., daily administration for several consecutive days or daily), or intermittent, such as in a cyclical manner (i.e., including drug-free periods of several days, weeks, or months).

[0153] As used herein, the term “daily” means the administration of a therapeutic compound (such as compound A, AS, or AR) once or more daily, for a period of time. The term “continuous” means the administration of a therapeutic compound (such as compound A, AS, or AR) daily for an uninterrupted period of at least 10 days to 52 weeks. As used herein, the terms “intermittent” or “intermittently” mean stopping and starting at regular or irregular time intervals. For example, intermittent administration of compound A, AS, or AR may be one to six days per week, cyclical administration (e.g., daily administration for two to eight consecutive weeks followed by a one-week break), or administration every other day. The term “cyclical” as used herein is intended to mean the administration of a therapeutic compound (such as compound A, AS, or AR) daily or continuously with a break period.

[0154] In some embodiments, the frequency of administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is in the range of about a daily dose to about a monthly dose. In some embodiments, the administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks.

[0155] In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for periods ranging from one day to six months, one week to three months, one week to four weeks, one week to three weeks, or one week to two weeks. In some embodiments, compound A, AS, or AR, or its pharmaceutically acceptable salts or solvates, are administered once daily for one week, two weeks, three weeks, or four weeks. In one embodiment, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for one week. In another embodiment, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for two weeks. In yet another embodiment, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for three weeks. In still another embodiment, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for four weeks.

[0156] In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for 21 days in a 28-day cycle, followed by a 7-day discontinuation. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily for 21 days, followed by a 7-day discontinuation. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered once daily from day 1 to day 21 of a 28-day cycle. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, or more cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for one cycle. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for two cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for three cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for four cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for seven cycles.In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for eight cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for nine cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for ten cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for eleven cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for twelve cycles. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for thirteen or more cycles.

[0157] In some embodiments, the bispecific antibody is administered once daily for periods ranging from one day to six months, one week to three months, one week to four weeks, one week to three weeks, or one week to two weeks. In some embodiments, the bispecific antibody is administered once daily for one, two, three, or four weeks. In one embodiment, the bispecific antibody is administered once daily for one week. In another embodiment, the bispecific antibody is administered once daily for two weeks. In yet another embodiment, the bispecific antibody is administered once daily for three weeks. In still another embodiment, the bispecific antibody is administered once daily for four weeks. In some embodiments, the frequency of administration of the bispecific antibody ranges from approximately a daily dose to approximately a monthly dose.

[0158] In some embodiments, the bispecific antibody is administered once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks.

[0159] In some embodiments, the bispecific antibody is administered on days 1 and 4 of the week. In some embodiments, the bispecific antibody is administered on day 1 of the week. In some embodiments, the bispecific antibody is administered on days 1, 4, and 8 of a 14-day period.

[0160] In some embodiments, the bispecific antibody is administered once a week, once every two weeks, or once every four weeks.

[0161] In some embodiments, patients seeking treatment using one of the methods provided herein were not treated with the bispecific antibody provided herein prior to administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs thereof. In some embodiments, patients seeking treatment using one of the methods provided herein were treated with the bispecific antibody provided herein after administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs thereof. In some embodiments, patients seeking treatment using one of the methods provided herein were treated with the bispecific antibody provided herein concurrently with administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs thereof. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered simultaneously with, before (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, 12 weeks, or 16 weeks prior to, or after (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, 12 weeks, or 16 weeks later than, the bispecific antibody provided herein. In some embodiments, the combination of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, with a bispecific antibody, may be administered on an alternating dosing schedule with or without a withdrawal period (e.g., no treatment on certain days of the schedule). In some embodiments, the administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, with a bispecific antibody, includes, but is not limited to, sequential and simultaneous administration.

[0162] In some embodiments, the bispecific antibody is administered once, twice, three times, or more prior to the administration of the compound. In some embodiments, the bispecific antibody is administered during the initial dosing cycle prior to the administration of the compound. In some embodiments, the initial dosing cycle is a 1-day cycle, a 3-day cycle, a 7-day cycle, a 14-day cycle, a 21-day cycle, or a 28-day cycle. In some embodiments, the bispecific antibody is administered during the 14-day initial dosing cycle prior to the administration of the compound. In some embodiments, the bispecific antibody is administered on day 1 of the 7-day or 14-day initial dosing cycle prior to the administration of the compound. In some embodiments, the bispecific antibody is administered on days 1 and 4 of the 7-day or 14-day initial dosing cycle prior to the administration of the compound. In some embodiments, the bispecific antibody is administered on days 1, 4, and 8 of the 14-day initial dosing cycle prior to the administration of the compound. In some embodiments, a minimum of 2 days are maintained between the first and second doses in the initial dosing cycle. In some embodiments, a minimum of 3 days are maintained between the second and third doses in the initial dosing cycle. In some embodiments, a minimum of 6 days is maintained between the third dose in the initial dosing cycle and subsequent doses of the bispecific antibody. In some embodiments, a minimum of 6 days is maintained between the third dose in the initial dosing cycle and the commencement of administration of compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs.

[0163] In some embodiments, the bispecific antibody is administered weekly, every two weeks, or every four weeks within a 28-day cycle. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for 21 days within a 28-day cycle, i.e., administered for 21 days followed by a 7-day withdrawal period. In some embodiments, compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered from day 1 to day 21 of a 28-day cycle.

[0164] In some embodiments, the bispecific antibody is administered weekly, i.e., on days 1, 8, 15, and 22 of a 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for day 21 of a 28-day cycle. In some embodiments, the bispecific antibody is administered every two weeks, i.e., on days 1 and 15 of a 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for day 21 of a 28-day cycle. In some embodiments, the bispecific antibody is administered once every four weeks, i.e., on day 1 of a 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered for day 21 of a 28-day cycle.

[0165] In some embodiments, such as Figure 3The combination therapy is administered as shown. In some embodiments, the combination therapy is administered over multiple 28-day cycles. In some embodiments, the bispecific antibody is administered on days 1, 4, and 8 of a 14-day initial dose cycle (C0) prior to the administration of the compound. In some embodiments, during the first 28-day cycle (C1), the bispecific antibody is administered weekly, i.e., on days 1, 8, 15, and 22 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered from days 1 to 21 of the 28-day cycle. In some embodiments, during the second to sixth 28-day cycles (C2-C6), the bispecific antibody is administered weekly, i.e., on days 1, 8, 15, and 22 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered on days 1 to 21 of the 28-day cycle. In some embodiments, during the seventh to twelfth 28-day cycles (C7-C12), if the patient has been treated for at least 6 months and the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months, the bispecific antibody is administered every two weeks, i.e., on days 1 and 15 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered from days 1 to 21 of the 28-day cycle. In some embodiments, during the thirteenth to the remaining 28-day cycles (C13+), if the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months, the bispecific antibody is administered every four weeks, i.e., on day 1 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered from day 1 to day 21 of the 28-day cycle.

[0166] In some embodiments, during the initial 14-day dose cycle (C0) prior to compound administration, the bispecific antibody is administered at a dose of 12 mg on day 1, 32 mg on day 4, and 76 mg on day 8. In some embodiments, during the first to sixth 28-day cycles (C1-C6), the bispecific antibody is administered weekly at a dose of 76 mg, i.e., on days 1, 8, 15, and 22 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered at doses of 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle. In some embodiments, during the seventh to twelfth 28-day cycles (C7-C12), if the patient has been treated for at least 6 months and the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months, the bispecific antibody is administered at a dose of 76 mg every two weeks, i.e., on days 1 and 15 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs are administered at a dose of 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle. In some embodiments, during the thirteenth to the remaining 28-day cycles (C13+), if the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months, the bispecific antibody is administered at a dose of 76 mg every four weeks, i.e., on day 1 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered at a dose of 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle. In some embodiments, after the initial dosing cycle and the subsequent six 28-day cycles, if the patient has been treated for at least 6 months and the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months, the bispecific antibody is administered at a dose of 76 mg every two weeks. In some embodiments, if the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months after the initial dosing cycle and the subsequent twelve 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every four weeks.

[0167] In some embodiments, such as Figure 5The combination therapy is administered as shown. In some embodiments, during the initial 14-day dose cycle (C0) prior to compound administration, the bispecific antibody is administered at a dose of 12 mg on day 1, 32 mg on day 4, and 76 mg on day 8. In some embodiments, during the first to third 28-day cycles (C1-C3), the bispecific antibody is administered weekly at a dose of 76 mg, i.e., on days 1, 8, 15, and 22 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered at doses of 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle. In some embodiments, during the fourth to sixth 28-day cycles (C4-C6), the bispecific antibody is administered at a dose of 76 mg every two weeks, i.e., on days 1 and 15 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs are administered at a dose of 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle. In some embodiments, during the seventh to the remaining 28-day cycles (C7+), the bispecific antibody is administered at a dose of 76 mg every four weeks, i.e., on day 1 of the 28-day cycle, while compound A, AS or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs are administered at a dose of 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle.

[0168] In some embodiments, such as Figure 4The bispecific antibody is further administered in one or more dose-escalation cycles, as shown. In some embodiments, after the initial dose cycle and subsequent seven or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every two weeks for three 28-day cycles, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is administered at a dose of 1.3 mg, 1 mg, or 0.75 mg. In some embodiments, after the initial dose cycle and subsequent ten or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every four weeks, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, is administered at a dose of 1.3 mg, 1 mg, or 0.75 mg.

[0169] In some embodiments, such as Figure 6 The combination therapy is administered as shown. In some embodiments, during the initial 14-day dose cycle (C0) prior to compound administration, the bispecific antibody is administered at a dose of 12 mg on day 1, 32 mg on day 4, and 76 mg on day 8. In some embodiments, during the first through third 28-day cycles (C1-C3), the bispecific antibody is administered at a dose of 76 mg every two weeks, i.e., on days 1 and 15 of the 28-day cycle, while compound A, AS, or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are administered at doses of 0.75 mg, 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle. In some embodiments, during the fourth to regional 28-day cycle (C4+), the bispecific antibody is administered at a dose of 76 mg every four weeks, i.e., on day 1 of the 28-day cycle, while compound A, AS or AR, or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs are administered at doses of 0.75 mg, 1.0 mg, 1.3 mg, or 1.6 mg daily from day 1 to day 21 of the 28-day cycle.

[0170] In some embodiments, the bispecific antibody is administered subcutaneously. In other embodiments, the bispecific antibody is administered subcutaneously via injection.

[0171] In some embodiments, a preoperative medication for the prevention of cytokine release syndrome (CRS) is administered prior to administration of the bispecific antibody. In some embodiments, during the initial dose cycle (C0) prior to compound administration, a preoperative medication for CRS prevention is administered approximately 30 minutes, approximately 45 minutes, approximately 60 minutes, approximately 75 minutes, or approximately 90 minutes before the first, second, and third doses of the bispecific antibody. In some embodiments, the preoperative medication for CRS prevention includes acetaminophen, diphenhydramine, and dexamethasone. In some embodiments, preoperative medication for CRS prevention includes acetaminophen (or acetaminophen in the form of 500 mg) orally or intravenously, diphenhydramine in the form of 25 mg (or equivalent; varying but equivalent amounts due to differences in local prescribing information), and dexamethasone in the form of 20 mg (or equivalent; varying but equivalent amounts due to differences in local prescribing information) orally or intravenously. Pharmaceutical Compositions and Dosage Forms

[0172] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising a compound A, AS, or AR, or an enantiomer or mixture of enantiomers thereof, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs thereof, which can be administered in combination with the bispecific antibody provided herein. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising a bispecific antibody provided herein, which can be administered in combination with a compound A, AS, or AR, or an enantiomer or mixture of enantiomers thereof, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs thereof. In yet another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0173] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising (i) compound A, AS, or AR, or an enantiomer or mixture of enantiomers thereof, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, and (ii) a bispecific antibody provided herein. In another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients.

[0174] In some embodiments, the pharmaceutical compositions and dosage forms provided herein also include one or more additional active agents in an effective amount to achieve modulation of a disease or disease symptom, including those described herein. Examples of optional additional active agents are disclosed herein (see, for example, the Definitions section).

[0175] In some embodiments, the pharmaceutical compositions provided herein may be administered orally, enterically, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir, preferably orally or by injection. Oral delivery forms include (but are not limited to) tablets, capsules, capsule-type tablets, solutions, suspensions, and syrups, and may also contain a plurality of particles, beads, powders, or pellets, which may be encapsulated or unencapsulated. In one embodiment, the pharmaceutical composition may contain any conventionally non-toxic, pharmaceutically acceptable carrier, adjuvant, or mediator. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. As used herein, the term enterically includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In some embodiments, the pharmaceutical compositions provided herein containing bispecific antibodies are administered enterically, and in some embodiments subcutaneously.

[0176] In some embodiments, the dosage forms provided herein for compound A, AS, or AR, or their enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs, are suitable for administration to patients orally, via mucosae (e.g., via the nose, sublingually, vaginally, buccally, or rectum), non-enterically (e.g., subcutaneously, intravenously, via bolus, intramuscularly, or intra-arterially), topically (e.g., eye drops or other ophthalmic preparations), transdermally, or percutaneously. Examples of dosage forms include (but are not limited to): tablets; capsule tablets; capsules, such as soft elastic gelatin capsules; flat capsules; sugar-coated tablets; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to patients, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs; liquid dosage forms suitable for non-enteral administration to patients; eye drops or other ophthalmic preparations suitable for topical application to the body surface; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for non-enteral administration to patients.

[0177] In some embodiments, the dosage forms of bispecific antibodies described herein are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), non-enteric (e.g., subcutaneous, intravenous, bolus, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or percutaneous administration to patients. Examples of dosage forms include, but are not limited to, tablets; capsule tablets; capsules, such as soft elastic gelatin capsules; flat capsules; sugar-coated tablets; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to patients, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs; and liquid dosage forms suitable for non-enteric administration to patients. In some embodiments, the dosage form of the bispecific antibody is for non-enteric administration and, in some embodiments, for subcutaneous administration. In one embodiment, the bispecific antibody is formulated as described in the ELREXFIO™ product information leaflet (bispecific BCMA-directed CD3 T cell conjugate sold under the ELREXFIO trademark).

[0178] Whether a particular excipient is suitable for inclusion in the pharmaceutical compositions or dosage forms provided herein depends on a number of factors, including (but not limited to) the route of administration. For example, oral dosage forms such as tablets may contain excipients that are not suitable for non-enteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredient in the dosage form. For example, the degradation of some active ingredients may be accelerated by certain excipients (such as lactose) or by exposure to water. Active ingredients containing primary or secondary amines are particularly susceptible to such accelerated degradation. Therefore, this document covers pharmaceutical compositions and dosage forms containing very little (if present) lactose. As used herein, the term “lactose-free” means that the amount of lactose present (if present) is insufficient to substantially increase the rate of degradation of the active ingredient.

[0179] The lactose-free compositions described herein may contain excipients such as those listed in US Pharmacopeia (USP) 25-NF20 (2002). In some embodiments, the lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredients, binders / fillers, and lubricants. In some embodiments, the lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0180] This article further covers anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can accelerate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in pharmaceutical technology as a way to simulate long-term storage in order to determine the characteristics of a formulation over time, such as shelf life or stability. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd ed., Marcel Dekker, NY, 1995, pp. 379-80. In reality, water and heat can accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be very significant because they are frequently exposed to moisture and / or humidity during manufacturing, processing, packaging, storage, shipping, and use.

[0181] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture components and under low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if substantial contact with moisture and / or humidity is anticipated during manufacturing, encapsulation, and / or storage.

[0182] Anhydrous pharmaceutical compositions should be prepared and stored in a manner that maintains their anhydrous properties. Therefore, in some embodiments, this document provides anhydrous compositions encapsulated using materials that prevent exposure to water, so that they can be included in suitable formulation kits. Examples of suitable encapsulation include, but are not limited to, hermetically sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0183] This document covers pharmaceutical compositions and dosage forms containing one or more compounds that reduce the rate of degradation of the active ingredient. Such compounds, referred to herein as “stabilizers,” include (but are not limited to) antioxidants such as ascorbic acid, pH buffers, or salt buffers. Oral dosage form

[0184] In some embodiments, the pharmaceutical compositions provided herein suitable for oral administration are formulated in discrete dosage forms, examples of which include (but are not limited to) tablets (e.g., chewable tablets), capsule tablets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain a predetermined amount of the active ingredient and can be prepared by some known pharmaceutical methods. See generally Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990).

[0185] In some embodiments, the oral dosage forms provided herein are prepared by combining the active ingredient with at least one excipient in a tightly blended form according to conventional pharmaceutical compounding techniques. Depending on the desired formulation, the excipient may be in various forms. For example, excipients suitable for oral liquid or spray dosage forms include (but are not limited to) water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for solid oral dosage forms (e.g., powders, tablets, capsules, and capsule-type tablets) include (but are not limited to) starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0186] Because tablets and capsules are easy to administer, they represent the most advantageous oral unit dosage forms, in which case solid excipients are used. Tablets can be encapsulated using standard aqueous or non-aqueous techniques if desired. Such dosage forms can be prepared using several known pharmaceutical methods. In some embodiments, pharmaceutical compositions and dosage forms are prepared by uniformly and tightly blending the active ingredient with a liquid carrier, a finely powdered solid carrier, or both, and subsequently shaping the product into the desired presentation form if necessary.

[0187] In some embodiments, the tablets are prepared by compression or molding. In some embodiments, compressed tablets can be prepared by compressing an active ingredient, optionally mixed with an excipient, in a free-flowing form (e.g., powder or granules) in a suitable machine. In some embodiments, molded tablets can be prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0188] Examples of excipients that may be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (such as gum arabic), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., Nos. 2208, 2906, and 2910), microcrystalline cellulose, and mixtures thereof.

[0189] Suitable forms of microcrystalline cellulose include (but are not limited to) AVICEL-PH-101, AVICEL-PH-103, AVICELRC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, AvicelSales, Marcus Hook, PA), and mixtures thereof. Specific binders are mixtures of microcrystalline cellulose with sodium carboxymethyl cellulose (e.g., AVICEL RC-581). Suitable anhydrous or low-moisture excipients or additives include AVICEL-PH-103™ and Starch 1500 LM.

[0190] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose binders, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder or filler in the pharmaceutical compositions provided herein is present in about 50% by weight to about 99% by weight of the pharmaceutical composition or dosage form.

[0191] A disintegrant is used in the compositions provided herein to enable the tablets to disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may not disintegrate at the desired rate or under the desired conditions. Therefore, a sufficient amount of disintegrant should be used to form the solid oral dosage form provided herein, neither too much nor too little, without adversely altering the release of the active ingredient. The amount of disintegrant used varies depending on the type of formulation. In some embodiments, the pharmaceutical compositions provided herein comprise about 0.5% by weight to about 15% by weight or about 1% by weight to about 5% by weight of disintegrant.

[0192] Disintegrants suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginate, calcium carbonate, microcrystalline cellulose, crospovidone sodium carboxymethyl cellulose, crospovidone, polacrilin potassium, sodium glycolate starch, potato or cassava starch, other starches, pregelatinized starches, other starches, clay, other alginates, other celluloses, gums, and mixtures thereof.

[0193] Lubricants suitable for the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Additional lubricants include, but are not limited to, syloid silica gel (AEROSIL200, WR Grace Co., Baltimore, MD), coagulated aerosols of synthetic silica (Degussa Co. of Plano, TX), CAB-O-SIL (pyrolytic silica, Cabot Co. of Boston, MA), and mixtures thereof. In some embodiments, if used in full, the lubricant is used in an amount less than about 1% by weight of the pharmaceutical composition or dosage form into which it is incorporated.

[0194] In some embodiments, this document provides solid oral dosage forms comprising compound A, AS, or AR or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, anhydrous colloidal silica, and gelatin.

[0195] In some embodiments, this document provides solid oral dosage forms comprising compound A, AS, or AR or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, anhydrous colloidal silica, and gelatin.

[0196] In some embodiments, this document provides solid oral dosage forms comprising a hydrochloride salt of compound A, AS, or AR, or an enantiomer or mixture of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, anhydrous colloidal silica, and gelatin.

[0197] In some embodiments, this document provides solid oral dosage forms comprising a hydrochloride salt of compound A, AS, or AR or an enantiomer or mixture of enantiomers thereof, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, anhydrous colloidal silica, and gelatin. Delayed-release formulation

[0198] In some embodiments, the active ingredient provided herein is administered via a controlled release method or via a delivery device. Examples include, but are not limited to, the controlled release methods or delivery devices described in U.S. Patent Nos. 3,845,770, 3,916,899, 3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety. In some embodiments, such dosage forms are used to provide slow or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeation systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, to provide a desired release profile in varying proportions. This document covers single-unit dosage forms suitable for oral administration, including (but not limited to) tablets, capsules, capsule tablets, and capsule-form tablets suitable for controlled release.

[0199] All controlled-release drug products share the common goal of achieving improved drug therapy superior to that achieved by uncontrolled counterparts. Ideally, the use of optimally designed controlled-release formulations in medical treatment is characterized by curing or controlling symptoms with minimal active pharmaceutical ingredient (API) dosage over the shortest time. Advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release formulations can influence the time to onset of action or other characteristics (such as drug blood concentration), and thus the occurrence of side effects (e.g., adverse effects).

[0200] Most controlled-release formulations are designed to first release a rapid amount of drug (active ingredient) to produce the desired therapeutic effect, and then release the remaining amount gradually and continuously to maintain this level of therapeutic or preventative effect over an extended period of time. To maintain this constant drug concentration in the body, the drug must be released from the dosage form at a rate that replaces the amount metabolized and secreted by the body. Controlled release of the active ingredient can be stimulated by a variety of conditions, including (but not limited to) pH, temperature, enzymes, water, or other physiological conditions or compounds. Non-enteric dosage form

[0201] Non-enteric dosage forms can be administered to patients via various routes, including but not limited to subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial administration. Because their administration typically bypasses the patient's natural defenses against contaminants, non-enteric dosage forms are preferably sterile or capable of being sterilized prior to administration to the patient. Examples of non-enteric dosage forms include, but are not limited to, ready-to-use injectable solutions, ready-to-use dried products to be dissolved or suspended in pharmaceutically acceptable media for injection, ready-to-use injectable suspensions, and emulsions. In some embodiments, the bispecific antibody is in the form of a 40 mg / mL solution for administration to the patient via subcutaneous injection.

[0202] Suitable mediators that may be used to provide the non-enteric dosage forms provided herein include (but are not limited to): water for injection (USP); aqueous mediators such as (but not limited to) sodium chloride injection, Ringer's injection, glucose injection, glucose and sodium chloride injection, and lactated Ringer's injection; water-miscible mediators such as (but not limited to) ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous mediators such as (but not limited to) corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and methylparaben. Compounds that increase the solubility of one or more active ingredients disclosed herein may also be incorporated into the non-enteric dosage forms provided herein. Reagent test kit

[0203] In some embodiments, the active ingredients provided herein are not administered to patients simultaneously or via the same route of administration. Therefore, this document covers kits that, when used by a practicing physician, simplify the administration of an appropriate amount of the active ingredient to a patient. In some embodiments, the kits provided herein comprise a dosage form of compound A, AS, or AR, or an enantiomer or mixture of enantiomers thereof, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs. In some embodiments, the kits provided herein further comprise a bispecific antibody provided herein. In some embodiments, the kits provided herein comprise a dosage form of a bispecific antibody provided herein. In some embodiments, the kits provided herein further comprise compound A, AS, or AR, or an enantiomer or mixture of enantiomers thereof, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, cocrystals, cage compounds, or polymorphs. In some embodiments, the kits provided herein further comprise a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, drop bags, patches, and inhalers.

[0204] In some embodiments, the kits provided herein further comprise cells or blood for transplantation and a pharmaceutically acceptable mediator for administration of one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for non-enteral administration, the kit may comprise a sealed container suitable for the mediator, wherein the active ingredient is resolvable to form a particulate-free sterile solution suitable for non-enteral administration. Examples of pharmaceutically acceptable mediators include (but are not limited to): water for injection (USP); aqueous mediators such as (but not limited to) sodium chloride injection, Ringer's solution, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer's solution; water-miscible mediators such as (but not limited to) ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous mediators such as (but not limited to) corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and methylparaben. Example

[0205] The following non-limiting examples illustrate certain embodiments of the present invention. Example 1: Phase 1b open-label study of enoatumab in combination with ibelidomide in participants with relapsed / refractory multiple myeloma. A. Studying basic principles

[0206] This case study evaluates the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of enatumab (BCMA × CD3 bispecific antibody) and ibelidomine (cereblon E3 ligase modulator) in participants with relapsed / refractory multiple myeloma (RRMM). This study includes identifying a recommended phase 2 dose (RP2D) or a recommended expanded dose (RDE) approach (Part 1), which is further evaluated in a randomized dose optimization approach (Part 2). B. Goals, endpoints, and the measure being evaluated

[0207] Part 1: Dosage Escalation

[0208] Part 2: Randomized Dose Optimization C. Overall Design

[0209] This study is a phase 1b open-label prospective, multicenter trial evaluating the safety, efficacy, pharmacokinetic (PK), and PD of the combination of enoatumab and ibelidomide in participants with RRMM. Two clinical trial designs (C1 and C2) are described below. C1. Overall Design 1

[0210] like Figure 2As shown, the study consists of two parts: The dose escalation (Part 1) assesses the tolerability and safety of the combination of enoatumab and ibelidomine to select the recommended dose (combination RP2D) for further evaluation in Part 2. Randomized dose optimization (Part 2) further evaluated the safety and preliminary efficacy of the combination of enoatumab and ibelidomine under RP2D. C1-1. Dosage escalation design

[0211] The dose escalation design under C1 is shown in Figure 2 For dose escalation, dose level 1 (DL1) is assessed. If DL1 is deemed tolerable, dose level 2 (DL2) is then assessed. After determining that DL2 is tolerable, dose level 3 (DL3) is assessed. Two combined dose levels of enoatumab and ibelidomide are selected as RP2D to be further evaluated in Part 2 as dose level A (DL A) and dose level B (DL B).

[0212] Approximately 6 to 9 DLT-evaluable participants were treated at each dose level of the combination therapy. At least 6 DLT-evaluable participants were treated at each of the two selected combination dose levels, which were further evaluated in Part 2. The actual number of participants enrolled will depend on the number of dose levels evaluated and the number of participants treated at each dose level. It is estimated that approximately up to 27 DLT-evaluable participants will be enrolled and treated in the Part 1 dose escalation.

[0213] A staggered enrollment strategy was applied for dose escalation: when enrollment opened at a dose level, the first bound participant was administered and observed for 24 hours after C1D1 (starting the enoxaparin plus ibelidomine combination). If no safety issues were observed during the 24-hour period after C1D1, subsequent participants were enrolled at the same dose level and combination.

[0214] The target DLT rate was ≤ 25%, and dose escalation decisions were guided by the Bayesian Optimal Interval Design (BOIN) method (Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. Journal of the Royal Statistical Society: Series C: Applied Statistics. 2015:507-23; Yuan L, Gu ZY, Gao CJ. P53-mediated Regulatory Mechanism of Ran Transcription in Multiple Myeloma Cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2016;24(3):760-4). The isotonicity toxicity rate estimate from the BOIN method guided the determination of RP2D for enoxaparin plus ibelidomine. However, other available evidence, such as safety data beyond the DLT window, clinical activity, PK, and PD data, were also evaluated when deciding on escalation. The dose escalation decision and RP2D selection are determined in agreement between the investigator and the trial commissioner at a dose level review meeting (DLRM). C1-2. Study arm and duration: Treatment period

[0215] Participants received a combination of enoatumab and ibelidomine over a 28-day cycle (plus the initial 14-day initial dose cycle of enoatumab), as detailed below: ●Day 1 of Cycle 0: Enartumab subcutaneous (SC) 12 mg ●Day 4 of Cycle 0: Enartumab SC 32 mg ●Day 8 of Cycle 0: Enartumab SC 76 mg ●Cycles 1 through 6: Enatuzumab weekly (QW) SC 76 mg, plus ibelidomide at the specified oral (PO) dose (1.0 mg, 1.3 mg, or 1.6 mg daily [QD]) depending on the cohort assigned from day 1 to day 21 of each 28-day cycle. ● Cycles 7 through 12: Enatumab every 2 weeks (Q2W) SC 76 mg (if the participant has been treated for at least 6 months (6 cycles) and the disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months), plus ibelidomide at the specified oral (PO) dose (1.0 mg, 1.3 mg, or 1.6 mg daily [QD]) depending on the cohort assigned from day 1 to day 21 of each 28-day cycle. ●Starting cycle 13: Enatumab 76 mg subcutaneously (SC) every 4 weeks (Q4W) (if disease response shows at least a partial response (PR) or better and the response lasts for at least 2 months), plus ibelidomide at the PO-specified dose (1.0 mg or 1.3 mg or 1.6 mg QD) depending on the cohort assigned from day 1 to day 21 of each 28-day cycle. ● All participants received the study intervention until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The total study duration for each participant was at least 2 years, as all participants were followed up for at least 2 years. C1-3. Randomized dose optimization design

[0216] The dose optimization design under C1 is presented in Figure 2 After identifying the combination RP2D in the dose escalation phase (Part 1), the dose optimization phase began. Approximately 60 participants were randomly assigned to DLA and DLA B in a 1:1 ratio, stratified according to the number of previous treatment lines (1 vs. >1). C1-4. Dosage adjustment:

[0217] Dosage adjustments may be made due to toxicity and efficacy. Table 4: Dosage adjustment for ibelidomine-related toxicity at C1 C2. Overall Design 2

[0218] like Figure 4 As shown, the design also consists of two parts: The dose escalation (Part 1) assesses the tolerability and safety of the combination of enoatumab and ibelidomine to select the recommended dose (combination RDE) for further evaluation in Part 2. Randomized dose optimization (Part 2) further evaluated the safety and preliminary efficacy of the combination of enoatumab and ibelidomine under randomized treatment (RDE). C2-1. Dosage escalation design

[0219] The dose escalation design under C2 is presented in Figure 4For dose escalation, dose level 1 (DL1) will be evaluated. If DL1 is considered tolerable, dose level 2 (DL 2) will then be evaluated. If DL1 (enatumab weekly [QW]) is intolerable, dose level-1 (DL -1; enatumab every 2 weeks [Q2W]) will be evaluated. If DL -1 is considered tolerable, DL2 will then be evaluated. If DL -1 is intolerable, dose level-2 (DL -2) will then be evaluated. Two dose levels of the enatumab and ibelidomine combination will be selected as the recommended expanded dose (RDE) in Part 2 (Dose Optimization). Figure 4 Further evaluation will be conducted at dose level A (DLA) and dose level B (DLB).

[0220] Approximately 6 to 9 DLT-evaluable participants were treated at each dose level of the combination therapy. At least 6 DLT-evaluable participants were treated at each of the two selected combination dose levels, which were further evaluated in Part 2. The actual number of participants enrolled will depend on the number of dose levels evaluated and the number of participants treated at each dose level. It is estimated that approximately up to 27 DLT-evaluable participants will be enrolled and treated in the Part 1 dose escalation.

[0221] A staggered enrollment strategy was applied for dose escalation in DL1 and DL2: when enrollment opened at a dose level, the first bound participant was administered and observed for 24 hours after C1D1 (starting the enoatumab plus ibelidomine combination). If no safety issues were observed during the 24-hour period of C1D1, subsequent participants were enrolled at the same dose level and combination. Depending on the safety observed at DL1 and DL2, a staggered enrollment strategy could be used for DL-1 and DL-2 (lower enoatumab and / or lower ibelidomine doses).

[0222] The target DLT rate is ≤ 25%, and dose escalation decisions are guided by the Best-in-Interval (BOIN) design method. The isotonicity toxicity rate estimate using the BOIN method guides the determination of the response factor (RDE) for enoatumab plus ibelidomine. However, other available evidence, such as safety data beyond the DLT window, clinical activity, PK, and PD data, are also evaluated when deciding on escalation. Dose escalation decisions and RDE selections are determined in agreement between the investigator and the trial commissioner at a dose level review meeting (DLRM). C2-2. Study arm and duration

[0223] Treatment period: Participants will receive a combination of enoatumab and ibelidomide over a 28-day cycle (plus the initial 14-day initial dose cycle of enoatumab).

[0224] The dosage levels in Part 1 are detailed below: Initial (14 days, all dose levels): ●Day 1 of Cycle 0: Enartumab subcutaneous (SC) 12 mg ●Day 4 of Cycle 0: Enartumab SC 32 mg ●Day 8 of Cycle 0: Enartumab SC 76 mg Dose level 1 (28-day cycle, DL1): ●Cycle 1 through 3: Enatuzumab weekly (QW) SC 76 mg, plus daily (QD) oral (PO) ibelidomide 1 mg for each 28-day cycle (D1-21). ●Cycles 4 through 6: Enatuzumab SC 76 mg Q2W, plus ibelidomide PO 1 mg QD for each 28-day cycle (D1-21). ●Start of cycle 7: Enatuzumab SC 76 mg every 4 weeks (Q4W), plus ibelidomine PO 1 mg QD for each 28-day cycle (D1-21). Dose level 2 (28-day cycle, DL2): ●Cycle 1 to Cycle 3: Enatuzumab SC 76 mg Q2W, plus ibelidomide PO 1.3 mg QD for each 28-day cycle (D1-21). ●Start of cycle 4: Enatuzumab SC 76 mg Q4W, plus ibelidomide PO 1.3 mg QD for each 28-day cycle from day 1 to day 21. Dose level-1 (28-day cycle, DL-1): ●Cycle 1 to Cycle 3: Enatuzumab SC 76 mg Q2W, plus ibelidomide PO 1 mg QD for each 28-day cycle (D1-21). ●Start of cycle 4: Enatuzumab SC 76 mg Q4W, plus ibelidomide PO1 mg QD for each 28-day cycle (D1-21). Dose level-2 (28-day cycle, DL-2): ●Cycle 1 to Cycle 3: Enatuzumab SC 76 mg Q2W, plus ibelidomide PO 0.75 mg QD for each 28-day cycle (D1-21). ●Start of cycle 4: Enatuzumab SC 76 mg Q4W, plus ibelidomide PO 0.75 mg QD for each 28-day cycle (D1-21).

[0225] Based on disease progression, toxicity, and other factors, participants may receive one or more of the following: initial, dose level 1, dose level 2, dose level-1, or dose level-2, or any combination thereof over periods. An exemplary dosing schedule is shown below. Figure 5 and Figure 6middle. C2-2. Randomized Dose Optimization

[0226] The dose optimization design under C2 is presented in Figure 4 After identifying the combination RDE in the dose escalation phase (Part 1), the dose optimization phase began. Approximately 60 participants were randomly assigned to DLA and DLA B in a 1:1 ratio, stratified according to the number of previous treatment lines (1 vs. >1). C2-4. Dosage adjustment:

[0227] Dosage adjustments may be made due to toxicity and efficacy. Table 5: Dosage reduction for ibelidomine-related toxicity at C2 D. Number of participants It is estimated that approximately 27 DLT-evaluable participants will be enrolled and treated in Part 1 and approximately 60 participants will be randomized in Part 2. E. Research Group Key Inclusion Criteria

[0228] Participants must meet the following key inclusion criteria to be eligible to enroll in the study: ● Participants must be ≥ 18 years of age at the time of informed consent. Female participants are eligible to participate if they are not pregnant or breastfeeding; they must follow the manufacturer's ibeduam pregnancy prevention regimen. ● A previous MM diagnosis as defined by the IMWG criteria, if defined by at least one of the following: ○ Serum M-protein ≥ 0.5 g / dL as measured by serum protein electrophoresis (SPEP) ○ Urinary M-protein excretion ≥ 200 mg / 24 hours as measured by urinary protein electrophoresis (UPEP) ○ Serum free light chain immunoglobulin (FLC) ≥ 10 mg / dL (≥ 100 mg / L) and abnormal serum free light chain ratio of immunoglobulin κ to λ (< 0.26 or > 1.65). ● Part 1: Participants who have received at least two and no more than four prior lines of treatment for MM (including at least one IMiD (lenalidomide or pomalidomide) and at least one proteasome inhibitor (PI)). ○ All participants in Part 1 must have received prior treatment with at least two consecutive cycles of a regimen containing lenalidomide or pomalidomide and at least two consecutive cycles of a PI or a PI-containing regimen. ● Part 2: Participants who have received at least one but no more than three prior lines of treatment for MM (including at least one IMiD (lenalidomide or pomalidomide) and at least one PI). ○ All participants in Part 2 must have received prior treatment with at least two consecutive cycles of a regimen containing lenalidomide or pomalidomide and at least two consecutive cycles of a PI or a PI-containing regimen. ●According to the IMWG guidelines, the last anti-MM regimen was either relapsed or refractory. Primary refractory MM (defined as a participant who has not achieved at least MR with any treatment during the course of the disease) does not qualify. ●The Eastern Cooperative Oncology Group (ECOG) performance status is 0 to 1. ●Sufficient liver, kidney, and bone marrow function. Exclusion criteria

[0229] Participants with any of the following characteristics / conditions were excluded: ● Plasma cell leukemia, stasis MM, Waldenström's macroglobulinemia, amyloidosis, polyneuropathy, visceral enlargement, endocrine disorders, protein and skin changes in myeloma (POEMS syndrome), clinical signs of known central nervous system (CNS) involvement or meningeal involvement in myeloma, active graft-versus-host disease (GVHD), and a history of stem cell transplantation within 12 weeks prior to enrollment. ●Improved cardiovascular function or clinically significant cardiovascular disease within 6 months prior to registration. ● A history of persistent grade ≥ 2 peripheral sensory or motor neuropathy, Guillain-Barré syndrome (GBS) or a variant of GBS, or any grade ≥ 3 peripheral motor polyneuropathy. ● Participants with active hepatitis B virus (HBV), hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus 2 (COVID-19 / SARS-CoV-2), HIV, or any active, uncontrolled bacterial, fungal, or viral infection. The active infection must have subsided at least 21 days prior to registration. Treatment with a systemic anti-infective agent must have been completed at least 28 days prior to registration. Prophylactic use of systemic anti-infective agents is permitted. ● Any other active malignant tumor within the 3 years prior to registration, except for completely treated basal cell or squamous cell skin cancer, or carcinoma in situ or stage 0 / 1 malignant tumors, among which the investigators have the lowest risk of recurrence. ● Gastrointestinal diseases that can significantly alter the absorption of ibelidomine. ●Previous treatment with B-cell maturation antigen (BCMA) or differentiation cluster 3 (CD3) repositioning therapy. ●Pre-treatment with ibelidomide (CC-220) or mezigdomide. ● Strong inhibitors or inducers of CYP3A4 / 5, including grapefruit, St. John's Wort, or related products, within 2 weeks prior to administration and during the study. ● Participants who are unable or unwilling to participate in the thromboembolic prevention required for the study. F. Statistical methods:

[0230] Part 1: The primary measure: the DLT rate based on DLT-evaluable participant data during the DLT observation period.

[0231] Part 2 is primarily estimated: the AE rate is estimated based on SAS data during the treatment period.

[0232] There are no secondary estimates in this study.

[0233] An interim safety assessment was conducted for this study. Individual assessments were performed for dose escalation in Part 1 and for each dose level in Part 2.

[0234] The examples provided above are intended to show those skilled in the art how to prepare and use the claimed embodiments, and are not intended to limit the scope of the disclosure herein. Modifications that are obvious to those skilled in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications referenced in this specification are incorporated herein by reference as if each such publication, patent, or patent application specifically and individually indicated to be incorporated herein by reference.

Claims

1. A method for treating or controlling multiple myeloma, comprising administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of a compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety to B cell maturation antigen (BCMA) and a second binding moiety to cluster of differentiation 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

2. The method of claim 1, wherein the first binding portion to BCMA comprises: (a) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 3, VH CDR2 containing the amino acid sequence of SEQ ID NO: 4, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 5; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 6, VL CDR2 containing the amino acid sequence of SEQ ID NO: 7, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (b) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 9, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (c) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 14, VH CDR2 containing the amino acid sequence of SEQ ID NO: 15, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (d) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (e) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 17, VH CDR2 containing the amino acid sequence of SEQ ID NO: 18, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 19; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 20, VL CDR2 containing the amino acid sequence of SEQ ID NO: 21, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 22; or (f) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 23, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO:

8.

3. The method of claim 1 or 2, wherein the second binding portion to CD3 comprises: (a) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 26, VH CDR2 containing the amino acid sequence of SEQ ID NO: 27, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 28; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 29, VL CDR2 containing the amino acid sequence of SEQ ID NO: 30, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (b) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 32, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (c) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 37, VH CDR2 containing the amino acid sequence of SEQ ID NO: 38, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (d) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (e) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 40, VH CDR2 containing the amino acid sequence of SEQ ID NO: 41, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 42; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 43, VL CDR2 containing the amino acid sequence of SEQ ID NO: 44, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 45; or (f) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 46, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO:

31.

4. The method according to any one of claims 1 to 3, wherein (a) The first binding portion to BCMA comprises a VH region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1 and a VL region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2, and (b) The second binding portion to CD3 comprises a VH region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24 and a VL region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

25.

5. The method according to any one of claims 1 to 4, wherein (a) The first binding portion to the BCMA comprises a heavy chain and a light chain; and (b) The second binding portion of the CD3 comprises a heavy chain and a light chain.

6. The method of claim 5, wherein (a) The heavy chain bound to the first binding portion of BCMA contains at least 95% amino acid sequence identical to the amino acid sequence of SEQ ID NO: 47, and the light chain bound to the first binding portion of BCMA contains at least 95% amino acid sequence identical to the amino acid sequence of SEQ ID NO:

48. (b) The heavy chain of the second binding portion bound to CD3 contains an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49, and the light chain of the second binding portion bound to CD3 contains an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

50.

7. The method of claim 5 or 6, wherein (a) The heavy chain bound to the first binding site of BCMA contains the amino acid sequence of SEQ ID NO: 47, and the light chain bound to the first binding site of BCMA contains the amino acid sequence of SEQ ID NO:

48. (b) The heavy chain of the second binding portion to CD3 contains the amino acid sequence of SEQ ID NO: 49, and the light chain of the second binding portion to CD3 contains the amino acid sequence of SEQ ID NO:

50.

8. The method of any one of claims 1 to 7, wherein the bispecific antibody is an IgG2κ antibody.

9. The method according to any one of claims 1 to 8, wherein the compound is compound AS. Compound AS Or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, cage compound, or polymorph thereof.

10. The method of claim 9, wherein the compound is the hydrochloride salt of compound AS.

11. The method of any one of claims 1 to 10, wherein the multiple myeloma is relapsed, refractory, or drug-resistant.

12. The method of claim 11, wherein the multiple myeloma is relapsed or refractory.

13. The method of claim 12, wherein the multiple myeloma is relapsed or refractory to at least two prior therapies, wherein the prior therapies are selected from lenalidomide, pomalidomide, and proteasome inhibitors.

14. The method of any one of claims 1 to 10, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

15. The method of any one of claims 1 to 14, wherein the compound is administered orally.

16. The method of any one of claims 1 to 15, wherein the compound is administered in an amount of about 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg or 1.6 mg per day.

17. The method of any one of claims 1 to 16, wherein the compound is administered once daily for 21 days, followed by a 7-day withdrawal period.

18. The method of any one of claims 1 to 17, wherein the bispecific antibody is administered subcutaneously.

19. The method of any one of claims 1 to 18, wherein the bispecific antibody is administered in an amount of about 12 mg, about 32 mg, or about 76 mg.

20. The method of any one of claims 1 to 19, wherein the bispecific antibody is administered once a week, once every two weeks, or once every four weeks.

21. The method of any one of claims 1 to 20, wherein the bispecific antibody is administered on days 1, 4, and 8 of a 14-day priming dose cycle prior to administration of the compound, and subsequently administered weekly, every two weeks, or every four weeks in a 28-day cycle, while the compound is administered daily from day 1 to day 21 of the 28-day cycle.

22. The method of claim 21, wherein during the initial 14-day dosing cycle prior to administration of the compound, the bispecific antibody is administered at a dose of 12 mg on day 1, at a dose of 32 mg on day 4, and at a dose of 76 mg on day 8.

23. The method of claim 21 or 22, wherein after the initial dosing cycle, the bispecific antibody is administered weekly, every two weeks, or every four weeks at a dose of 76 mg during a 28-day cycle, while the compound is administered daily at a dose of 1.0 mg, 1.3 mg, or 1.6 mg from day 1 to day 21 of the 28-day cycle.

24. The method of claim 21 or 22, wherein after the initial dosing cycle, the bispecific antibody is administered weekly, every two weeks, or every four weeks at a dose of 76 mg during a 28-day cycle, while the compound is administered daily at a dose of 0.75 mg from day 1 to day 21 of the 28-day cycle.

25. The method of any one of claims 21 to 24, wherein (a) Following the initial dose cycle and the subsequent six 28-day cycles, if the patient has been treated for at least 6 months and the disease response shows at least a partial or better response lasting for at least 2 months, the bispecific antibody shall be administered at a dose of 76 mg every two weeks; and / or (b) If, after the initial dose cycle and the subsequent twelve 28-day cycles, the disease response shows at least a partial response or better and the response lasts for at least 2 months, the bispecific antibody shall be administered at a dose of 76 mg every four weeks.

26. The method of any one of claims 21 to 23, wherein (a) Following this initial dosing cycle and the subsequent three 28-day cycles, the bispecific antibody was administered at a dose of 76 mg every two weeks; and / or (b) After the initial dose cycle and the subsequent six 28-day cycles, the bispecific antibody was administered at a dose of 76 mg every four weeks.

27. The method of claim 26, wherein the compound is administered once daily at a dose of 1.0 mg on days 1 through 21 of each 28-day cycle.

28. The method of any one of claims 21 to 24, wherein (a) Following the initial dose cycle and subsequent seven or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every two weeks for three 28-day cycles; and / or (b) After the initial dose cycle and subsequent ten or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every four weeks.

29. The method of any one of claims 21 to 24, wherein (a) Following this initial dosing cycle, the bispecific antibody shall be administered at a dose of 76 mg every two weeks; and / or (b) After the initial dose cycle and the subsequent three 28-day cycles, the bispecific antibody was administered at a dose of 76 mg every four weeks.

30. The method of claim 28 or 29, wherein the compound is administered once daily at an amount of 0.75 mg, 1.0 mg, or 1.3 mg from day 1 to day 21 of each 28-day cycle.

31. A compound in a method for treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient suffering from multiple myeloma: (a) A therapeutically effective amount of the compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of a bispecific antibody comprising a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

32. A bispecific antibody in a method for treating multiple myeloma, wherein the method comprises administering a combination of the following to a patient with multiple myeloma: (a) A therapeutically effective amount of the bispecific antibody, wherein the bispecific antibody comprises a first binding portion binding to B-cell maturation antigen (BCMA) and a second binding portion binding to differentiation cluster 3 (CD3), wherein the first binding portion binding to BCMA comprises (i) a VH region comprising VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; VHCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region comprising VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22. CDR3; and wherein the second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45; and (b) A therapeutically effective amount of the compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds or polymorphs.

33. A compound and a bispecific antibody in a method for treating multiple myeloma, wherein the method comprises administering the following combination to a patient with multiple myeloma: (a) A therapeutically effective amount of the compound, wherein the compound is compound A. Compound A Or its enantiomers or mixtures of enantiomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, eutectics, cage compounds, or polymorphs; and (b) A therapeutically effective amount of the bispecific antibody, which comprises a first binding moiety binding to B-cell maturation antigen (BCMA) and a second binding moiety binding to differentiation cluster 3 (CD3). The first binding portion to BCMA comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 9, 14, 16 and 17; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, 10, 15, 18 and 23; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 11 and 19; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12 and 20; a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, 13 and 21; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 22; and The second binding portion to CD3 comprises (i) a VH region having a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 26, 32, 37, 39 and 40; a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 27, 33, 38, 41 and 46; and a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 28, 34 and 42; and (ii) a VL region having a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 29, 35 and 43; a VLCDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 30, 36 and 44; and a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 31 and 45.

34. The compound used as claimed in claim 31, the bispecific antibody used as claimed in claim 32, or the compound and bispecific antibody used as claimed in claim 33, wherein the first binding portion to BCMA comprises: (a) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 3, VH CDR2 containing the amino acid sequence of SEQ ID NO: 4, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 5; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 6, VL CDR2 containing the amino acid sequence of SEQ ID NO: 7, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (b) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 9, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (c) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 14, VH CDR2 containing the amino acid sequence of SEQ ID NO: 15, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (d) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 10, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 8; (e) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 17, VH CDR2 containing the amino acid sequence of SEQ ID NO: 18, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 19; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 20, VL CDR2 containing the amino acid sequence of SEQ ID NO: 21, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 22; or (f) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 16, VH CDR2 containing the amino acid sequence of SEQ ID NO: 23, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 11; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 12, VL CDR2 containing the amino acid sequence of SEQ ID NO: 13, and VL CDR3 containing the amino acid sequence of SEQ ID NO:

8.

35. The compound used as described in claim 31 or 34, the bispecific antibody used as described in claim 32 or 34, or the compound and bispecific antibody used as described in claim 33 or 34, wherein the second binding portion to CD3 comprises: (a) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 26, VH CDR2 containing the amino acid sequence of SEQ ID NO: 27, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 28; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 29, VL CDR2 containing the amino acid sequence of SEQ ID NO: 30, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (b) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 32, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (c) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 37, VH CDR2 containing the amino acid sequence of SEQ ID NO: 38, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (d) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 33, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 31; (e) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 40, VH CDR2 containing the amino acid sequence of SEQ ID NO: 41, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 42; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 43, VL CDR2 containing the amino acid sequence of SEQ ID NO: 44, and VL CDR3 containing the amino acid sequence of SEQ ID NO: 45; or (f) A VH region comprising VH CDR1 containing the amino acid sequence of SEQ ID NO: 39, VH CDR2 containing the amino acid sequence of SEQ ID NO: 46, and VH CDR3 containing the amino acid sequence of SEQ ID NO: 34; and a VL region comprising VL CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL CDR2 containing the amino acid sequence of SEQ ID NO: 36, and VL CDR3 containing the amino acid sequence of SEQ ID NO:

31.

36. The compound used as described in any one of claims 31 and 34 to 35, the bispecific antibody used as described in any one of claims 32 and 34 to 35, or the compound and bispecific antibody used as described in any one of claims 33 to 35, wherein... (a) The first binding portion to BCMA comprises a VH region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1 and a VL region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2, and (b) The second binding portion to CD3 comprises a VH region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 24 and a VL region containing an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

25.

37. The compound used as described in any one of claims 31 and 34 to 36, the bispecific antibody used as described in any one of claims 32 and 34 to 36, or the compound and bispecific antibody used as described in any one of claims 33 to 36, wherein... (a) The first binding portion to the BCMA comprises a heavy chain and a light chain; and (b) The second binding portion of the CD3 comprises a heavy chain and a light chain.

38. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 37, wherein... (a) The heavy chain bound to the first binding portion of BCMA contains at least 95% amino acid sequence identical to the amino acid sequence of SEQ ID NO: 47, and the light chain bound to the first binding portion of BCMA contains at least 95% amino acid sequence identical to the amino acid sequence of SEQ ID NO:

48. (b) The heavy chain of the second binding portion bound to CD3 contains an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49, and the light chain of the second binding portion bound to CD3 contains an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

50.

39. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 37 or 38, wherein... (a) The heavy chain bound to the first binding site of BCMA contains the amino acid sequence of SEQ ID NO: 47, and the light chain bound to the first binding site of BCMA contains the amino acid sequence of SEQ ID NO:

48. (b) The heavy chain of the second binding portion to CD3 contains the amino acid sequence of SEQ ID NO: 49, and the light chain of the second binding portion to CD3 contains the amino acid sequence of SEQ ID NO:

50.

40. The compound used as described in any one of claims 31 and 34 to 39, the bispecific antibody used as described in any one of claims 32 and 34 to 39, or the compound and bispecific antibody used as described in any one of claims 33 to 39, wherein the bispecific antibody is an IgG2κ antibody.

41. The compound used as described in any one of claims 31 and 34 to 40, the bispecific antibody used as described in any one of claims 32 and 34 to 40, or the compound and bispecific antibody used as described in any one of claims 33 to 40, wherein the compound is compound AS. Compound AS Or a pharmaceutically acceptable salt, solvate, hydrate, eutectic, cage compound, or polymorph thereof.

42. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 41, wherein the compound is the hydrochloride salt of compound AS.

43. The compound used as described in any one of claims 31 and 34 to 42, the bispecific antibody used as described in any one of claims 32 and 34 to 42, or the compound and bispecific antibody used as described in any one of claims 33 to 42, wherein the multiple myeloma is relapsed, refractory, or drug-resistant.

44. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 43, wherein the multiple myeloma is relapsed or refractory.

45. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 44, wherein the multiple myeloma is relapsed or refractory to at least two prior therapies, wherein such prior therapies are selected from lenalidomide, pomalidomide, and proteasome inhibitors.

46. ​​The compound used as described in any one of claims 31 and 34 to 42, the bispecific antibody used as described in any one of claims 32 and 34 to 42, or the compound and bispecific antibody used as described in any one of claims 33 to 42, wherein the multiple myeloma is a newly diagnosed multiple myeloma.

47. The compound used as described in any one of claims 31 and 34 to 46, the bispecific antibody used as described in any one of claims 32 and 34 to 46, or the compound and bispecific antibody used as described in any one of claims 33 to 46, wherein the compound is administered orally.

48. The compound used as described in any one of claims 31 and 34 to 47, the bispecific antibody used as described in any one of claims 32 and 34 to 47, or the compound and bispecific antibody used as described in any one of claims 33 to 47, wherein the compound is administered in an amount of about 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, or 1.6 mg per day.

49. The compound used as described in any one of claims 31 and 34 to 48, the bispecific antibody used as described in any one of claims 32 and 34 to 48, or the compound and bispecific antibody used as described in any one of claims 33 to 48, wherein the compound is administered once daily for 21 days, followed by a 7-day break.

50. The compound used as described in any one of claims 31 and 34 to 49, the bispecific antibody used as described in any one of claims 32 and 34 to 49, or the compound and bispecific antibody used as described in any one of claims 33 to 49, wherein the bispecific antibody is administered subcutaneously.

51. The compound used as described in any one of claims 31 and 34 to 50, the bispecific antibody used as described in any one of claims 32 and 34 to 50, or the compound and bispecific antibody used as described in any one of claims 33 to 50, wherein the bispecific antibody is administered in an amount of about 12 mg, about 32 mg, or about 76 mg.

52. The compound used as described in any one of claims 31 and 34 to 51, the bispecific antibody used as described in any one of claims 32 and 34 to 51, or the compound and bispecific antibody used as described in any one of claims 33 to 51, wherein the bispecific antibody is administered once a week, once every two weeks, or once every four weeks.

53. The compound used as described in any one of claims 31 and 34 to 52, the bispecific antibody used as described in any one of claims 32 and 34 to 52, or the compound and bispecific antibody used as described in any one of claims 33 to 52, wherein the bispecific antibody is administered on days 1, 4, and 8 of an initial 14-day dosing cycle prior to administration of the compound, and subsequently administered weekly, every two weeks, or every four weeks in a 28-day cycle, while the compound is administered daily from day 1 to day 21 of the 28-day cycle.

54. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 53, wherein during the initial 14-day dosing cycle prior to administration of the compound, the bispecific antibody is administered at a dose of 12 mg on day 1, 32 mg on day 4, and 76 mg on day 8.

55. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 53 or 54, wherein after the initial dosing cycle, the bispecific antibody is administered weekly, every two weeks, or every four weeks at a dose of 76 mg over a 28-day cycle, while the compound is administered daily at a dose of 1.0 mg, 1.3 mg, or 1.6 mg from day 1 to day 21 of the 28-day cycle.

56. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 53 or 54, wherein after the initial dosing cycle, the bispecific antibody is administered weekly, every two weeks, or every four weeks at a dose of 76 mg during a 28-day cycle, while the compound is administered daily at a dose of 0.75 mg from day 1 to day 21 of the 28-day cycle.

57. The compound, bispecific antibody, or compound and bispecific antibody used as described in any one of claims 53 to 56, wherein... (a) Following the initial dose cycle and the subsequent six 28-day cycles, if the patient has been treated for at least 6 months and the disease response shows at least a partial or better response lasting for at least 2 months, the bispecific antibody shall be administered at a dose of 76 mg every two weeks; and / or (b) If, after the initial dose cycle and the subsequent twelve 28-day cycles, the disease response shows at least a partial response or better and the response lasts for at least 2 months, the bispecific antibody shall be administered at a dose of 76 mg every four weeks.

58. The compound, bispecific antibody, or compound and bispecific antibody used as described in any one of claims 53 to 55, wherein... (a) Following this initial dosing cycle and the subsequent three 28-day cycles, the bispecific antibody was administered at a dose of 76 mg every two weeks; and / or (b) After the initial dose cycle and the subsequent six 28-day cycles, the bispecific antibody was administered at a dose of 76 mg every four weeks.

59. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 58, wherein the compound is administered once daily at a dose of 1.0 mg from day 1 to day 21 of each 28-day cycle.

60. The compound, bispecific antibody, or compound and bispecific antibody used as described in any one of claims 53 to 56, wherein... (a) Following the initial dose cycle and subsequent seven or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every two weeks for three 28-day cycles; and / or (b) After the initial dose cycle and subsequent ten or more 28-day cycles, the bispecific antibody is administered at a dose of 76 mg every four weeks.

61. The compound, bispecific antibody, or compound and bispecific antibody used as described in any one of claims 53 to 56, wherein... (a) Following this initial dosing cycle, the bispecific antibody shall be administered at a dose of 76 mg every two weeks; and / or (b) After the initial dose cycle and the subsequent three 28-day cycles, the bispecific antibody was administered at a dose of 76 mg every four weeks.

62. The compound, bispecific antibody, or compound and bispecific antibody used as described in claim 60 or 61, wherein the compound is administered once daily at an amount of 0.75 mg, 1.0 mg, or 1.3 mg from day 1 to day 21 of each 28-day cycle.

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