Anti-proliferative compounds for combined use and bispecific antibodies against BCMA and CD3

Abstract

This text relates to anti-proliferative compounds for combined use and bispecific antibodies targeting BCMA and CD3. Provided herein are methods of treating, preventing, or controlling multiple myeloma using 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile or an enantiomer thereof, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3e (CD3) provided herein.

Description

[0001] This application is a divisional application of a Chinese patent application for invention titled "Anti-proliferative Compounds for Combined Use and Bispecific Antibodies Against BCMA and CD3", with application number 201980046500.X, filed on May 22, 2019.

[0002] This application claims priority to U.S. Provisional Application No. 62 / 675,639, filed on May 23, 2018, the entire content of which is incorporated herein by reference.

[0003] This application contains a sequence listing, which is submitted electronically under the file name 10624-451-228_SeqListing.txt, created on May 21, 2019, and has a size of 70,646 bytes. The sequence listing is incorporated herein by reference in its entirety. 1. Technical Field

[0004] Provided herein are methods for treating, preventing, or controlling multiple myeloma using a combination of 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile or an enantiomer, mixture of enantiomers, tautomer, or pharmaceutically acceptable salt thereof with a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3). 2. Background Art

[0005] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, the uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications. Although the exact cause of multiple myeloma is unknown, multiple myeloma is the second most common hematological malignancy. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M protein and other immunoglobulins (antibodies), albumin, and β-2-microglobulin, except in some patients (estimated to be 1% to 5%) in whom the myeloma cells do not secrete these proteins (referred to as non-secretory myeloma). The M protein (short for monoclonal protein, also called paraprotein) is a particularly abnormal protein produced by myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma, except those with non-secretory myeloma or those in whom the myeloma cells produce immunoglobulin light and heavy chains.

[0006] Skeletal symptoms, including bone pain, are the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast-stimulating factors (including IL-1, IL-6, and TNF), which cause calcium to leach from the bones, resulting in lytic lesions; hypercalcemia is another symptom. Osteoclast-stimulating factors (also known as cytokines) can prevent myeloma cell apoptosis or death. 50% of patients have radiologically detectable myeloma-related bone lesions at diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infection, and renal insufficiency.

[0007] Current multiple myeloma therapies can involve one or more of surgery, stem cell transplantation, chemotherapy, immunotherapy, and / or radiotherapy to eradicate multiple myeloma cells in patients. All existing treatment methods have significant drawbacks for patients.

[0008] In the past decade, novel therapeutic agents, particularly immunomodulatory drugs such as lenalidomide and pomalidomide, have significantly improved the response rate and extended the progression-free survival (PFS) and overall survival (OS) of multiple myeloma patients. However, there is a persistent level of residual disease in many multiple myeloma patients, which is below the sensitivity of bone marrow (BM) morphology, immunofixation protein electrophoresis, and light chain quantification assays, even after these patients achieve a complete response (CR), and will ultimately lead to disease recurrence. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and is being considered as an alternative trial endpoint to improve the identification of effective treatments, especially for first-line trials, which currently require 5 to 10 years of follow-up to identify survival differences. Therefore, monitoring minimal residual disease (MRD) in multiple myeloma patients can provide prognostic value for predicting PFS and OS and for making treatment decisions. Detection of minimal residual disease (MRD) in myeloma can be performed after treatment using a 0.01% threshold (10 -4 ), i.e., myeloma cells that account for 10 -4 cells or fewer in total bone marrow mononuclear cells are considered MRD negative, and those with 10 -4 cells or more are MRD positive. The 10 -4 MRD threshold was initially based on technical capabilities, but quantitative MRD detection is now achievable by flow cytometry at 10 -5 and by high-throughput sequencing at 10 -6。(Rawstron et al., Blood 2015; 125(12):1932-1935). Methods for measuring MRD include DNA sequencing of VDJ, polymerase chain reaction (PCR) (including allele-specific PCR, ASO PCR), and multi-parameter flow cytometry (MPF). For example, MRD assays based on clonotype profiling are also described in U.S. Patent No. 8,628,927 to Faham et al., which is incorporated herein by reference.

[0009] There is an urgent need for safe and effective compounds and methods for the treatment, prevention, and control of multiple myeloma, including for patients newly diagnosed with multiple myeloma or refractory to standard treatment, while reducing or avoiding the toxicity and / or side effects associated with conventional therapies.

[0010] The citation or identification of any reference in Section 2 of this application should not be construed as an admission that such reference is prior art to this application.

[0011] In general, the technical teachings of one embodiment provided herein can be combined with the technical teachings disclosed in any other embodiment provided herein. 3. Summary of the Invention

[0012] Provided herein are methods for treating, preventing, or controlling multiple myeloma using a combination of 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile or an enantiomer, mixture of enantiomers, tautomer, or pharmaceutically acceptable salt thereof with a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3).

[0013] In one such embodiment, the compound used in the compositions and methods provided herein is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 1):

[0014]

[0015] or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof.

[0016] In another embodiment, the compound used in the compositions and methods provided herein is (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 2):

[0017]

[0018] or a tautomer, isotopologue or pharmaceutically acceptable salt thereof.

[0019] In another embodiment, the compound for use in the compositions and methods provided herein is (R)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 3):

[0020]

[0021] or a tautomer, isotopologue or pharmaceutically acceptable salt thereof.

[0022] In one embodiment, the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0023] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0024] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0025] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0026] Also provided are pharmaceutical compositions for use in the methods described herein, which are formulated for administration by a suitable route and manner, and which contain an effective concentration of a compound provided herein, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and optionally comprise at least one pharmaceutical carrier. Also provided are pharmaceutical compositions for use in the methods described herein, which are formulated for administration by a suitable route and manner, and which contain an effective concentration of an antibody provided herein, such as a bispecific antibody, which bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and is characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0027] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0028] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0029] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0030] In one embodiment, the pharmaceutical composition delivers an amount effective for treating multiple myeloma. In one embodiment, the pharmaceutical composition delivers an amount effective for preventing multiple myeloma. In one embodiment, the pharmaceutical composition delivers an amount effective for ameliorating multiple myeloma.

[0031] Also provided herein is a combination therapy that uses a compound or composition provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) in combination with another therapy (such as another agent having activity against multiple myeloma or its symptoms). Examples of therapies within the scope of the methods include, but are not limited to, surgery, chemotherapy, radiotherapy, biotherapy, stem cell transplantation, cell therapy, and combinations thereof.

[0032] The compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, can be administered simultaneously with each other and with one or more of the aforementioned therapies, before or after each other and with one or more of the aforementioned therapies. Also provided are pharmaceutical compositions containing the compounds provided herein and one or more of the aforementioned therapies.

[0033] In practicing the method, an effective amount of the compound or a composition containing the compound at a therapeutically effective concentration is administered to an individual exhibiting symptoms of multiple myeloma to be treated. The amount can be effective to ameliorate or eliminate one or more symptoms of multiple myeloma.

[0034] Further provided is a pharmaceutical pack or kit comprising one or more containers filled with one or more ingredients of the pharmaceutical composition. Optionally, associated with such one or more containers can be a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of drugs or biological products, which notice reflects approval by the agency of manufacture, use, or sale for human administration. The pack or kit can be labeled with information about the mode of administration, the order of drug administration (e.g., separately, sequentially, or simultaneously), etc.

[0035] These and other aspects of the subject matter described herein will become apparent after reference to the following detailed description. 4. Detailed Description

[0036] A. Definitions

[0037] 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 to which this application belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. Unless otherwise indicated, in cases where there are multiple definitions for a term herein, the definitions in this section shall prevail.

[0038] The use of the word "a / an" in the claims and / or the specification, when used in conjunction with the term "comprising", can mean "one", but it is also consistent with the meaning of "one or more", "at least one", and "one or more than one".

[0039] 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 as mentioned, but not precluding 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". Thus, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide a more specific embodiment of the invention.

[0040] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components that make it up. In another embodiment, the term "consisting of" excludes from any subsequently recited scope any other features or components, except those that are not essential for the technical effect to be achieved.

[0041] As used herein, the term "or" shall be interpreted as an inclusive "or", meaning either or any combination. Thus, "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 acts are mutually exclusive in some way.

[0042] “IC 50 ” refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximum response (such as receptor binding, receptor activity, cell growth or proliferation) as measured by any one of the in vitro or cell-based assays described herein.

[0043] Pharmaceutically acceptable salts include, but are not limited to, amine salts such as, but not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts such as, but not limited to, lithium, potassium and sodium, alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; transition metal salts such as, but not limited to, zinc; and other metal salts such as, but not limited to, sodium hydrogen phosphate and disodium phosphate; and also include, but are not limited to, salts of inorganic acids such as, but not limited to, hydrochloride and sulfate; and salts of organic acids such as, but not limited to, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, fumarate and organic sulfonates.

[0044] Unless specifically stated otherwise, in cases where a compound can assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers are intended to be covered within the scope of the claimed subject matter. For example, in cases where a compound can have one of two tautomeric forms, both tautomers are intended to be covered herein.

[0045] Thus, the compounds provided herein can be enantiomerically pure, or a mixture of stereoisomers or a mixture of diastereoisomers. As used herein and unless otherwise specified, the term "stereoisomerically pure" means a composition that contains one stereoisomer of a compound and is substantially free of other stereoisomers of the compound. For example, a diastereomerically pure composition of a compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure composition of a compound having two chiral centers will be substantially free of other diastereoisomers of the compound. A typical stereoisomerically pure compound contains greater 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 greater 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 greater 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 greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. A stereoisomerically pure compound as used herein contains greater than about 80% by weight of one stereoisomer of the compound, in one embodiment greater than about 90% by weight of one stereoisomer of the compound, in one embodiment greater than about 95% by weight of one stereoisomer of the compound, and in one embodiment, greater than about 97% by weight of one stereoisomer of the compound. As used herein and unless otherwise specified, the term "stereoisomerically enriched" means a composition that contains greater than about 60% by weight of one stereoisomer of a compound, in one embodiment greater than about 70% by weight, and in one embodiment greater than about 80% by weight of one stereoisomer of the compound. As used herein and unless otherwise specified, the term "enantiomerically pure" means a stereoisomerically pure composition of a compound having one chiral center. Similarly, the term "stereoisomerically enriched" means a stereoisomerically enriched composition of a compound having one chiral center. As used herein, a mixture of stereoisomers or diastereoisomers means a composition that contains more than one stereoisomer of a compound.A typical mixture of stereoisomers of a compound contains about 50% by weight of one stereoisomer of the compound and about 50% by weight of the other stereoisomers of the compound, or contains more than about 50% by weight of one stereoisomer of the compound and less than about 50% by weight of the other stereoisomers of the compound, or contains more than about 45% by weight of one stereoisomer of the compound and less than about 55% by weight of the other stereoisomers of the compound, or contains more than about 40% by weight of one stereoisomer of the compound and less than about 60% by weight of the other stereoisomers of the compound, or contains more than about 35% by weight of one stereoisomer of the compound and less than about 65% by weight of the other stereoisomers of the compound.

[0046] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers can have the (R) or (S) configuration, or can be a mixture thereof. It should be understood that the chiral centers of the compounds provided herein can undergo epimerization in vivo. Thus, those skilled in the art will recognize that for compounds that undergo epimerization in vivo, administering the compound in the (R) form of the compound is equivalent to administering the compound in the (S) form of the compound.

[0047] They can be prepared using chiral synthons or chiral reagents, or resolved into optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers using conventional techniques such as chromatography on a chiral stationary phase.

[0048] As used herein, an "isotopologue" is an isotope-enriched compound. The term "isotope-enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of the atom. "Isotope enrichment" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radioactively labeled and isotope-enriched compounds can be used as therapeutic agents, such as therapeutic agents for multiple myeloma; research reagents, such as binding assay reagents; and diagnostic agents, such as in vivo imaging agents. All isotopic variants of the compounds described herein (whether radioactive or not) are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds are provided, such as isotopologues of Compound 1, Compound 2, or Compound 3 that are deuterium, carbon-13, or nitrogen-15 enriched compounds. In some embodiments, the isotopologues provided herein are deuterium-enriched compounds. In some embodiments, the isotopologues provided herein are deuterium-enriched compounds where deuteration occurs at chiral centers.

[0049] In the specification herein, if there is any discrepancy between the chemical name and the chemical structure, the structure shall prevail.

[0050] As used herein, "multiple myeloma" refers to a hematological disorder characterized by malignant plasma cells and includes the following conditions: monoclonal gammopathy of undetermined significance (MGUS); relapsed, refractory or resistant multiple myeloma; low-risk, intermediate-risk and high-risk multiple myeloma; newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk and high-risk multiple myeloma); transplant-eligible and transplant-ineligible multiple myeloma; indolent (latent) multiple myeloma (including low-risk, intermediate-risk and high-risk indolent multiple myeloma); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; non-secretory myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma; 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; del(17 / 17p), non-hyperdiploidy and gain of (1q)).

[0051] As used herein and unless otherwise indicated, the terms "treat", "treating" and "treatment" refer to reducing or lessening the severity of symptoms associated with the disease or disorder being treated (e.g., multiple myeloma).

[0052] The term "prevent" includes suppressing the symptoms of a particular disease or disorder such as multiple myeloma. In some embodiments, patients with a family history of multiple myeloma are candidates for a prevention regimen. Generally, the term "prevent" refers to administering a medicament prior to the onset of symptoms, particularly to patients at risk of multiple myeloma.

[0053] As used herein and unless otherwise indicated, the term "control" encompasses preventing the recurrence of a disease or disorder in a patient suffering from a particular disease or disorder such as multiple myeloma, prolonging the time a patient suffering from the disease or disorder remains in remission, reducing the mortality rate of the patient, and / or maintaining a reduced severity of the disease or disorder being controlled or avoiding symptoms associated with the disease or disorder.

[0054] As used herein, "subject" or "patient" is an animal, typically a mammal, including a human, e.g., a human patient.

[0055] The term "relapse" refers to the return of myeloma cells and / or reduction of normal cells in the bone marrow of a patient who has achieved remission from multiple myeloma after treatment.

[0056] The term "refractory or resistant" refers to a situation where, even after intensive treatment, a patient still has residual myeloma cells and / or reduction of normal cells in the bone marrow.

[0057] As used herein, "induction therapy" refers to the first therapy administered for a disease, or the first treatment administered to induce a complete remission of a disease such as cancer. When used alone, induction therapy is a recognized best available treatment. If residual cancer is detected, another therapy, called re-induction, is used. If a patient achieves a complete remission after induction therapy, additional consolidation and / or maintenance therapy is given to prolong the remission or potentially cure the patient.

[0058] As used herein, "consolidation therapy" refers to the treatment administered for a disease after remission is first achieved. For example, consolidation therapy for cancer is administered after the cancer has disappeared after the initial therapy. Consolidation therapy may include radiation therapy, stem cell transplantation, or treatment with cancer drug therapy. Consolidation therapy is also referred to as intensification therapy and post-remission therapy.

[0059] As used herein, "maintenance therapy" refers to the treatment administered for a disease after remission or optimal response has been achieved to prevent or delay relapse. Maintenance therapy may include chemotherapy, hormone therapy, or targeted therapy.

[0060] As used herein and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention, and / or control of a disease (e.g., multiple myeloma), or to delay or minimize one or more symptoms associated with the disease or condition to be treated. The terms "therapeutically effective amount" and "effective amount" may encompass an amount that improves the overall therapy, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0061] The terms "co-administer" and "in combination with" include the simultaneous, concurrent, or sequential administration of one or more therapeutic agents (e.g., the compounds provided herein and another anti-multiple myeloma agent, cancer agent, or supportive care agent) without a specific time limit. In one embodiment, the agents are present in a cell or in a patient simultaneously or exert their biological or therapeutic effects simultaneously. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In another embodiment, the therapeutic agents are in separate compositions or unit dosage forms.

[0062] The term "supportive care agent" refers to any substance that treats, prevents, or controls adverse effects resulting from treatment with Compound 1, Compound 2, or Compound 3, or their enantiomers or mixtures of enantiomers, tautomers, isotopomers, or pharmaceutically acceptable salts.

[0063] The term "biotherapy" refers to the administration of biotherapeutic agents such as cord blood, stem cells, growth factors, etc.

[0064] In the context of cancer, inhibition can be evaluated by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumors, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors, delay in the appearance of primary or secondary tumors, slowing of the development of primary or secondary tumors, reduction in the incidence of primary or secondary tumors, slowing or reduction in the severity of secondary effects of the disease, tumor growth arrest and tumor regression, increased time to progression (TTP), increased progression-free survival (PFS), increased overall survival (OS), etc. As used herein, OS refers to the time from the start of treatment until death from any cause. As used herein, TTP refers to the time from the start of treatment until tumor progression; TTP does not include death. In one embodiment, PFS refers to the time from the start of treatment until tumor progression or death. In one embodiment, PFS refers to the time from the first dose of the compound to the first occurrence of disease progression or death from any cause. In one embodiment, the Kaplan-Meier estimate will be used to calculate the PFS rate. Event-free survival (EFS) refers to the time from the start of treatment until any treatment failure (including disease progression, treatment discontinuation for any reason) 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 response and a partial response. In one embodiment, ORR refers to the percentage of patients with a best response ≥ partial response (PR) according to the IMWG unified response criteria. In one embodiment, the duration of response (DoR) is the time from achieving a response until recurrence or disease progression. In one embodiment, DoR is the time from achieving a response ≥ partial response (PR) until recurrence or disease progression. In one embodiment, DoR is the time from the first record of a response until the first record of progressive disease or death. In one embodiment, DoR is the time from the first record of a response ≥ partial response (PR) until the first record of progressive disease or death. In one embodiment, the time to response (TTR) is the time from the first dose of the compound to the first record of a response. In one embodiment, TTR is the time from the first dose of the compound to the first record of a response ≥ partial response (PR). In extreme cases, complete inhibition is referred to herein as prevention 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 the pre-clinically apparent stage of cancer. This definition is also intended to cover the prevention of transformation into malignant cells or the prevention or reversal of the progression of pre-cancerous cells into malignant cells. This includes prophylactic treatment of individuals at risk of developing cancer.

[0065] In the case of multiple myeloma, the consensus criteria of the International Myeloma Working Group (IMWG) for response and minimal residual disease assessment can be used to evaluate response (Rajkumar et al., Blood, 2011, 117(18):4691-5; Kumar et al., Lancet Oncol., 2016, 17(8):e328-e346). The criteria can be summarized as follows (further details can be obtained in Lancet Oncol., 2016, 17(8):e328-e346).

[0066]

[0067]

[0068]

[0069]

[0070]

[0071] RD = minimal residual disease. NGF = next-generation flow cytometry. NGS = next-generation sequencing. FLC = free light chain. M protein = myeloma protein. SPD = sum of products of the maximum perpendicular diameters of the measured lesions. CRAB features = hypercalcemia, renal failure, anemia, osteolytic lesions. FCM = flow cytometry. SUVmax = maximum standardized uptake value. 18 F-FDG PET = 18 F-fluorodeoxyglucose PET.

[0072] In certain embodiments, the treatment of multiple myeloma can also be evaluated by the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, 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:

[0073]

[0074] Abbreviations: CR, complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response.

[0075] aAll response categories require two consecutive assessments at any time prior to the implementation of any new therapy; if radiographic studies are performed, all categories also do not require evidence of known progressive or new bone lesions. Radiographic studies are not required to meet these response requirements.

[0076] b Repeat bone marrow biopsy confirmation is not required.

[0077] c The presence / absence of clonal cells is based on the κ / λ ratio. An abnormal κ / λ ratio by immunohistochemistry and / or immunofluorescence requires a minimum of 100 plasma cells for analysis. The abnormal ratio reflecting the presence of an abnormal clone is κ / λ > 4:1 or < 1:2.

[0078] d Measurable disease defined by at least one of the following measurements: bone marrow plasma cells ≥ 30%; serum M protein ≥ 1 g / dl (≥ 10 g / l); urine M protein ≥ 200 mg / 24 hours; serum FLC assay: involved FLC level ≥ 10 mg / dl (≥ 100 mg / l); provided that the serum FLC ratio is abnormal.

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

[0080]

[0081] Unless otherwise specified, the term "about" as used herein, when used in conjunction with a numerical value or range of values, means that the said value or range of values may vary to an extent considered reasonable by a person of ordinary skill in the art. In one embodiment, the term "about" means that the numerical value or range 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 recited value or range 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 said term. For example, the term "about 10 mg / m 2 " refers to a range of 9 mg / m 2 to 11 mg / m 2 .

[0082] As used herein, the terms “BCMA, target BCMA, human BCMA” refer to human B cell maturation antigen, also known as BCMA; TR17_human, TNFRSF17 (UniProt Q02223), which is a member of the tumor necrosis factor receptor superfamily preferentially expressed in differentiated plasma cells. The extracellular domain of BCMA consists of amino acids 1 - 54 (or 5 - 51) according to UniProt. As used herein, the terms “antibody against BCMA, anti - BCMA antibody” refer to an antibody that specifically binds to the extracellular domain of BCMA.

[0083] “Specifically binds to BCMA or binds to BCMA” means an antibody that can bind to target BCMA with sufficient affinity such that the antibody can be used as a therapeutic agent targeting BCMA. In some embodiments, the anti - BCMA antibody binds to an unrelated non - BCMA protein at a level about 10 - fold lower, preferably > 100 - fold lower, than the antibody's binding to BCMA, as measured, for example, by surface plasmon resonance (SPR), such as enzyme - linked immunosorbent assay (ELISA) or flow cytometry (FACS). In one embodiment, the antibody that binds to BCMA has a dissociation constant (Kd) of 10 -8 M or lower, in one embodiment 10 -8 M to 10 -13 M, in one embodiment 10 -9 M to 10 -13 M. In one embodiment, the anti - BCMA antibody binds to an epitope of BCMA that is conserved in BCMA from different species, in one embodiment in humans and cynomolgus monkeys, and in additional embodiments also binds to mouse and rat BCMA. “Bispecific antibody that specifically binds to CD3 and BCMA, bispecific antibody against CD3 and BCMA” refers to the corresponding definitions for antibodies that bind to two targets. An antibody that specifically binds to BCMA (or BCMA and CD3) does not bind to other human antigens. Thus, in ELISA, the OD value of such unrelated targets will be equal to or lower than the OD value of the detection limit of a particular assay, in one embodiment > 0.3 ng / mL, or equal to or lower than the OD value of a control sample without plate - bound BCMA or with untransfected HEK293 cells.

[0084] As used herein, the term “APRIL” refers to recombinant, truncated murine APRIL (amino acids 106 - 241; NP_076006). APRIL can be produced as described in Ryan, 2007 (Mol Cancer Ther; 6(11):3009–18).

[0085] As used herein, the term "BAFF" refers to recombinant, truncated human BAFF (UniProt Q9Y275 (TN13B_human)), which can be produced as described in Gordon, 2003 (Biochemistry; 42(20):5977-5983). In one embodiment, His-tagged BAFF is used according to the present invention. In one embodiment, His-tagged BAFF is produced by cloning a DNA fragment encoding BAFF residues 82-285 into an expression vector to produce a fusion with an N-terminal His-tag, followed by a thrombin cleavage site, expressing the vector and cleaving the recovered protein with thrombin.

[0086] The term "antibody against CD3, 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 "CD3ε or CD3" refers to human CD3ε as described under UniProt P07766 (CD3E_human).

[0087] 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) (such a light chain (LC) / heavy chain pair is abbreviated as LC / HC in this text). The light and heavy chains of such an antibody are polypeptides consisting of several domains. Each heavy chain contains a heavy chain variable region (abbreviated as HCVR or VH in the text) 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 interspersed with more conserved regions called framework regions (FR), called complementarity determining regions (CDR). Each VH and VL consists of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The "constant domains" of the heavy and light chains do not directly participate in the binding of the antibody to the target, but exhibit various effector functions. As used herein, the term "antibody" also encompasses at least the antibody portion required for specific binding to the antigens CD3 and BCMA. Thus, if such an antibody portion is included in a bispecific antibody according to the present invention, such an antibody (or antibody portion) can be a Fab fragment in one embodiment. The antibodies according to the present invention can also be Fab', F(ab’)2, scFv, di-scFv, or bispecific T cell engagers

[0088] The term "antibody" includes, for example, murine antibodies, human antibodies, chimeric antibodies, humanized antibodies, and genetically engineered antibodies (variant or mutant antibodies), provided that their characteristic properties are retained. In one embodiment, the antibody is a human or humanized antibody, particularly a recombinant human or humanized antibody. Other embodiments are hetero-specific antibodies (bispecific, trispecific, etc.) and other conjugates, e.g., conjugates with cytotoxic small molecules.

[0089] Bispecific antibody formats are well known in 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 and Chan AC, Carter PJ Nature Reviews Immunology 10, 301-316 (2010) as well as Cuesta AM et al., Trends Biotech 28 (2011) 355-362. The term "bispecific antibody" as used herein refers in one embodiment to an antibody in which one of the 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 prior art. In one embodiment, the term "bispecific antibody" includes bispecific single-chain antibodies such as antibodies in the form of , DART antibodies, diabodies, tandem scFv, and antibody mimetics such as DARPins. In one embodiment, the bispecific antibodies that specifically bind to human B cell maturation antigen (BCMA) and human CD3ε (CD3) are among those described in International Application Publication No. WO 2018 / 083204, the entire content of which is incorporated herein by reference.

[0090] The term "TCB" as used herein refers to a bispecific antibody that specifically binds to BCMA and CD3. The term "83A10-TCBcv" as used herein refers to a bispecific antibody that specifically binds to BCMA and CD3, as specified by the combination of its heavy and light chains of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47 (2x), and SEQ ID NO:48, and as shown in Figure 2Aas shown and described in EP14179705. As used herein, the terms "21-TCBcv, 22-TCBcv, 42-TCBcv" refer to the respective bispecific antibodies of Mab21 as specified by the combination of its heavy and light chains of SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51(2x), Mab22 as specified by the combination of its heavy and light chains of SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:53 and SEQID NO:54(2x), and Mab42 as specified by the combination of its heavy and light chains of SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:56 and SEQ ID NO:57-(2x).

[0091] B. BRIEF DESCRIPTION OF THE DRAWINGS

[0092] Figure 1A and Figure 1B . Bispecific bivalent antibody that contains only Fab fragments (specific for CD3 and BCMA) and an Fc portion as specified: ( Figure 1A ) Fab BCMA(RK / EE)-Fc-Fab CD3; ( Figure 1B ) Fab BCMA-Fc-Fab CD3(RK / EE). An amino acid substitution of RK / EE is introduced in CL-CH1 to reduce LC mismatches / by-products in production. The Fab CD3 contains a VL-VH crossover to reduce LC mismatches and by-products.

[0093] Figure 2A 、 Figure 2B 、 Figure 2C and Figure 2D . Preferred bispecific trivalent antibody that contains only Fab fragments (specific for CD3 and BCMA) and an Fc portion as specified: ( Figure 2A ) Fab BCMA(RK / EE)-Fc-Fab CD3-Fab BCMA(RK / EE); ( Figure 2B ) Fab BCMA-Fc-Fab CD3(RK / EE)-Fab BCMA; ( Figure 2C ) Fab BCMA(RK / EE)-Fc-Fab BCMA(RK / EE)-Fab CD3; ( Figure 2D)Fab BCMA-Fc-Fab BCMA-Fab CD3(RK / EE). An amino acid substitution of RK / EE was introduced in CL-CH1 to reduce LC mispairing / by-products during production. Preferably, the Fab CD3 comprises a VL-VH crossover to reduce LC mispairing and by-products. Preferably, Fab CD3 and Fab BCMA are connected to each other by a flexible linker.

[0094] Figure 3A , Figure 3B , Figure 3C and Figure 3D . Bispecific bivalent antibodies that contain only Fab fragments (specific for CD3 and BCMA) and a designated Fc portion: ( Figure 3A )Fc-Fab CD3-Fab BCMA(RK / EE); ( Figure 3B )Fc-Fab CD3(RK / EE)-Fab BCMA; ( Figure 3C )Fc-Fab BCMA(RK / EE)-Fab CD3; ( Figure 3D )Fc-Fab BCMA-Fab CD3(RK / EE). Preferably, the Fab CD3 comprises a VL-VH crossover to reduce LC mispairing and by-products. Fab CD3 and Fab BCMA are connected to each other by a flexible linker.

[0095] Figure 4A , Figure 4B and Figure 4C show that pretreatment of effector T cells or multiple myeloma (MM) or PCL target cells with compound 2 enhances potency and also enhances maximum target cell killing achieved with bispecific antibodies that specifically bind to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein. Effector T cells (CD3+) were pretreated with DMSO (control) or compound 2 (1 nM) for 16 hours, then washed and used for co-culture. H929 ( Figure 4A ), L363 ( Figure 4B ) and OPM-2 ( Figure 4C) The target cell line was pretreated with DMSO (control) or compound 2 (1 nM) for 72 hours, then washed and used for co - culture at effector T cell (E) to target cell (T) ratios of 1:3, 1:1, and 1:5, respectively. "DMSO - DMSO" row: Target cells and effector cells pretreated with DMSO (control). "Compound 2 - DMSO" row: Target cells pretreated with compound 2 and effector cells pretreated with DMSO (control). "DMSO - Compound 2" row: Target cells pretreated with DMSO (control) and effector cells pretreated with compound 2. "Compound 2 - Compound 2" row: Target and effector cells pretreated with compound 2. The y - axis represents the percentage of live tumor cells normalized to the number of live cells in the absence of bispecific antibody; the x - axis shows the log[concentration] of bispecific antibody (in pM).

[0096] Figure 5 Shows that compound 2 enhances the potency and maximum target cell killing achieved with a bispecific antibody that specifically binds to human B - cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein. In the presence of DMSO (control), effector T cells (CD3+) from three different donors were co - cultured with the MM target cell line H929 at a fixed effector T cell (E) to target cell (T) ratio of 1:3 or treated with compound 2 (1 nM) for 72 hours. The y - axis represents the percentage of live tumor cells normalized to the number of live cells in the absence of bispecific antibody. The x - axis shows the log[concentration] of bispecific antibody (in pM).

[0097] Figure 6 Shows that pretreatment of lenalidomide - resistant multiple myeloma cells with compound 2 (instead of pomalidomide) enhances the potency and maximum target cell killing achieved with a bispecific antibody that specifically binds to human B - cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein. The H929 - 1051 target cell line was pretreated with DMSO (control), pomalidomide (100 nM), or compound 2 (1 nM) for 72 hours, then washed and co - cultured at an effector T cell (E) to target cell (T) ratio of 1:3. The y - axis represents the percentage of live tumor cells normalized to the number of live cells in the absence of bispecific antibody; the x - axis shows the log[concentration] of bispecific antibody (in pM).

[0098] C. Compound

[0099] Provided for use in the methods herein is the compound 4 - (4 - (4 - (((2 - (2,6 - dioxopiperidin - 3 - yl)-1 - oxoisoindolin - 4 - yl)oxy)methyl)benzyl)piperazin - 1 - yl)-3 - fluorobenzonitrile, referred to as "compound 1":

[0100]

[0101] or an enantiomer or mixture of enantiomers, tautomer, isotopomer or pharmaceutically acceptable salt thereof.

[0102] Also provided for use in the methods herein is the compound (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, referred to as "Compound 2":

[0103]

[0104] or a tautomer, isotopomer or pharmaceutically acceptable salt thereof.

[0105] Also provided for use in the methods herein is the compound (R)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, referred to as "Compound 3":

[0106]

[0107] or a tautomer, isotopomer or pharmaceutically acceptable salt thereof.

[0108] D. Preparation of Compound 1, Compound 2 and Compound 3

[0109] The compounds for use in the methods provided herein can be prepared by methods known to those skilled in the art and according to procedures similar to those described in the Examples section herein and their routine modifications. Exemplary reaction schemes for preparing the compounds are illustrated below in Scheme 1 for Compound 1, Compound 2 and Compound 3 and Scheme 2 for Compound 2.

[0110] As shown in Scheme 1, 3-hydroxy-2-methylbenzoic acid is protected (e.g., formation of methyl ester and tert-butyl(dimethyl)silyl ether), followed by bromination using, for example, N-bromosuccinimide and azobisisobutyronitrile. Reaction with methyl 4,5-diamino-5-oxo-pentanoate in the presence of a base (such as DIEA) gives rise to the formation of a derivatized isoindoline, followed by TBS deprotection using a base such as potassium carbonate. The derivatized isoindoline is reacted with 1,4-bis(bromomethyl)benzene in the presence of a base (such as potassium carbonate), and then glutarimide is formed in the presence of potassium tert-butoxide. Finally, reaction with 3-fluoro-4-(piperazin-1-yl)benzonitrile gives the target Compound 1. Chiral separation then gives Compound 2 and Compound 3.

[0111]

[0112] Solution 1

[0113] Alternatively, as exemplified in Scheme 2, methyl 2-(bromomethyl)-3-[(tert-butyl(dimethyl)silyl)oxy]benzoate intermediate reacts with chiral (4S)-4,5-diamino-5-oxo-tert-butyl pentanoate in the presence of a base (such as DIEA) to produce derivatized isoindoline formation, and then TBS deprotection is carried out using tetrabutylammonium fluoride. The derivatized isoindoline reacts with 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile in the presence of a base (such as potassium carbonate), then deprotection is carried out and glutarimide is formed to obtain the target compound 2.

[0114]

[0115] Solution 2.

[0116] Those skilled in the art will know how to modify the procedures set forth in the illustrative schemes and examples to obtain the desired products.

[0117] E. Bispecific antibodies that specifically bind to BCMA and CD3

[0118] Provided for use in the methods herein are bispecific antibodies that specifically bind to human B cell maturation antigen (BCMA) and human CD3ε (CD3).

[0119] In one embodiment, the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0120] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0121] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0122] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0123] In one embodiment, the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0124] a) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0125] b) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0126] In one embodiment, the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20, a CDR1L region of SEQ ID NO:23, and a CDR2L region of SEQ ID NO:24.

[0127] In one embodiment, the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20, a CDR1L region of SEQ ID NO:25, and a CDR2L region of SEQ ID NO:26.

[0128] In one embodiment, the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20, a CDR1L region of SEQ ID NO:27, and a CDR2L region of SEQ ID NO:28.

[0129] In one embodiment, the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), wherein the first binding portion comprises the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:12, the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:13, or the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:14.

[0130] In one embodiment, the first binding portion comprises the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:12.

[0131] In one embodiment, the first binding portion comprises the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:13.

[0132] In one embodiment, the first binding portion comprises the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:14.

[0133] In one embodiment, the first binding portion is characterized by comprising a VL region selected from the group consisting of the VL regions of SEQ ID NO:12, 13, and 14, wherein amino acid 49 is selected from the group consisting of amino acids tyrosine (Y), glutamate (E), serine (S), and histidine (H). In one embodiment, amino acid 49 is E within SEQ ID NO:12, S within SEQ ID NO:13, or H within SEQ ID NO:14.

[0134] In one embodiment, the first binding portion is characterized by comprising a VL region selected from the group consisting of the VL regions of SEQ ID NO:12, 13, and 14, wherein amino acid 74 is threonine (T) or alanine (A). In one embodiment, amino acid 74 is A within SEQ ID NO:14.

[0135] In one embodiment, the first binding portion is characterized by comprising the VH region of SEQ ID NO:10 as the BCMA VH.

[0136] In one embodiment, the first binding portion is characterized by comprising a VL region selected from the group consisting of the VL regions of SEQ ID NOs: 12, 13, and 14, wherein amino acid 49 is selected from the group consisting of amino acids tyrosine (Y), glutamic acid (E), serine (S), and histidine (H). In one embodiment, amino acid 49 is E (SEQ ID NO: 12), S (SEQ ID NO: 13), or H (SEQ ID NO: 14). In one embodiment of the present invention, the first binding portion is characterized by comprising a VL region selected from the group consisting of the VL regions of SEQ ID NOs: 12, 13, and 14, wherein amino acid 74 is threonine (T) or alanine (A). In one embodiment, amino acid 74 is A within SEQ ID NO: 14.

[0137] In one embodiment, the first binding portion is characterized by comprising a CDR3H region of SEQ ID NO: 17 and a CDR3L region of SEQ ID NO: 20 and a combination of CDR1H, CDR2H, CDR1L, and CDR2L regions selected from the group consisting of: a) a CDR1H region of SEQ ID NO: 21 and a CDR2H region of SEQ ID NO: 22, a CDR1L region of SEQ ID NO: 23 and a CDR2L region of SEQ ID NO: 24; b) a CDR1H region of SEQ ID NO: 21 and a CDR2H region of SEQ ID NO: 22, a CDR1L region of SEQ ID NO: 25 and a CDR2L region of SEQ ID NO: 26; c) a CDR1H region of SEQ ID NO: 21 and a CDR2H region of SEQ ID NO: 22, a CDR1L region of SEQ ID NO: 27 and a CDR2L region of SEQ ID NO: 28; d) a CDR1H region of SEQ ID NO: 29 and a CDR2H region of SEQ ID NO: 30, a CDR1L region of SEQ ID NO: 31 and a CDR2L region of SEQ ID NO: 32; e) a CDR1H region of SEQ ID NO: 34 and a CDR2H region of SEQ ID NO: 35, a CDR1L region of SEQ ID NO: 31 and a CDR2L region of SEQ ID NO: 32; and f) a CDR1H region of SEQ ID NO: 36 and a CDR2H region of SEQ ID NO: 37, a CDR1L region of SEQ ID NO: 31 and a CDR2L region of SEQ ID NO: 32.

[0138] In one embodiment, the first binding portion is characterized by comprising a VH region selected from the group consisting of SEQ ID NO: 38, 39, and 40 as the VH region. In one embodiment of the present invention, the first binding portion is characterized by comprising the VH region of SEQ ID NO: 38 as the VH region and the VL region of SEQ ID NO: 12 as the VL region. In one embodiment of the present invention, the first binding portion is characterized by comprising the VH region of SEQ ID NO: 39 as the VH region and the VL region of SEQ ID NO: 12 as the VL region. In one embodiment of the present invention, the first binding portion is characterized by comprising the VH region of SEQ ID NO: 40 as the VH region and the VL region of SEQ ID NO: 12 as the VL region.

[0139] In one embodiment, the first binding portion is characterized by comprising the CDR1H region of SEQ ID NO: 15, the CDR2H region of SEQ ID NO: 16, and the CDR3H region of SEQ ID NO: 17, the CDR1L region of SEQ ID NO: 18, the CDR2L region of SEQ ID NO: 19, and the CDR3L region of SEQ ID NO: 20.

[0140] The first binding portion according to the present invention comprises the same CDR regions as the CDR3H and CDR3L regions of antibody 83A10 (see Tables 1A and 1B later in this article for antibody 83A10).

[0141] In one embodiment, the first binding portion is characterized by comprising the VH region of SEQ ID NO: 9 as the VH region and the VL region of SEQ ID NO: 11 as the VL region.

[0142] In one embodiment, the bispecific antibody comprises no more than one Fab fragment of the anti-CD3 antibody portion, no more than two Fab fragments of the anti-BCMA antibody portion, and no more than one Fc portion (in one embodiment, a human Fc portion). In one embodiment, no more than one Fab fragment of the anti-CD3 antibody portion and no more than one Fab fragment of the anti-BCMA antibody portion are linked to the Fc portion and are linked by binding to the hinge region via the C-terminus of one or more Fab fragments. In one embodiment, the second Fab fragment of the anti-BCMA antibody portion is linked via its C-terminus to the N-terminus of the Fab fragment of the anti-CD3 antibody portion or to the hinge region of the Fc portion and is thus between the Fc portion and the anti-CD3 antibody portion. Preferred bispecific antibodies are shown in Figure 1A 、 1B Figures 2A to 2D and 3A to 3D.

[0143] Particularly preferred are bispecific antibodies that contain only the Fab fragments and Fc portion as specified, with or without "amino acid substitutions": Fab BCMA-Fc-Fab CD3 (bispecific form Figure 1A or Figure 1B ), Fab BCMA-Fc-Fab CD3-FabBCMA (bispecific form Figure 2A or Figure 2B ), Fab BCMA-Fc-Fab BCMA-Fab CD3 (bispecific form Figure 2C or Figure 2D ), Fc-Fab CD3-Fab BCMA (bispecific form Figure 3A or Figure 3B ), Fc-Fab BCMA-Fab CD3 (bispecific form Figure 3C or Figure 3D ).

[0144] As Figure 1A , 1B shown in 2A to 2D and 3A to 3D, "Fab BCMA-Fc, "Fab BCMA-Fc-Fab CD3" and "FabBCMA-Fc-Fab CD3" mean that one or more Fab fragments are bound via their (its) C-terminus to the N-terminus of the Fc fragment. "Fab CD3-Fab BCMA" means that the Fab CD3 fragment is bound at its N-terminus to the C-terminus of the Fab BCMA fragment. "FabBCMA-Fab CD3" means that the Fab BCMA fragment is bound at its N-terminus to the C-terminus of the Fab CD3 fragment.

[0145] In one embodiment, the bispecific antibody comprises a second Fab fragment of the anti-BCMA antibody, the second Fab fragment being linked at its C-terminus to the N-terminus of the CD3 antibody portion of the bispecific antibody. In one embodiment, the VL domain of the first anti-CD3 antibody portion is linked to the CH1 or CL domain of the second anti-BCMA antibody.

[0146] In one embodiment, the bispecific antibody comprises a second Fab fragment of the anti-BCMA antibody, the second Fab fragment being linked at its C-terminus to the Fc portion (such as the first Fab fragment of the anti-BCMA antibody) and at its N-terminus to the C-terminus of the CD3 antibody portion. In one embodiment, the CH1 domain of the anti-CD3 antibody portion is linked to the VH domain of the second anti-BCMA antibody portion.

[0147] In one embodiment, the bispecific antibody comprises an Fc portion that is linked at its N-terminus to the C-terminus of the Fab fragment of the anti-CD3 antibody. In one embodiment, the bispecific antibody comprises an Fc portion that is linked at its first N-terminus to the C-terminus of the Fab fragment of the anti-CD3 antibody; and a second Fab fragment of the anti-BCMA antibody, the second Fab fragment being linked at its C-terminus to the second N-terminus of the Fc portion. In one embodiment, the CL domain of the Fab fragment of the anti-CD3 antibody is linked to the hinge region of the Fc portion. In one embodiment, the CH1 domain of the Fab fragment of the anti-BCMA antibody is linked to the hinge region of the Fc portion.

[0148] According to the prior art, the Fab fragments are linked together by using a suitable linker. In one embodiment, the (Gly4-Ser1)3 linker is used (Desplancq DK et al., Protein Eng. August 1994; 7(8):1027-33 and Mack M. et al., PNAS July 18, 1995, Vol. 92, No. 15, 7021-7025). Since the linker is a peptide linker, this covalent conjugation is generally carried out by biochemical recombination using nucleic acids encoding the VL and / or VH domains of the corresponding Fab fragments, and the linker and, if appropriate, the Fc portion chains.

[0149] In one embodiment, the anti-CD3ε antibody comprises a variable domain VH that comprises heavy chain CDRs of SEQ ID NOs: 1, 2, and 3 as heavy chain CDR1H, CDR2H, and CDR3H, respectively; and a variable domain VL that comprises light chain CDRs of SEQ ID NOs: 4, 5, and 6 as light chain CDR1L, CDR2L, and CDR3L, respectively. In one embodiment, the antibody comprises variable domains of SEQ ID NO: 7 (VH) and SEQ ID NO: 8 (VL).

[0150] In one embodiment, the bispecific antibody is characterized in that the variable domains of the anti-CD3 antibody portion are SEQ ID NOs: 7 and 8.

[0151] In one embodiment of the present invention, the bispecific antibody is characterized in that the anti-CD3 antibody portion (the second binding portion of the bispecific antibody) is linked at its N-terminus to the C-terminus of the anti-BCMA antibody portion (the first binding portion of the bispecific antibody), and the variable domains VL and VH or the constant domains CL and CH1 of the anti-CD3 antibody portion are permuted with each other.

[0152] In one embodiment, the VH domain of the anti-CD3 antibody portion is linked to the CH1 or CL domain of the anti-BCMA antibody portion. In one embodiment, the VL domain of the anti-CD3 antibody portion is linked to the CH1 or CL domain of the anti-BCMA antibody portion.

[0153] In one embodiment, such antibody portion is the Fab fragment of the corresponding antibody.

[0154] The bispecific antibody against BCMA and CD3 is characterized in one embodiment by comprising:

[0155] a) the light and heavy chains of an antibody that specifically binds to one of the targets CD3 and BCMA; and

[0156] b) the light and heavy chains of an antibody that specifically binds to the other of the targets, wherein the variable domains VL and VH or the constant domains CL and CH1 are permuted with each other.

[0157] In one embodiment, the VH domain of the anti-CD3 antibody portion is linked to the CH1 or CL domain of the anti-BCMA antibody portion. In one embodiment, the VL domain of the anti-CD3 antibody portion is linked to the CH1 or CL domain of the anti-BCMA antibody portion.

[0158] In another embodiment, the bispecific antibody (wherein the variable domains VL and VH in the light chain and the corresponding heavy chain of the anti-CD3 antibody portion or the anti-BCMA antibody portion are swapped with each other) is characterized by comprising the constant domain CL of the anti-CD3 antibody portion or the anti-BCMA antibody portion, wherein the amino acid at position 124 is independently replaced by lysine (K), arginine (R), or histidine (H) (according to Kabat numbering), and in the corresponding constant domain CH1, the amino acid at position 147 and the amino acid at position 213 are independently replaced by glutamic acid (E) or aspartic acid (D). In one embodiment, the antibody is monovalent for CD3 binding. In one embodiment, in addition to the amino acid substitution at position 124 in the constant domain CL, the amino acid at position 123 is independently replaced by lysine (K), arginine (R), or histidine (H) (further referred to as "charge variant exchange"). In one embodiment, the antibody is monovalent for CD3 binding, and amino acid 124 is K, amino acid 147 is E, amino acid 213 is E, and amino acid 123 is R. In one embodiment, the bispecific antibody further comprises again the same anti-BCMA binding portion (in one embodiment, a Fab fragment). This also means that if the first anti-BCMA binding portion contains a charge variant exchange, the second anti-BCMA binding portion contains the same charge variant exchange. (All amino acid numberings are according to Kabat).

[0159] In one embodiment, the bispecific antibody is characterized by comprising

[0160] a) a first light chain and a first heavy chain of a first antibody that specifically binds to BCMA; and

[0161] b) a second light chain and a second heavy chain of a second antibody that specifically binds to CD3, and wherein the variable domains VL and VH in the second light chain and the second heavy chain of the second antibody are swapped with each other; and

[0162] c) wherein in the constant domain CL of the first light chain in a), the amino acid at position 124 is independently replaced by lysine (K), arginine (R), or histidine (H) (according to Kabat numbering), and wherein in the constant domain CH1 of the first heavy chain in a), the amino acid at position 147 and the amino acid at position 213 are independently replaced by glutamic acid (E) or aspartic acid (D) (according to Kabat numbering) (see, for example Figure 1A , 2A , 2C, 3A, 3C).

[0163] In one embodiment, the bispecific antibody described in the previous paragraph is further characterized in that the bispecific antibody further comprises a Fab fragment of the first antibody (also further designated as "BCMA-Fab"), and in the constant domain CL of the BCMA-Fab, the amino acid at position 124 is independently replaced by lysine (K), arginine (R), or histidine (H) (according to Kabat numbering), and wherein in the constant domain CH1 of the BCMA-Fab, the amino acids at positions 147 and 213 are independently replaced by glutamic acid (E) or aspartic acid (D) (according to Kabat numbering) (see, for example Figure 2A , 2C ).

[0164] In one embodiment of the present invention, the bispecific antibody consists of a CD3-Fab and a BCMA-Fab and an Fc portion and a second BCMA-Fab, wherein the CD3-Fab and the BCMA-Fab are linked via their C-termini to the hinge region of the Fc portion, and the second BCMA-Fab is linked at its C-terminus to the N-terminus of the CD3-Fab. The CD3-Fab contains a crossover, and the CD3-Fab or both BCMA-Fabs contain amino acid substitutions ( Figure 2A and 2B ). Particularly preferred is a bispecific antibody comprising BCMA-Fab-Fc-CD3-Fab-BCMA-Fab, wherein both BCMA-Fabs contain amino acid substitutions, and the CD3-Fab contains a VL / VH crossover ( Figure 2A ). Particularly preferred is a bispecific antibody consisting of BCMA-Fab-Fc-CD3-Fab-BCMA-Fab, wherein both BCMA-Fabs contain the amino acid substitutions Q124K, E123R, K147E, and K213E, and the CD3-Fab contains a VL / VH crossover. Particularly preferred is that both BCMA-Fabs contain the CDRs of antibody 21, 22, or 42 as CDRs, or the VH / VL of antibody 21, 22, or 42 as VH / VL (for antibodies 21, 22, and 42, see Tables 1A and 1B below)

[0165] In one embodiment, the first and second Fab fragments of the antibody that specifically binds to BCMA are derived from the same antibody and are identical in one embodiment in the CDR sequences, the variable domain sequences VH and VL, and / or the constant domain sequences CH1 and CL. In one embodiment, the amino acid sequences of the first and second Fab fragments of the antibody that specifically binds to BCMA are identical. In one embodiment, the BCMA antibody is an antibody comprising the CDR sequences of antibody 21, 22, or 42, an antibody comprising the VH and VL sequences of antibody 21, 22, or 42, or an antibody comprising the VH, VL, CH1, and CL sequences of antibody 21, 22, or 42.

[0166] In one embodiment, the bispecific antibody is characterized by comprising

[0167] a) a first light chain and a first heavy chain of a first antibody that specifically binds to BCMA; and

[0168] b) a second light chain and a second heavy chain of a second antibody that specifically binds to CD3, and wherein the variable domains VL and VH in the second light chain and the second heavy chain of the second antibody are permuted with each other; and wherein

[0169] c) in the constant domain CL of the second light chain in b), the amino acid at position 124 is independently replaced with lysine (K), arginine (R), or histidine (H) (according to Kabat numbering), and wherein in the constant domain CH1 of the second heavy chain in b), the amino acids at positions 147 and 213 are independently replaced with glutamic acid (E) or aspartic acid (D) (according to Kabat numbering).

[0170] In one embodiment, in addition to the replacement of the amino acid at position 124 in the constant domain CL of the first or second light chain, the amino acid at position 123 is independently replaced with lysine (K), arginine (R), or histidine (H).

[0171] In one embodiment, in the constant domain CL, the amino acid at position 124 is replaced with lysine (K), and in the constant domain CH1, the amino acids at positions 147 and 213 are replaced with glutamic acid (E). In one embodiment, additionally in the constant domain CL, the amino acid at position 123 is replaced with arginine (R).

[0172] In one embodiment, the bispecific antibody consists of two BCMA-Fabs and an Fc portion, wherein one BCMA-Fab and a CD3 Fab are connected via their C-termini to the hinge region of the Fc portion, and the second BCMA-Fab is connected at its C-terminus to the N-terminus of the CD3-Fab. The CD3-Fab contains a crossover, and the CD3-Fab or both BCMA-Fabs contain amino acid substitutions ( Figure 2A and 2B ).

[0173] In one embodiment, the bispecific antibody is characterized in that the CH3 domain of one heavy chain and the CH3 domain of the other heavy chain meet at an interface that includes the original interface between the antibody CH3 domains; wherein the interface is altered to facilitate the formation of the bispecific antibody, and the alteration is characterized in that:

[0174] a) The CH3 domain of one heavy chain is altered such that within the original interface of the CH3 domain of one heavy chain that meets the original interface of the CH3 domain of the other heavy chain within the bispecific antibody, amino acid residues are replaced with amino acid residues having a larger side chain volume, thereby creating a protrusion within the interface of the CH3 domain of one heavy chain, and the protrusion can be positioned within a cavity within the interface of the CH3 domain of the other heavy chain, and

[0175] b) The CH3 domain of the other heavy chain is altered such that within the original interface of the second CH3 domain that meets the original interface of the first CH3 domain within the bispecific antibody, amino acid residues are replaced with amino acid residues having a smaller side chain volume, thereby creating a cavity within the interface of the second CH3 domain, and the protrusion within the interface of the first CH3 domain can be positioned within the cavity.

[0176] In one embodiment, the bispecific antibody is characterized in that the amino acid residues having a larger side chain volume are selected from the group consisting of: arginine (R), phenylalanine (F), tyrosine (Y), tryptophan (W).

[0177] In one embodiment, the bispecific antibody is characterized in that the amino acid residues having a smaller side chain volume are selected from the group consisting of: alanine (A), serine (S), threonine (T), valine (V).

[0178] In one embodiment, such a bispecific antibody is characterized in that the two CH3 domains are further altered by introducing cysteine (C) as an amino acid at corresponding positions in each CH3 domain.

[0179] In one embodiment, this bispecific antibody is characterized in that one of the constant heavy chain domains CH3 of the two heavy chains is replaced by the constant heavy chain domain CH1; and the other constant heavy chain domain CH3 is replaced by the constant light chain domain CL.

[0180] In one embodiment, the bispecific antibody comprises a modified Fc portion. Using the same antibody with the parental Fc portion as a control, under the same conditions and relative to the control, the bispecific antibody induces cell death of 20% or more of the cells in a preparation of cells expressing BCMA after 24 hours at a concentration of 100 nM of the antibody by ADCC. In one embodiment, such an antibody is a naked antibody.

[0181] In one embodiment, the bispecific antibody is an antibody in which the amount of fucose at Asn297 is 60% or less of the total amount of oligosaccharide (sugar) (see, for example, US20120315268).

[0182] In one embodiment, the Fc portion comprises amino acid substitutions introduced in the human Fc portion and disclosed in SEQ ID NOs: 55 and 56.

[0183] In one embodiment, the anti - BCMA antibody is Mab21, Mab22, Mab42, Mab27, Mab33, and Mab39 as described herein by their CDR sequences and / or VH / VL sequences and the described CL and CH1 sequences (for antibodies Mab21, 22, 42, 27, 33, 39, see Tables 1A and 1B below). In one embodiment, the bispecific antibody comprises an Fc portion or does not comprise an Fc portion, especially in the 2 + 1 form, and the heavy and light chains of the bispecific antibody are especially as described in Table 1A.

[0184] The anti-BCMA antibody depletes human malignant plasma cells in MM bone marrow aspirates to at least 80% after 48-hour treatment at a concentration between 10 nM and 1 fM (including the end values) in a bispecific format, especially in the 2+1 format. The variable heavy chain (VH) and variable light chain (VL) phage display libraries of antibody 83A10 (VH library, VL library) have been panned with cynomolgus BCMA at 1 - 50 nM for 1 - 3 rounds and variable light and heavy chains having such properties as such bispecific T cell binders have been characterized. Preferably, the panning is carried out in 3 rounds, using 50 nM cynoBCMA for the first round, 25 nM cyBCMA for the second round, and 10 nM cyBCMA for the third round. Preferably, the library is randomized in light chain CDR1 and CDR2 or heavy chain CDR1 and CDR2. Preferably, light and heavy chains are identified that bind to huBCMA with a Kd of 50 pM to 5 nM and to cynomolgus BCMA with a Kd of 0.1 nM to 20 nM, each as a Fab fragment additionally comprising the respective VH or VL of antibody 83A10. Preferably, the bispecific format is Figure 2A of the form that contains the respective constant domains VL and VH of the CD3Fab swapped with each other and within the two BCMA Fabs, amino acid exchanges K213E in the CH1 domain and K147E and amino acid exchanges E123R and Q124K in the CL domain.

[0185] The bispecific antibody as mentioned herein can be prepared by the steps of: transforming a host cell with a vector comprising nucleic acid molecules encoding the light and heavy chains of the antibody molecule, culturing the host cell under conditions allowing synthesis of the antibody molecule; and recovering the antibody molecule from the culture.

[0186] The bispecific antibody as mentioned herein can be prepared by the steps of: transforming a host cell with a vector comprising nucleic acid molecules encoding the light and heavy chains of an antibody that specifically binds to a first target vector, the first target vector comprising nucleic acid molecules encoding the light and heavy chains of an antibody that specifically binds to a second target, wherein the variable domains VL and VH or the constant domains CL and CH1 are swapped with each other; culturing the host cell under conditions allowing synthesis of the antibody molecule; and recovering the antibody molecule from the culture.

[0187] In one embodiment, the bispecific antibody specifically binds to the extracellular domain of human BCMA and human CD3ε, and is characterized by comprising a heavy chain and light chain set selected from the group consisting of the following polypeptides:

[0188] i) SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51 (2x) (the first set of TCBs of antibody 21),

[0189] ii) SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54 (2x) (the second set of TCBs of antibody 22), and

[0190] iii) SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:56, and SEQ ID NO:57 (2x) (the third set of TCBs of antibody 42).

[0191] In one embodiment, the bispecific antibody specifically binds to the extracellular domain of human BCMA and human CD3ε, and is characterized by comprising a heavy chain and a light chain set selected from the group consisting of: SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, and SEQ ID NO:51 (2x) (the first set of TCBs of antibody 21).

[0192] In one embodiment, the bispecific antibody specifically binds to the extracellular domain of human BCMA and human CD3ε, and is characterized by comprising a heavy chain and a light chain set selected from the group consisting of: SEQ ID NO:48, SEQ ID NO:52, SEQ ID NO:53, and SEQ ID NO:54 (2x) (the second set of TCBs of antibody 22).

[0193] In one embodiment, the bispecific antibody specifically binds to the extracellular domain of human BCMA and human CD3ε, and is characterized by comprising a heavy chain and a light chain set selected from the group consisting of: SEQ ID NO:48, SEQ ID NO:55, SEQ ID NO:56, and SEQ ID NO:57 (2x) (the third set of TCBs of antibody 42).

[0194] Table 1A: Antibody Sequences

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206] Note: SEQ ID NO:20 and SEQ ID NO:33 are the same

[0207] Table 1B: Antibody Sequences (Short List)

[0208]

[0209] Table 2A: Additional Constructs

[0210]

[0211] Table 2B: Additional Constructs

[0212]

[0213] To prepare the following (2+1) Fc-containing anti-BCMA / anti-CD3 TCBs, the corresponding constructs / sequence IDs mentioned in Table 2B above were used:

[0214] 83A10-TCBcv: 45, 46, 47(x2), 48( Figure 2A )

[0215] 21-TCBcv: 48, 49, 50, 51(x2)( Figure 2A )

[0216] 22-TCBcv: 48, 52, 53, 54(x2)( Figure 2A )

[0217] 42-TCBcv: 48, 55, 56, 57(x2)( Figure 2A )

[0218] F. Methods of Treatment and Prevention and Compounds for Use in Such Methods

[0219] The combinations of Compounds 1, 2, and 3 and their enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts provided herein with the bispecific antibodies provided herein that specifically bind to human B cell maturation antigen (BCMA) and human CD3ε (CD3) can be used in all of the therapeutic methods provided herein.

[0220] In one embodiment, provided herein is a method of treating multiple myeloma, the method comprising administering to a patient a Compound 1 provided herein or its enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0221] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0222] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0223] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0224] In one embodiment, provided herein is a compound for use in a method of treating multiple myeloma, wherein the compound is Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient the Compound 1 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof provided herein and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0225] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0226] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0227] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0228] In one embodiment, provided herein is a method of treating multiple myeloma, the method comprising administering to a patient the Compound 2 or a tautomer, isotopologue or pharmaceutically acceptable salt thereof provided herein and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0229] i) The CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0230] ii) The CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0231] iii) The CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0232] In one embodiment, the present disclosure provides a compound for use in a method of treating multiple myeloma, wherein the compound is compound 2 or a tautomer, isotopomer or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient the compound 2 or a tautomer, isotopomer or pharmaceutically acceptable salt thereof provided herein and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22 and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0233] i) The CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0234] ii) The CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0235] iii) The CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0236] In one embodiment, provided herein is a method for treating multiple myeloma, the method comprising administering to a patient a compound 3 provided herein or a tautomer, isotopologue or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0237] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0238] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0239] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0240] In one embodiment, provided herein is a compound for use in a method for treating multiple myeloma, wherein the compound is compound 3 provided herein or a tautomer, isotopologue or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient a compound 3 provided herein or a tautomer, isotopologue or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0241] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0242] ii) the CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0243] iii) the CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0244] In one embodiment, provided herein is a method of preventing multiple myeloma, the method comprising administering to a patient a compound provided herein (e.g., compound 1, compound 2, or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein, the bispecific antibody comprising a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), optionally wherein the bispecific antibody is characterized in that the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22, and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0245] i) the CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0246] ii) the CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0247] iii) the CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0248] In one embodiment, provided herein is a compound for use in a method of preventing multiple myeloma, wherein the compound is a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient a compound provided herein (such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein, the bispecific antibody comprising a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), optionally wherein the bispecific antibody is characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0249] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0250] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0251] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0252] In another embodiment, provided herein is a method of controlling multiple myeloma, the method comprising administering to a patient a compound provided herein (such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein, the bispecific antibody comprising a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), optionally wherein the bispecific antibody is characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0253] i) The CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0254] ii) The CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0255] iii) The CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0256] In another embodiment, the present invention provides a compound for use in a method of controlling multiple myeloma, wherein the compound is a compound provided herein, such as compound 1, compound 2 or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient a compound provided herein (such as compound 1, compound 2 or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein, the bispecific antibody comprising a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), optionally wherein the bispecific antibody is characterized in that the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22 and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0257] i) The CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0258] ii) The CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0259] iii) The CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0260] In one embodiment, provided herein is also a method for inducing a therapeutic response in a patient, the response being evaluated using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10)10:1-7), the method comprising administering to a patient suffering from multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein, optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0261] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0262] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0263] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0264] In one embodiment, provided herein is also a method for inducing a therapeutic response in a patient, the response being evaluated using the consensus criteria for International Myeloma Working Group (IMWG) response and minimal residual disease assessment (Rajkumar et al., Blood, 2011, 117(18):4691-5; Kumar et al., Lancet Oncol., 2016, 17(8):e328-e346), the method comprising administering to a patient suffering from multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein, optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0265] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0266] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0267] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0268] In one embodiment, provided herein is a method for inducing a therapeutic response in a patient, the response being evaluated using the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia, 2006; (10)10:1-7), wherein the compound is a compound provided herein, e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0269] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0270] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0271] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0272] In one embodiment, provided herein is a compound for use in a method of inducing a therapeutic response in a patient, the response being evaluated using the International Myeloma Working Group (IMWG) response and minimal residual disease assessment consensus criteria (Rajkumar et al., Blood, 2011, 117(18):4691-5; Kumar et al., Lancet Oncol., 2016, 17(8):e328-e346), wherein the compound is a compound provided herein, e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0273] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0274] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0275] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0276] In another embodiment, provided herein are methods for achieving stringent complete response, complete response, or very good partial response as determined according to the International Uniform Response Criteria (IURC) for multiple myeloma in a patient, the methods comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein, optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22, and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0277] i) the CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0278] ii) the CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0279] iii) the CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0280] In another embodiment, provided herein is a method for achieving sustained MRD-negative, flow MRD-negative, sequencing MRD-negative, imaging plus MRD-negative, stringent complete response, complete response or very good partial response in a patient as determined according to the consensus criteria for International Myeloma Working Group (IMWG) response and minimal residual disease assessment, the method comprising administering to a patient suffering from multiple myeloma an effective amount of a compound described herein (e.g., compound 1, compound 2 or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof) and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein, optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22 and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0281] i) the CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0282] ii) the CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0283] iii) the CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0284] In another embodiment, provided herein are compounds for use in methods for achieving stringent complete response, complete response, or very good partial response as determined according to the International Uniform Response Criteria (IURC) for multiple myeloma in a patient, wherein the compound is a compound provided herein such as compound 1, compound 2, or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., compound 1, compound 2, or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B-cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B-cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0285] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0286] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0287] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0288] In another embodiment, provided herein are compounds for use in a method for achieving sustained MRD negative, flow MRD negative, sequencing MRD negative, imaging plus MRD negative, stringent complete response, complete response or very good partial response as determined according to the consensus criteria for International Myeloma Working Group (IMWG) response and minimal residual disease assessment in a patient, wherein the compound is a compound provided herein, such as Compound 1, Compound 2 or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., Compound 1, Compound 2 or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0289] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0290] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0291] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0292] In another embodiment, provided herein are methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival of a patient, the methods comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0293] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0294] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0295] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0296] In another embodiment, provided herein are compounds for use in methods of achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival of a patient, wherein the compound is a compound provided herein, such as compound 1, compound 2, or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., compound 1, compound 2, or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and is characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0297] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0298] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0299] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0300] In another embodiment, provided herein are methods for achieving an increase in the overall survival of a patient, the methods comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0301] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0302] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0303] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0304] In another embodiment, provided herein are compounds for use in a method of achieving an increase in overall survival of a patient, wherein the compound is a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0305] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0306] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0307] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0308] In another embodiment, provided herein are methods for achieving an increase in progression-free survival of a patient, the methods comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region comprising a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region comprising a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0309] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0310] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0311] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0312] In another embodiment, provided herein are compounds for use in a method of achieving an increase in progression-free survival of a patient, wherein the compound is a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0313] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0314] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0315] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0316] In another embodiment, provided herein are methods for achieving an increase in event-free survival of a patient, the methods comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0317] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0318] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0319] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0320] In another embodiment, provided herein are compounds for use in a method of achieving an increase in event-free survival of a patient, wherein the compound is a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, wherein the method comprises administering to a patient suffering from multiple myeloma an effective amount of a compound described herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B-cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B-cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0321] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0322] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0323] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0324] In another embodiment, provided herein are methods for achieving an increased time to progression in a patient, the method comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0325] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0326] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0327] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0328] In another embodiment, the present disclosure provides compounds for use in a method of increasing the progression time of a patient, wherein the compound is a compound provided herein, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22, and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0329] i) the CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0330] ii) the CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0331] iii) the CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0332] In another embodiment, provided herein are methods for achieving an increase in disease - free survival of a patient, the methods comprising administering to a patient having multiple myeloma an effective amount of a compound described herein (e.g., Compound 1, Compound 2, or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B - cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B - cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0333] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0334] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0335] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0336] In another embodiment, provided herein are compounds for use in a method of achieving an increase in disease - free survival of a patient, wherein the compound is a compound provided herein, such as compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and wherein the method comprises administering to a patient having multiple myeloma an effective amount of the compound described herein (e.g., compound 1, compound 2, or compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof) and a bispecific antibody provided herein that specifically binds to human B - cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B - cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22, and the CDR3H region of SEQ ID NO:17; and a VL region that comprises the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0337] i) the CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0338] ii) the CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0339] iii) the CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0340] Also provided herein are methods of treating patients who have previously been treated for multiple myeloma but are non - responsive to standard therapies and those patients who have not previously been treated. Further encompassed are methods of treating patients who have undergone surgery in an attempt to treat multiple myeloma and those patients who have not undergone surgery. Also provided herein are methods of treating patients who have previously undergone transplantation therapy and those patients who have not undergone transplantation therapy. Also provided herein are compounds for use in methods of treating patients who have previously been treated for multiple myeloma but are non - responsive to standard therapies and those patients who have not previously been treated. Further encompassed are compounds for use in methods of treating patients who have undergone surgery in an attempt to treat multiple myeloma and those patients who have not undergone surgery. Also provided herein are compounds for use in methods of treating patients who have previously undergone transplantation therapy and those patients who have not undergone transplantation therapy.

[0341] The methods provided herein include treating relapsed, refractory, or resistant multiple myeloma. The methods provided herein include preventing relapsed, refractory, or resistant multiple myeloma. The methods provided herein include controlling relapsed, refractory, or resistant multiple myeloma. In some such embodiments, the myeloma is primary, secondary, tertiary, quaternary, or quinary relapsed multiple myeloma. The methods provided herein include treating multiple myeloma that is newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma). The methods provided herein include preventing multiple myeloma that is newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma). The methods provided herein include controlling multiple myeloma that is newly diagnosed multiple myeloma (including low-risk, intermediate-risk, and high-risk newly diagnosed multiple myeloma). In one embodiment, the methods provided herein reduce, maintain, or eliminate minimal residual disease (MRD). In one embodiment, the methods provided herein encompass treating, preventing, or controlling various types of multiple myeloma by administering a therapeutically effective amount of a compound described herein, such as monoclonal gammopathy of undetermined significance (MGUS), low-risk, intermediate-risk, and high-risk multiple myeloma, transplant-eligible and transplant-ineligible multiple myeloma, indolent (smoldering) multiple myeloma (including low-risk, intermediate-risk, and high-risk indolent multiple myeloma), active multiple myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma. In one embodiment, the multiple myeloma is plasma cell leukemia. In another embodiment, the methods provided herein encompass treating, preventing, or controlling multiple myeloma characterized by genetic abnormalities by administering a therapeutically effective amount of a compound described herein, such genetic abnormalities 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; del(17 / 17p), non-hyperdiploidy, and gain of (1q)).In one embodiment, the method comprises administering a therapeutically effective amount of Compound 1 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopologue or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0342] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0343] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0344] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0345] In another embodiment, the method comprises administering a therapeutically effective amount of Compound 2 provided herein or a tautomer, isotopologue or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22 and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0346] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0347] ii) The CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0348] iii) The CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0349] In another embodiment, the method comprises administering a therapeutically effective amount of compound 3 provided herein or a tautomer, isotopomer or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region, the VH region comprising the CDR1H region of SEQ ID NO:21, the CDR2H region of SEQ ID NO:22 and the CDR3H region of SEQ ID NO:17; and a VL region, the VL region comprising the CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0350] i) The CDR1L region of SEQ ID NO:23 and the CDR2L region of SEQ ID NO:24,

[0351] ii) The CDR1L region of SEQ ID NO:25 and the CDR2L region of SEQ ID NO:26, or

[0352] iii) The CDR1L region of SEQ ID NO:27 and the CDR2L region of SEQ ID NO:28.

[0353] In one embodiment, high-risk multiple myeloma is multiple myeloma that recurs within 12 months after first treatment. In yet another embodiment, high-risk multiple myeloma is multiple myeloma characterized by genetic abnormalities such as one or more of del(17 / 17p and t(14;16)(q32;q32).

[0354] In some such embodiments, the multiple myeloma is newly diagnosed multiple myeloma that is suitable for transplantation. In another embodiment, the multiple myeloma is newly diagnosed multiple myeloma that is not suitable for transplantation. In other embodiments, the multiple myeloma is characterized by early progression (e.g., less than 12 months) after initial treatment. In other embodiments, the multiple myeloma is characterized by early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, the multiple myeloma is lenalidomide refractory or resistant. In another embodiment, the multiple myeloma is lenalidomide refractory. In another embodiment, the multiple myeloma is lenalidomide resistant. In another embodiment, the multiple myeloma is pomalidomide refractory or resistant. In another embodiment, the multiple myeloma is pomalidomide refractory. In another embodiment, the multiple myeloma is pomalidomide resistant. In some such embodiments, the multiple myeloma is predicted to be pomalidomide refractory (e.g., by molecular profiling). In another embodiment, the multiple myeloma has relapsed or is refractory to three or more treatments and has been exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, CC122, or CC220), or is dual resistant to a proteasome inhibitor and an immunomodulatory compound. In other embodiments, the multiple myeloma has relapsed or is refractory to three or more prior therapies, the prior therapies including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, CC122, or CC220), or is dual resistant to a proteasome inhibitor or an immunomodulatory compound and a CD38 mAb. In other embodiments, the multiple myeloma is triple refractory, e.g., the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, CC122, or CC220), and one other active agent as described herein.

[0355] In certain embodiments, provided herein are methods of treating, preventing, and / or controlling multiple myeloma, including relapsed / refractory multiple myeloma or its symptoms in patients with impaired renal function, the methods comprising administering to a patient with relapsed / refractory multiple myeloma with impaired renal function a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0356] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0357] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0358] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0359] In certain embodiments, provided herein are compounds for use in methods of treating, preventing, and / or controlling multiple myeloma, including relapsed / refractory multiple myeloma or its symptoms in patients with impaired renal function, wherein the compounds are those provided herein, such as compound 1, compound 2, or compound 3, or their enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts, wherein the methods comprise administering to a patient with relapsed / refractory multiple myeloma with impaired renal function a therapeutically effective amount of compound 1, compound 2, or compound 3 provided herein, or their enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0360] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0361] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0362] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0363] In certain embodiments, provided herein are methods of treating, preventing, and / or controlling multiple myeloma, including recurrent or refractory multiple myeloma or its symptoms in frail patients, the methods comprising administering to a frail patient having multiple myeloma a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0364] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0365] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0366] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0367] In certain embodiments, provided herein are compounds for use in methods of treating, preventing, and / or controlling multiple myeloma, including relapsed or refractory multiple myeloma or its symptoms in frail patients, wherein the compounds are those provided herein, such as compound 1, compound 2, or compound 3, or their enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts, wherein the methods comprise administering to a frail patient having multiple myeloma a therapeutically effective amount of compound 1, compound 2, or compound 3 provided herein, or their enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), and wherein the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0368] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0369] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0370] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28.

[0371] In some such embodiments, the frail patient is characterized as being ineligible for induction therapy or intolerant to dexamethasone treatment. In some such embodiments, the frail patient is an elderly person, e.g., greater than 65 years of age.

[0372] In certain embodiments, prior to administering Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), a patient to be treated by one of the methods provided herein has not been treated with a multiple myeloma therapy. In certain embodiments, prior to administering Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), a patient to be treated by one of the methods provided herein has been treated with a multiple myeloma therapy.

[0373] In certain embodiments, a patient to be treated by one of the methods provided herein has developed resistance to anti-multiple myeloma therapies. In some such embodiments, the patient has developed resistance to one, two, three, four, five, or more anti-multiple myeloma therapies. In one embodiment, the therapies are selected from CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, CC122, or CC220). In one embodiment, the therapies include one or more of CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, CC122, or CC220). In one embodiment, the therapies include one or more of alkylating agents (e.g., melphalan, cyclophosphamide, bendamustine), histone deacetylase inhibitors (e.g., panobinostat), other monoclonal antibodies (e.g., anti-SLAMF7 antibodies, e.g., elotuzumab), glucocorticoids (e.g., dexamethasone, prednisone), other anti-multiple myeloma therapies (e.g., cisplatin, etoposide, doxorubicin), and cell therapies (e.g., CAR-T).

[0374] The methods provided herein cover treating a patient regardless of the patient's age. In some embodiments, the subject is 18 years of age or older. In other embodiments, the subject is greater than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years old. In other embodiments, the subject is less than 65 years old. In other embodiments, the subject is greater than 65 years old. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject greater than 65 years old. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject greater than 75 years old.

[0375] G. Administration of Compound 1, Compound 2, or Compound 3

[0376] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 25 mg per day, from about 0.01 to about 10 mg per day, from about 0.01 to about 5 mg per day, from about 0.01 to about 2 mg per day, from about 0.01 to about 1 mg per day, from about 0.01 to about 0.5 mg per day, from about 0.01 to about 0.25 mg per day, from about 0.1 to about 25 mg per day, from about 0.1 to about 10 mg per day, from about 0.1 to about 5 mg per day, from about 0.1 to about 2 mg per day, from about 0.1 to about 1 mg per day, from about 0.1 to about 0.5 mg per day, from about 0.1 to about 0.25 mg per day, from about 0.5 to about 25 mg per day, from about 0.5 to about 10 mg per day, from about 0.5 to about 5 mg per day, from about 0.5 to about 2 mg per day, from about 1 to about 25 mg per day, from about 1 to about 10 mg per day, from about 1 to about 5 mg per day, from about 1 to about 2.5 mg per day, or from about 1 to about 2 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 25 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 10 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 2 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 1 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 0.5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.01 to about 0.25 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 25 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 10 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 2 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 1 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 0.5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.1 to about 0.25 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.5 to about 25 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.5 to about 10 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.5 to about 5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is from about 0.5 to about 2 mg per day.In one embodiment, a therapeutically or prophylactically effective amount of the compound is about 0.5 to about 1 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is about 1 to about 25 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is about 1 to about 10 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is about 1 to about 5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is about 1 to about 2.5 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of the compound is about 1 to about 2 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of Compound 1, Compound 2 or Compound 3 is about 0.1 mg to about 0.4 mg per day.

[0377] In certain embodiments, a therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, or about 25 mg per day. In some such embodiments, a therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, or about 0.7 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.1 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.2 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.3 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.4 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.5 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.6 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.7 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.8 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 0.9 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 1 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 2 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 3 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 4 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 5 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 6 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 7 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 8 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 9 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 10 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 15 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 20 mg per day. In certain embodiments, a therapeutically or prophylactically effective amount is about 25 mg per day.

[0378] In one embodiment, for the disorders described herein, the recommended daily dose range of Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is in the range of about 0.1 mg to about 25 mg per day, and in one embodiment is administered as a single once-daily dose or in divided doses within a day. In other embodiments, the dose is in the range of about 0.1 to about 10 mg per day. Specific daily doses include 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per day. More specific daily doses include 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day. In one embodiment, the specific daily dose is 0.1 mg per day. In one embodiment, the specific daily dose is 0.2 mg per day. In one embodiment, the specific daily dose is 0.3 mg per day. In one embodiment, the specific daily dose is 0.4 mg per day. In one embodiment, the specific daily dose is 0.5 mg per day. In one embodiment, the specific daily dose is 1 mg per day. In one embodiment, the specific daily dose is 2 mg per day. In one embodiment, the specific daily dose is 3 mg per day. In one embodiment, the specific daily dose is 4 mg per day. In one embodiment, the specific daily dose is 5 mg per day. In one embodiment, the specific daily dose is 6 mg per day. In one embodiment, the specific daily dose is 7 mg per day. In one embodiment, the specific daily dose is 8 mg per day. In one embodiment, the specific daily dose is 9 mg per day. In one embodiment, the specific daily dose is 10 mg per day. In one embodiment, the specific daily dose is 11 mg per day. In one embodiment, the specific daily dose is 12 mg per day. In one embodiment, the specific daily dose is 13 mg per day. In one embodiment, the specific daily dose is 14 mg per day. In one embodiment, the specific daily dose is 15 mg per day. In one embodiment, the specific daily dose is 16 mg per day. In one embodiment, the specific daily dose is 17 mg per day. In one embodiment, the specific daily dose is 18 mg per day. In one embodiment, the specific daily dose is 19 mg per day. In one embodiment, the specific daily dose is 20 mg per day. In one embodiment, the specific daily dose is 21 mg per day. In one embodiment, the specific daily dose is 22 mg per day. In one embodiment, the specific daily dose is 23 mg per day. In one embodiment, the specific daily dose is 24 mg per day.In one embodiment, the specific dose per day is 25 mg per day.

[0379] In a specific embodiment, the recommended starting dose can be 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20 or 25 mg per day. In another embodiment, the recommended starting dose can be 0.1, 0.2, 0.3, 0.4 or 0.5 mg per day. The dose can be increased to 1, 2, 3, 4 or 5 mg per day.

[0380] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.001 to about 5 mg / kg / day, about 0.001 to about 4 mg / kg / day, about 0.001 to about 3 mg / kg / day, about 0.001 to about 2 mg / kg / day, about 0.001 to about 1 mg / kg / day, about 0.001 to about 0.05 mg / kg / day, about 0.001 to about 0.04 mg / kg / day, about 0.001 to about 0.03 mg / kg / day, about 0.001 to about 0.02 mg / kg / day, about 0.001 to about 0.01 mg / kg / day, or about 0.001 to about 0.005 mg / kg / day.

[0381] The dose administered can also be expressed in units other than mg / kg / day. For example, the dose administered parenterally can be expressed as mg / m 2 / day. One of ordinary skill in the art will readily know how to convert the dose from mg / kg / day to mg / m 2 / day for a given height or weight or both of the subject (see, www.fda.gov / cder / cancer / animalframe.htm). For example, for a 65 kg person, a dose of 1 mg / kg / day is approximately equal to 38 mg / m 2 / day.

[0382] Depending on the condition of the disease to be treated and the subject, Compound 1, Compound 2 or Compound 3 provided herein or their enantiomers, mixtures of enantiomers, tautomers, isotopomers or pharmaceutically acceptable salts can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual or topical (e.g., transdermal or topical) administration routes. Compound 1, Compound 2 or Compound 3 provided herein or their enantiomers, mixtures of enantiomers, tautomers, isotopomers or pharmaceutically acceptable salts can be formulated alone or together with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles into suitable dosage units suitable for each administration route.

[0383] In one embodiment, the compounds provided herein, compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof are administered orally. In another embodiment, the compounds provided herein, compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof are administered parenterally. In another embodiment, the compounds provided herein, compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof are administered intravenously.

[0384] The compounds provided herein, compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof can be delivered as a single dose, such as a single bolus injection or an oral tablet or pill; or over time, such as a continuous infusion over time or fractionated bolus doses over time. If desired, the compounds as described herein can be administered repeatedly, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or its absence is determined by methods known in the art, such as patient symptom assessment, physical examination, laboratory evaluation, visualization of tumors using X-ray, CAT, PET, or MRI scans, and other generally accepted evaluation modalities.

[0385] In one embodiment of the methods provided herein, the compounds provided herein, such as compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof are administered prior to the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3). In one embodiment of the methods provided herein, the compounds provided herein, such as compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof are administered simultaneously with the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3). In one embodiment of the methods provided herein, the compounds provided herein, such as compound 1, compound 2, or compound 3, or enantiomers, mixtures of enantiomers, tautomers, isotopologues, or pharmaceutically acceptable salts thereof are administered after the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3).

[0386] Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, 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). Additionally, administration may be continuous (e.g., daily administration over a number of days, or every day), intermittent, e.g., in cycles (e.g., including a drug-free period of days, weeks, or months). As used herein, the term "daily" refers to the administration of a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, once or more than once per day (e.g., over a period of time). The term "continuous" is intended to mean the daily administration of a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, during an uninterrupted period of at least 7 days to 52 weeks. As used herein, the terms "intermittent" or "intermittently" are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, is administration one to six days per week, in cycles (e.g., daily administration for two to eight consecutive weeks, followed by a drug-free period of up to one week), or every other day. The term "cycle" as used herein is intended to mean daily or continuous administration of a therapeutic compound, such as Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, but with a drug-free period. In some such embodiments, administration is once daily for two to six days, followed by a drug-free period of five to seven days without administration.

[0387] In some embodiments, the administration frequency ranges from about daily dosing to about monthly dosing. In certain embodiments, the administration is once daily, twice daily, three times daily, four times daily, once every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered once daily. In another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered twice daily. In another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered three times daily. In another embodiment, Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered four times daily.

[0388] In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 20 days, followed by a drug-free period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 15 days, followed by a drug-free period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 10 days, followed by a drug-free period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 7 days, followed by a drug-free period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 5 days, followed by a drug-free period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 4 days, followed by a drug-free period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered in a treatment cycle that includes a dosing period of up to 3 days, followed by a drug-free period.

[0389] In one embodiment, the treatment cycle comprises a dosing period of up to 14 days, followed by a drug-free period. In one embodiment, the treatment cycle comprises a dosing period of up to 10 days, followed by a drug-free period. In one embodiment, the treatment cycle comprises a dosing period of up to 7 days, followed by a drug-free period. In one embodiment, the treatment cycle comprises a dosing period of up to 5 days, followed by a drug-free period. In one embodiment, the treatment cycle comprises a dosing period of up to 4 days, followed by a drug-free period. In one embodiment, the treatment cycle comprises a dosing period of up to 3 days, followed by a drug-free period.

[0390] In one embodiment, the drug-free period is from about 2 days to about 11 days. In one embodiment, the drug-free period is from about 2 days to about 10 days. In one embodiment, the drug-free period is about 2 days. In one embodiment, the drug-free period is about 3 days. In one embodiment, the drug-free period is about 4 days. In one embodiment, the drug-free period is about 5 days. In one embodiment, the drug-free period is about 6 days. In another embodiment, the drug-free period is about 7 days. In another embodiment, the drug-free period is about 8 days. In another embodiment, the drug-free period is about 9 days. In another embodiment, the drug-free period is about 10 days. In another embodiment, the drug-free period is about 11 days.

[0391] In one embodiment, the treatment cycle comprises a dosing period of up to 15 days, followed by a drug-free period of from about 2 days to about 10 days. In one embodiment, the treatment cycle comprises a dosing period of up to 10 days, followed by a drug-free period of from about 2 days to about 10 days. In one embodiment, the treatment cycle comprises a dosing period of up to 7 days, followed by a drug-free period of from about 2 days to about 10 days. In one embodiment, the treatment cycle comprises a dosing period of up to 5 days, followed by a drug-free period of from about 2 days to about 10 days. In one embodiment, the treatment cycle comprises a dosing period of up to 3 days, followed by a drug-free period of from about 10 days to about 15 days. In one embodiment, the treatment cycle comprises a dosing period of up to 3 days, followed by a drug-free period of from about 3 days to about 15 days.

[0392] In one embodiment, the treatment cycle comprises an administration period of up to 15 days, followed by a drug withdrawal period of 7 days. In one embodiment, the treatment cycle comprises an administration period of up to 10 days, followed by a drug withdrawal period of 5 days. In one embodiment, the treatment cycle comprises an administration period of up to 10 days, followed by a drug withdrawal period of 4 days. In one embodiment, the treatment cycle comprises an administration period of up to 10 days, followed by a drug withdrawal period of 3 days. In one embodiment, the treatment cycle comprises an administration period of up to 10 days, followed by a drug withdrawal period of 2 days. In one embodiment, the treatment cycle comprises an administration period of up to 7 days, followed by a drug withdrawal period of 7 days. In one embodiment, the treatment cycle comprises an administration period of up to 5 days, followed by a drug withdrawal period of 5 days. In one embodiment, the treatment cycle comprises an administration period of up to 3 days, followed by a drug withdrawal period of 11 days. In another embodiment, the treatment cycle comprises an administration period of up to 5 days, followed by a drug withdrawal period of 9 days. In another embodiment, the treatment cycle comprises an administration period of up to 5 days, followed by a drug withdrawal period of 2 days. In another embodiment, the treatment cycle comprises an administration period of up to 3 days, followed by a drug withdrawal period of 4 days.

[0393] In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 5 of a 28-day cycle. In another embodiment, the treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 on Days 1 to 10 of a 28-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 21 of a 28-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 5 of a 7-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 7 of a 7-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 10 and Days 15 to 24 of a 28-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 3 and Days 15 to 18 of a 28-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 7 and Days 15 to 21 of a 28-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 5 and Days 15 to 19 of a 28-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 on Days 1 to 3 and Days 15 to 17 of a 28-day cycle.

[0394] In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 14 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 from day 1 to day 4 and from day 8 to day 11 of a 21-day cycle. In one embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 5 and from day 8 to day 12 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 5 and from day 11 to day 15 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 5, from day 8 to day 12, and from day 15 to day 19 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 4, from day 8 to day 11, and from day 15 to day 18 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 4, from day 8 to day 10, and from day 15 to day 17 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 3 and from day 8 to day 11 of a 21-day cycle. In another embodiment, the treatment cycle comprises administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 from day 1 to day 3 and from day 11 to day 13 of a 21-day cycle.

[0395] Any treatment cycle described herein may be repeated at least 2, 3, 4, 5, 6, 7, 8 or more cycles. In some cases, the treatment cycles described herein comprise from 1 to about 24 cycles, from about 2 to about 16 cycles, or from about 2 to about 4 cycles. In some cases, the treatment cycles described herein comprise from 1 to about 4 cycles. In certain embodiments, cycles 1 to 4 are all 28-day cycles. In some embodiments, a therapeutically effective amount of Compound 1, Compound 2, or Compound 3 is administered for 1 to 13 28-day cycles (e.g., about 1 year). In some cases, the cyclical therapy is not limited to the number of cycles and treatment continues until disease progression. In some cases, the cycles may include varying the duration of the administration period and / or the drug-free period described herein.

[0396] In one embodiment, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 once daily at a dose of about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 5.0 mg / day, or 10 mg / day. In one embodiment, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 once daily at a dose of about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, or 0.8 mg / day. In some such embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 once daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 10 of a 28-day cycle. In some such embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 once daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 10 and days 15 to 24 of a 28-day cycle. In some such embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 once daily at a dose of about 0.1 mg on days 1 to 10 and days 15 to 24 of a 28-day cycle. In other embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 twice daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 of a 28-day cycle. In other embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 twice daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and days 15 to 19 of a 28-day cycle. In other embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 twice daily at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and days 15 to 17 of a 28-day cycle. In other embodiments, a treatment cycle comprises administering Compound 1, Compound 2, or Compound 3 twice daily at a dose of about 0.2 mg on days 1 to 3 and days 15 to 17 of a 28-day cycle. In one such embodiment, the compound is administered on days 1 to 3 (morning and evening), day 14 (only evening), days 15 and 16 (morning and evening), and day 17 (only morning) of Cycle 1.

[0397] H. Administration of Bispecific Antibodies that Specifically Bind to BCMA and CD3

[0398] In one embodiment, the bispecific antibody is administered once or twice a week via subcutaneous administration (e.g., in one embodiment, in a dose range of 0.1 to 2.5, in one embodiment up to 25 mg / m 2 / week, in one embodiment up to 250 mg / m 2 / week). Due to the excellent cytotoxic activity of the bispecific antibody, they can be administered at a clinical dose range size that is at least the same (or even lower) compared to conventional monospecific antibodies or conventional bispecific antibodies that are not T-cell bispecific (i.e., do not bind to CD3 on one arm). It is contemplated that subcutaneous administration is preferred in a clinical setting for bispecific antibodies (e.g., within a dose range of 0.1 - 250 mg / m 2 / week). Additionally, in patients with high levels of serum APRIL and BAFF (e.g., multiple myeloma patients), it may not be necessary to increase the dose of the bispecific antibody as it may not be affected by ligand competition. In contrast, an increased dose of other ligand-blocking / competing anti-BCMA antibodies may be required in those patients. Another advantage of the bispecific antibody is an elimination half-life of about 4 to 12 days, which allows for administration at least once or twice / week.

[0399] In one embodiment, the bispecific antibody is an antibody having properties that allow for once / twice-a-week treatment via the intravenous route but, in one embodiment, via subcutaneous administration (e.g., for 4 weeks at a dose within the range of 200 - 2000 mg / m 2 / week). It is contemplated that subcutaneous administration is possible and preferred in a clinical setting for bispecific antibodies (e.g., within a dose range of 200 - 2000 mg / m 2 / week, depending on the disease indication). Additionally, in patients with high levels of serum APRIL and BAFF (e.g., multiple myeloma patients), it may not be necessary to increase the dose of the bispecific antibody (e.g., non-ligand-blocking / competing antibody) as it may not be affected by ligand competition. In contrast, an increased dose of other ligand-blocking / competing anti-BCMA antibodies may be required in those patients, making subcutaneous administration technically more challenging (e.g., the drug). Another advantage of the bispecific antibody is based on the inclusion of an Fc portion, which is associated with an elimination half-life of 4 to 12 days and allows for administration at least once or twice / week.

[0400] I. Combination Therapy with Additional Active Agents

[0401] Treatment with Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) can also be combined or used in conjunction with conventional therapies (e.g., before, during, or after conventional therapy), which include but are not limited to surgery, biotherapy (including immunotherapy, e.g., using checkpoint inhibitors), radiotherapy, chemotherapy, stem cell transplantation, cell therapy, or other non-drug-based therapies currently used to treat, prevent, or control multiple myeloma. The combined use of the compounds provided herein and conventional therapies can provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being bound by theory, it is believed that treatment with Compound 1, Compound 2, or Compound 3 provided herein and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) can provide additive or synergistic effects when administered concurrently with conventional therapies.

[0402] As discussed elsewhere herein, methods for alleviating, treating, and / or preventing adverse or unwanted effects associated with conventional therapies (including but not limited to surgery, chemotherapy, radiotherapy, biotherapy, and immunotherapy) are encompassed herein. The compounds provided herein, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), and additional active ingredients can be administered to a patient before, during, or after the occurrence of side effects associated with conventional therapy.

[0403] Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) can also be combined or used in combination with additional therapeutic agents useful for treating and / or preventing multiple myeloma as described herein.

[0404] In one embodiment, provided herein is a method for treating multiple myeloma, the method comprising administering to a patient a combination of Compound 1 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent. In one embodiment, provided herein is a method for preventing multiple myeloma, the method comprising administering to a patient a combination of Compound 1 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent. In one embodiment, provided herein is a method for controlling multiple myeloma, the method comprising administering to a patient a combination of Compound 1 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent. In one embodiment, provided herein is a method for treating multiple myeloma, the method comprising administering to a patient a combination of Compound 2 provided herein or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent. In one embodiment, provided herein is a method for preventing multiple myeloma, the method comprising administering to a patient a combination of Compound 2 provided herein or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent. In one embodiment, provided herein is a method for controlling multiple myeloma, the method comprising administering to a patient a combination of Compound 2 provided herein or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent. In one embodiment, provided herein is a method for treating multiple myeloma, the method comprising administering to a patient a combination of Compound 3 provided herein or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and an additional active agent.In one embodiment, provided herein is a method of preventing multiple myeloma, the method comprising administering to a patient a combination of compound 3 provided herein or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), and an additional active agent. In one embodiment, provided herein is a method of controlling multiple myeloma, the method comprising administering to a patient a combination of compound 3 provided herein or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), and an additional active agent.

[0405] In one embodiment, provided herein is a method of treating, preventing, or controlling multiple myeloma, the method comprising administering to a patient a combination of compound 1, compound 2, or compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), and one or more additional active agents, and optionally in combination with radiotherapy, blood transfusion, or surgery.

[0406] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient having a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein, e.g., compound 1, compound 2, or compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof, and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3)) can be administered 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, or 12 weeks before), simultaneously with, 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, or 12 weeks after) administration of an additional therapy (e.g., a prophylactic or therapeutic agent). Quadruple therapy is also contemplated herein, and quintuple therapy is also contemplated. In one embodiment, the third therapy is dexamethasone.

[0407] Administration to a patient of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) and one or more additional active agents can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing before entering the bloodstream).

[0408] The route of administration of Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is independent of the route of administration of an additional active agent. In one embodiment, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered orally, and the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is administered by an intravenous route (but in one embodiment via subcutaneous administration). In another embodiment, Compound 1, Compound 2, or Compound 3 is administered intravenously, and the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is administered by an intravenous route (but in one embodiment via subcutaneous administration). Thus, according to these embodiments, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered orally or intravenously, the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is administered by an intravenous route (but in one embodiment via subcutaneous administration), and an additional therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, via inhalation, vaginally, intravitreally, via local delivery through a catheter or stent, subcutaneously, intradermally, intra-articularly, intrathecally, or in a slow-release formulation. In one embodiment, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and an additional therapy are administered orally or by IV by the same mode of administration, and the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is administered by an intravenous route (but in one embodiment via subcutaneous administration). In another embodiment, Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, is administered by one mode of administration, such as by IV, while an additional agent (an anti-multiple myeloma agent) is administered by another mode of administration, and the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is administered by an intravenous route (but in one embodiment via subcutaneous administration).

[0409] In one embodiment, the additional active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the additional active agent will depend on the specific agent used, the type of multiple myeloma being treated or controlled, the severity and stage of the disease, and the amount of Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and the bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein, as well as any optional additional active agent being co-administered to the patient.

[0410] One or more additional active ingredients or agents can be used in the methods and compositions provided herein in combination with Compound 1, Compound 2, or Compound 3, and the bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein. The additional active agent can be a macromolecule (e.g., a protein), a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule), or a cell therapy (e.g., CAR cells).

[0411] Examples of additional active agents that can be used in the methods and compositions described herein include melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), histone deacetylase inhibitors (e.g., panobinostat, ACY241), BET inhibitors (e.g., GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, C90010, ABBV-075, BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, EP11313, and EP11336), BCL2 inhibitors (e.g., venetoclax or navitoclax), MCL-1 inhibitors (e.g., AZD5991, AMG176, MIK665, S64315, or S63845), corticosteroids (e.g., prednisone), dexamethasone, antibodies (e.g., CS1 antibodies such as elotuzumab; CD38 antibodies such as daratumumab, isatuximab; or BCMA antibodies or antibody-drug conjugates such as GSK2857916 or BI 836909), checkpoint inhibitors (as described herein), or CAR cells (as described herein), or one or more of the foregoing.

[0412] In one embodiment, the additional active agent used in the methods and compositions described herein in combination with Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is dexamethasone.

[0413] In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 3, 14, and 17 of cycle 1. In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle (in one embodiment, cycles 1 to 8). In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 2, 8, and 9 of a 21-day cycle (in one embodiment, cycles ≥9). In some other embodiments, dexamethasone is administered at a dose of 4 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0414] In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 8 mg on days 1, 3, 14, and 17 of cycle 1. In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle (in one embodiment, cycles 1 to 8). In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 2, 8, and 9 of a 21-day cycle (in one embodiment, cycles ≥9).

[0415] In some other embodiments, dexamethasone is administered at a dose of 8 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0416] In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1 and 8 of a 21-day cycle.

[0417] In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 10 mg on days 1, 3, 14, and 17 of cycle 1. In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle (in one embodiment, cycles 1 to 8). In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, and 9 of a 21-day cycle (in one embodiment, cycles ≥9). In some other embodiments, dexamethasone is administered at a dose of 10 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0418] In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 10, 15, and 22 of cycle 1. In some embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 20 mg on days 1, 3, 14, and 17 of cycle 1. In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle (in one embodiment, cycles 1 to 8). In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, and 9 of a 21-day cycle (in one embodiment, cycles ≥9). In some other embodiments, dexamethasone is administered at a dose of 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0419] In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1 and 8 of a 21-day cycle. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, and 11 of a 21-day cycle. In some embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, and 15 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 10, 15, and 22 of cycle 1. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. In other such embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered at a dose of 40 mg on days 1, 3, 14, and 17 of cycle 1. In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle (in one embodiment, cycles 1 to 8). In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 2, 8, and 9 of a 21-day cycle (in one embodiment, cycles ≥9). In some other embodiments, dexamethasone is administered at a dose of 40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.

[0420] In another embodiment, an additional active agent to be used in the methods and compositions described herein in combination with Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is bortezomib. In another embodiment, an additional active agent to be used in the methods and compositions described herein in combination with Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) is daratumumab. In some such embodiments, the method further comprises administering dexamethasone. In some embodiments, the method comprises administering Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), in combination with a proteasome inhibitor as described herein, a CD38 antibody as described herein, and a corticosteroid as described herein.

[0421] In certain embodiments, Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) are administered in combination with a checkpoint inhibitor. In one embodiment, a checkpoint inhibitor is used in combination with Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) in the methods provided herein. In another embodiment, two checkpoint inhibitors are used in combination with Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) in the methods provided herein. In another embodiment, three or more checkpoint inhibitors are used in combination with Compound 1, Compound 2, or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) in the methods provided herein.

[0422] As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" refers to a molecule that fully or partially reduces, inhibits, interferes with, or modulates one or more checkpoint proteins. Without being limited by a particular theory, checkpoint proteins regulate T cell activation or function. Many checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 and its ligands PD-L1 and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). These proteins appear to be responsible for co-stimulatory or inhibitory interactions of T cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance as well as the duration and magnitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

[0423] In one embodiment, the checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, those described in U.S. Patent Nos. 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; 6,682,736; 6,984,720; and 7,605,238, the entire contents of which are incorporated herein by reference in their entirety. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is sold under the trade name Yervoy TM for sale.

[0424] In one embodiment, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of PD-1 / PD-L1 inhibitors include, but are not limited to, those described in U.S. Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149 and PCT Patent Application Publication Nos. WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400 and WO2011161699, the entire contents of which are incorporated herein by reference in their entirety.

[0425] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558 or MDX1106), or pembrolizumab (also known as MK-3475, SCH 900475 or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody and is sold under the trade name Opdivo TM for sale. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is sold under the trade name Keytruda TM for sale. In another embodiment, the anti-PD-1 antibody is CT-011 (a humanized antibody). Administration of CT-011 alone did not show a response to the treatment of acute myeloid leukemia (AML) at relapse. In another embodiment, the anti-PD-1 antibody is AMP-224 (a fusion protein). In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind to Fcγ receptor I has been specifically engineered out and it has a unique binding profile to PD-1 with high affinity and excellent target specificity.

[0426] In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A and ).

[0427] In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD-L2 antibody is rHIgM12B7A.

[0428] In one embodiment, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is IMP321 (a soluble Ig fusion protein) (Brignone et al., J. Immunol., 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

[0429] In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271 (an anti-B7-H3 antibody) (Loo et al., Clin. Cancer Res., 2012, 3834).

[0430] In one embodiment, the checkpoint inhibitor is a TIM3 (T cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp. Med., 2010, 207, 2187-94).

[0431] In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.

[0432] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti-GITR antibody is TRX518.

[0433] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566.

[0434] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.

[0435] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

[0436] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod.

[0437] In certain embodiments, the combination therapies provided herein include two or more checkpoint inhibitors (including checkpoint inhibitors of the same or different classes) described herein. Additionally, in cases suitable for treating the diseases described herein and understood in the art, the combination therapies described herein can be used in combination with one or more second active agents described herein.

[0438] In certain embodiments, Compound 1, Compound 2, or Compound 3 provided herein, and a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) can be used in combination with one or more immune cells (e.g., modified immune cells) that express one or more chimeric antigen receptors (CARs) on their surface. Generally, a CAR comprises an extracellular domain, a transmembrane domain, and an intracellular signaling domain from a first protein (e.g., an antigen-binding protein). In certain embodiments, once the extracellular domain binds to a target protein such as a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA), a signal is generated via the intracellular signaling domain that activates the immune cell, e.g., to target and kill cells expressing the target protein.

[0439] Extracellular domain: The extracellular domain of the CAR binds to the target antigen. In certain embodiments, the extracellular domain of the CAR comprises a receptor or a portion of a receptor that binds to the antigen. In certain embodiments, the extracellular domain comprises or is an antibody or an antigen-binding portion thereof. In a specific embodiment, the extracellular domain comprises or is a single-chain Fv (scFv) domain. The single-chain Fv domain can comprise, for example, a V H of V L connected to a V L via a flexible linker, where the V H and V

[0440] In certain embodiments, the antigen recognized by the extracellular domain of the polypeptides described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is, but not limited to, Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), CA19-9, calretinin, MUC-1, B cell maturation antigen (BCMA), epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma antigen recognized by T lymphocytes 24 (MAGE), CD19, CD22, CD27, CD30, CD34, CD45, CD70, CD99, CD117, EGFRvIII (epidermal growth factor variant III), mesothelin, PAP (prostatic acid phosphatase), prostasin, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAP1 (prostate six transmembrane epithelial antigen 1), chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein-15 (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-1), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysin, thyroglobulin, thyroid transcription factor-1, the dimeric form of pyruvate kinase isoenzyme M2 type (tumor M2-PK), abnormal ras protein or abnormal p53 protein. In certain other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is integrin alpha v beta 3 (CD61), prolactin or Ral-B.

[0441] In certain embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a cancer / testis (CT) antigen, e.g., BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ESO-1, NY-SAR-35, OY-TES-1, SPANXBI, SPA17, SSX, SYCP1 or TPTE.

[0442] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is a carbohydrate or a ganglioside, e.g., fuc-GM1, GM2 (carcinoembryonic antigen-immunogenic-1; OFA-I-1); GD2 (OFA-I-2), GM3, GD3, etc.

[0443] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of the CAR is α-actin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, β-catenin, CA 125, CA 15-3 (CA 27.29\BCAA), CA195, CA 242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa-1, dek-can fusion protein, EBNA, EF2, Epstein Barr virus antigen, ETV6-AML1 fusion protein, HLA-A2, HLA-All, hsp70-2, KIAA0205, Mart2, Mum-1, 2 and 3, neo-PAP, class I myosin, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, triosephosphate isomerase, Gage 3, 4, 5, 6, 7, GnTV, Herv-K-mel, Lage-1, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP2-Int2, gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, RAGE, GAGE-1, GAGE-2, p15(58), RAGE, SCP-1, Hom / Mel-40, PRAME, p53, HRas, HER-2 / neu, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, β-catenin, Mum-1, p16, TAGE, PSMA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, βHCG, BCA225, BTAA, CD68\KP1, C0-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-C0-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP or TPS.

[0444] In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is an AML-related tumor antigen as described by S. Anguille et al., Leukemia (2012), 26, 2186-2196.

[0445] Other tumor - associated antigens and tumor - specific antigens are known to those skilled in the art.

[0446] Receptors, antibodies, and scFvs that bind to TSAs and TAAs and can be used to construct chimeric antigen receptors are known in the art, and the nucleotide sequences encoding them are also known in the art.

[0447] In certain specific embodiments, the antigen recognized by the extracellular domain of the chimeric antigen receptor is an antigen that is not generally considered to be a TSA or TAA, but is still associated with tumor cells or damage caused by tumors. In some embodiments, for example, the antigen is a growth factor, cytokine, or interleukin, such as a growth factor, cytokine, or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines, or interleukins can include, for example, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet - derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin - like growth factor (IGF), or interleukin 8 (IL - 8). Tumors can also create a hypoxic environment locally in the tumor. Thus, in other specific embodiments, the antigen is a hypoxia - related factor, such as, for example, HIF - 1α, HIF - 1β, HIF - 2α, HIF - 2β, HIF - 3α, or HIF - 3β. Tumors can also cause local damage to normal tissues, resulting in the release of molecules called damage - associated molecular pattern molecules (DAMPs; also known as alarmin). Thus, in certain other specific embodiments, the antigen is a DAMP, such as heat - shock proteins, the chromatin - associated protein high - mobility group box 1 (HMGB 1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or can be deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparan sulfate.

[0448] Transmembrane domain: In certain embodiments, the extracellular domain of the CAR is linked to the transmembrane domain of the polypeptide by a linker, spacer, or hinge polypeptide sequence (e.g., a sequence from CD28 or a sequence from CTLA4). The transmembrane domain can be obtained from or derived from the transmembrane domain of any transmembrane protein and can include all or part of such a transmembrane domain. In specific embodiments, the transmembrane domain can be obtained from or derived from, for example, CD8, CD16, cytokine receptors, interleukin receptors, or growth factor receptors.

[0449] Intracellular signaling domain: In certain embodiments, the intracellular domain of the CAR is or comprises the intracellular domain or motif of a protein that is expressed on the surface of a T cell and triggers activation and / or proliferation of the T cell. Such a domain or motif is capable of transmitting the primary antigen-binding signal necessary to activate T lymphocytes in response to binding of an antigen to the extracellular portion of the CAR. Typically, this domain or motif comprises or is an ITAM (immunoreceptor tyrosine-based activation motif). ITAM-containing polypeptides suitable for the CAR include, for example, the ζ-CD3 chain (CD3ζ) or its ITAM-containing portion. In one specific embodiment, the intracellular domain is the CD3ζ intracellular signaling domain. In other specific embodiments, the intracellular domain is from a lymphocyte receptor chain, a TCR / CD3 complex protein, an Fe receptor subunit, or an IL-2 receptor subunit. In certain embodiments, the CAR further comprises one or more co-stimulatory domains or motifs, for example as part of the intracellular domain of a polypeptide. The one or more co-stimulatory domains or motifs can be or can comprise one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD134) polypeptide sequence, a co-stimulatory 4-1BB (CD137) polypeptide sequence, or a co-stimulatory inducible T cell co-stimulator (ICOS) polypeptide sequence or other co-stimulatory domains or motifs or any combination thereof.

[0450] The CAR can also comprise a T cell survival motif. The T cell survival motif can be any polypeptide sequence or motif that promotes the survival of T lymphocytes upon antigen stimulation. In certain embodiments, the T cell survival motif is or is derived from the intracellular signaling domain of CD3, CD28, the interleukin-7 receptor (IL-7R), the interleukin-12 receptor, the interleukin-15 receptor, the interleukin-21 receptor, or the transforming growth factor β (TGFβ) receptor.

[0451] The modified immune cells expressing a CAR can be, for example, T lymphocytes (T cells, such as CD4+ T cells or CD8+ T cells), cytotoxic lymphocytes (CTLs), or natural killer (NK) cells. The T lymphocytes used in the compositions and methods provided herein can be naive T lymphocytes or MHC-restricted T lymphocytes. In certain embodiments, the T lymphocytes are tumor-infiltrating lymphocytes (TILs). In certain embodiments, the T lymphocytes have been isolated from a tumor biopsy or the T lymphocytes isolated from a tumor biopsy have been expanded. In certain other embodiments, the T cells have been isolated or expanded from T lymphocytes isolated from peripheral blood, cord blood, or lymph. Conventional methods well known in the art can be used to isolate the immune cells to be used for generating the modified immune cells expressing a CAR, for example, blood collection followed by apheresis, and optionally antibody-mediated cell separation or sorting.

[0452] The modified immune cells are preferably autologous to the individual to whom the modified immune cells are to be administered. In certain other embodiments, the modified immune cells are allogeneic to the individual to whom the modified immune cells are to be administered. When allogeneic T lymphocytes or NK cells are used to prepare modified T lymphocytes, T lymphocytes or NK cells that will reduce the likelihood of graft-versus-host disease (GVHD) in the individual are preferably selected. For example, in certain embodiments, virus-specific T lymphocytes are selected for preparing modified T lymphocytes; it is expected that such lymphocytes will have a greatly reduced natural ability to bind to any receptor antigen and thus be activated by any receptor antigen. In certain embodiments, receptor-mediated rejection of allogeneic T lymphocytes can be reduced by co-administering to the host one or more immunosuppressive agents, such as cyclosporine, tacrolimus, sirolimus, cyclophosphamide, and the like.

[0453] T lymphocytes (such as unmodified T lymphocytes or T lymphocytes expressing CD3 and CD28 or T lymphocytes comprising a polypeptide containing a CD3ζ signaling domain and a CD28 co-stimulatory domain) can be expanded using antibodies against CD3 and CD28, such as antibodies attached to beads; see, for example, U.S. Patent Nos. 5,948,893; 6,534,055; 6,352,694; 6,692,964; 6,887,466; and 6,905,681.

[0454] Modified immune cells, such as modified T lymphocytes, may optionally contain a "suicide gene" or "safety switch" that is capable of killing substantially all modified immune cells when needed. For example, in certain embodiments, the modified T lymphocytes may contain the herpes simplex virus thymidine kinase gene (HSV-TK), which causes the death of the modified T lymphocytes upon contact with ganciclovir. In another embodiment, the modified T lymphocytes contain an inducible caspase, such as inducible caspase 9 (icaspase9), such as a fusion protein between caspase 9 and the human FK506 binding protein, thereby allowing dimerization using a specific small molecule drug. See Straathof et al., Blood 105(11):4247-4254 (2005).

[0455] J. Pharmaceutical compositions

[0456] The pharmaceutical compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

[0457] In another embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein and a bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3), and a pharmaceutically acceptable excipient, optionally wherein the bispecific antibody comprises a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), characterized in that the first binding portion comprises a VH region that comprises a CDR1H region of SEQ ID NO:21, a CDR2H region of SEQ ID NO:22, and a CDR3H region of SEQ ID NO:17; and a VL region that comprises a CDR3L region of SEQ ID NO:20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0458] i) a CDR1L region of SEQ ID NO:23 and a CDR2L region of SEQ ID NO:24,

[0459] ii) a CDR1L region of SEQ ID NO:25 and a CDR2L region of SEQ ID NO:26, or

[0460] iii) a CDR1L region of SEQ ID NO:27 and a CDR2L region of SEQ ID NO:28. In one embodiment, the composition is for combination therapy of multiple myeloma.

[0461] In another embodiment, the present disclosure provides a pharmaceutical composition comprising Compound 1, Compound 2, or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopomer, or pharmaceutically acceptable salt thereof, and a bispecific antibody, the bispecific antibody comprising a first binding portion that specifically binds to human B cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε (CD3), optionally wherein the bispecific antibody is characterized in that the first binding portion comprises a VH region comprising a CDR1H region of SEQ ID NO: 21, a CDR2H region of SEQ ID NO: 22, and a CDR3H region of SEQ ID NO: 17; and a VL region comprising a CDR3L region of SEQ ID NO: 20 and a combination of CDR1L and CDR2L regions selected from the group consisting of:

[0462] i) a CDR1L region of SEQ ID NO: 23 and a CDR2L region of SEQ ID NO: 24,

[0463] ii) a CDR1L region of SEQ ID NO: 25 and a CDR2L region of SEQ ID NO: 26, or

[0464] iii) a CDR1L region of SEQ ID NO: 27 and a CDR2L region of SEQ ID NO: 28,

[0465] and a pharmaceutically acceptable excipient. In one embodiment, the composition is for combination therapy of multiple myeloma.

[0466] The compounds can be formulated into suitable pharmaceutical preparations, such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or elixirs for oral administration, or in the form of sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch formulations and dry powder inhalers. Generally, the above compounds are formulated into pharmaceutical compositions using techniques and methods well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, 7th Edition 1999).

[0467] In the composition, an effective concentration of one or more compounds or pharmaceutically acceptable salts is mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective for delivering an amount that treats, prevents, or ameliorates one or more symptoms and / or progression of multiple myeloma upon administration.

[0468] Typically, the compositions are formulated for single-dose administration. To formulate the compositions, the weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed at an effective concentration in a selected vehicle to alleviate or ameliorate the disorder being treated. Pharmaceutical carriers or vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art as being suitable for the particular mode of administration.

[0469] Additionally, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. Liposome suspensions, including tissue-targeted liposomes such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These can be prepared by methods known to those skilled in the art. For example, liposomal formulations can be prepared according to methods known in the art. Briefly, liposomes such as multilamellar vesicles (MLV) can be formed by drying phosphatidylcholine and phosphatidylserine (molar ratio 7:3) inside a flask. A solution of the compound provided herein in phosphate buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0470] The active compound is included in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect without producing adverse side effects on the patient being treated. The therapeutically effective concentration can be determined empirically by testing the compound in the in vitro and in vivo systems described herein and then extrapolating the dose for humans therefrom.

[0471] The concentration of the active compound in the pharmaceutical composition will depend on the absorption, tissue distribution, inactivation, metabolism, and excretion rates of the active compound, the physicochemical properties of the compound, the dosing regimen and the amount administered, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to ameliorate one or more symptoms of cancer, including solid tumors and hematogenous tumors.

[0472] Solutions or suspensions for parenteral, intradermal, subcutaneous, or topical administration may contain any of the following components: a sterile diluent such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerol, propylene glycol, dimethylacetamide, or other synthetic solvents; an antimicrobial such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citrate, or phosphate; and an agent for adjusting tonicity such as sodium chloride or dextrose. Parenteral formulations can be enclosed in ampoules, pens, disposable syringes, or single-dose or multi-dose vials made of glass, plastic, or other suitable materials.

[0473] In cases where the compound exhibits insufficient solubility, methods for solubilizing the compound can be used. Such methods are known to those skilled in the art and include, but are not limited to, using co-solvents such as dimethyl sulfoxide (DMSO), using surfactants such as or dissolving in an aqueous sodium bicarbonate solution.

[0474] After mixing or adding the compound, the resulting mixture can be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to improve the symptoms of the disease, disorder, or condition being treated and can be determined empirically.

[0475] A pharmaceutical composition is provided for administration to humans and animals in unit dosage forms such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-in-water emulsions containing a suitable amount of the compound or its pharmaceutically acceptable salt. The pharmaceutically active compounds and their salts are formulated and administered in unit dosage forms or multiple dosage forms. As used herein, a unit dosage form refers to physically discrete units suitable for human and animal subjects and individually packaged as known in the art. Each unit dose contains a predetermined amount of the pharmaceutically active compound sufficient to produce the desired therapeutic effect, as well as the required pharmaceutical carrier, vehicle, or diluent. Examples of unit dosage forms include ampoules and syringes, as well as individually packaged tablets or capsules. The unit dosage form can be administered in fractions or multiples thereof. A multi-dose form is a plurality of identical unit dosage forms packaged in a single container for administration in separate unit dose forms. Examples of multi-dose forms include vials, bottles of tablets or capsules, or pints or gallons of bottles. Thus, a multi-dose form is a multiple of unit doses not separated in the package.

[0476] Dosage forms or compositions can be prepared containing from 0.005% to 100% of the active ingredient, with the remainder consisting of a non-toxic carrier. For oral administration, pharmaceutically acceptable non-toxic compositions can be formed by incorporating any commonly used excipients such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, talc, cellulose derivatives, sodium carboxymethyl cellulose, glucose, sucrose, magnesium carbonate, or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained release formulations such as, but not limited to, implants and microencapsulated delivery systems, as well as biodegradable biocompatible polymers such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid, etc. Methods for preparing these compositions are known to those skilled in the art.

[0477] The active compound or pharmaceutically acceptable salt can be prepared with a carrier that protects the compound from rapid clearance from the body, such as a sustained release formulation or coating.

[0478] The composition may comprise other active compounds to obtain a desired combination of properties. The compounds provided herein or their pharmaceutically acceptable salts may also be advantageously administered together with another pharmacological agent known in the art to be valuable in the treatment of one or more of the above-mentioned diseases or medical conditions (such as diseases associated with oxidative stress) for therapeutic or prophylactic purposes. It is understood that such combination therapy constitutes another aspect of the compositions and methods of treatment provided herein.

[0479] K. Evaluation of the Activity and Properties of the Combinations

[0480] Standard physiological, pharmacological, and biochemical procedures can be used to test the compounds to identify compounds having the desired properties, including anti - multiple myeloma proliferative activity and adequate safety. Such assays include, for example, biochemical assays such as binding assays, radio - incorporation assays, and various cell - based assays.

[0481] It is understood that the above - detailed description and the accompanying examples are illustrative only and should not be considered as limiting the scope of the subject matter. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention, including but not limited to those related to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods of use provided herein. The U.S. patents and publications cited herein are incorporated by reference.

[0482] 5. Examples

[0483] Certain embodiments of the invention are illustrated by the following non - limiting examples.

[0484] Abbreviations:

[0485] AIBN: Azobisisobutyronitrile;

[0486] Boc tert - Butoxycarbonyl

[0487] Boc2O Di - tert - butyl dicarbonate

[0488] tBuOK Potassium tert - butoxide

[0489] DIEA Diisopropylethylamine

[0490] DMF N,N’ - Dimethylformamide

[0491] EtOAc Ethyl acetate

[0492] MeOH Methanol

[0493] MM Multiple myeloma

[0494] NBS: N-bromosuccinimide,

[0495] NMR nuclear magnetic resonance

[0496] i-PrOAc: isopropyl acetate

[0497] TBSCl tert-butyldimethylchlorosilane

[0498] THF tetrahydrofuran

[0499] TLC thin layer chromatography

[0500] TMSCl trimethylchlorosilane

[0501] Example 1: Synthesis of 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 1).

[0502]

[0503] 2-Amino-5-methoxy-5-oxopentanoic acid. Trimethylchlorosilane (277 g, 2.55 mol) was added to a suspension of 2-aminoglutaric acid (250 g, 1.70 mol) in dry methanol (2.5 L) under nitrogen over 30 minutes. The resulting clear solution was stirred at room temperature (20 °C) for 30 minutes. 1 1H NMR showed complete consumption of the starting material. The reaction mixture was used for the next step without further workup. 1 1HNMR: 400 MHz CD3OD δ: 4.17 - 4.15 (m, 1H), 3.71 (s, 3H), 2.70 - 2.60 (m, 2H), 2.33 - 2.25 (m, 2H).

[0504] 2-((tert-Butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid. Triethylamine (275 g, 2.72 mol) and di-tert-butyl dicarbonate (447.35 g, 2.05 mol) were added to the above solution. The reaction mixture was stirred at 25 °C for 2 hours. The solution was concentrated to dryness, then water (2.5 L) was added to dissolve the residue. The resulting aqueous phase was washed with ethyl acetate (200 mL), then acidified to pH = 3 with HCl (1 N) and extracted with ethyl acetate (1 L × 3). The combined organic layers were washed with brine (800 mL), dried over sodium sulfate, filtered and concentrated to afford 2-(tert-butoxycarbonylamino)-5-methoxy-5-oxo-pentanoic acid as a white solid (250 g, 56% yield, two steps). 11H NMR: 400 MHz in CD3OD δ: 4.18 - 4.11 (m, 1H), 3.69 (s, 3H), 2.48 - 2.43 (m, 2H), 2.21 - 2.15 (m, 1H), 1.95 - 1.91 (m, 1H), 1.46 (s, 9H).

[0505] Methyl 5 - amino - 4 - (tert - butoxycarbonylamino) - 5 - oxopentanoate. To a solution of 2 - (tert - butoxycarbonylamino) - 5 - methoxy - 5 - oxopentanoic acid (200 g, 765 mmol) in 1,4 - dioxane (1.5 L) was added di - tert - butyl dicarbonate (267 g, 1.22 mol) and pyridine (121 g, 1.53 mol). After stirring the reaction mixture at 25 °C for 30 minutes, ammonium carbonate (182 g, 2.30 mol) was added to the mixture and stirring was continued at 25 °C for 16 hours. The organic solvent was removed by rotary evaporation, the residue was acidified to pH = 3 with HCl (6 M), and then extracted with ethyl acetate (800 mL x 3). The combined organic phases were washed with brine (800 mL), dried over sodium sulfate and filtered. Volatile organic compounds were removed under reduced pressure to give methyl 5 - amino - 4 - (tert - butoxycarbonylamino) - 5 - oxopentanoate as a white solid (180 g, 90% yield). 1 1H NMR: 400 MHz in CDCl3 δ: 6.51 (s, 1H), 5.94 (s, 1H), 5.43 (s, 1H), 4.21 (s, 1H), 3.63 (s, 3H), 2.59 - 2.40 (m, 2H), 2.15 - 2.11 (m, 1H), 1.94 - 1.90 (m, 1H), 1.42 (s, 9H).

[0506] Methyl 4,5 - diamino - 5 - oxopentanoate hydrochloride. A mixture of methyl 5 - amino - 4 - (tert - butoxycarbonylamino) - 5 - oxopentanoate (180 g, 692 mmol) and HCl / ethyl acetate (300 mL, 4 M) was stirred at 25 °C for 12 hours. The precipitated solid was collected by vacuum filtration and washed with ethyl acetate (500 mL) to give methyl 4,5 - diamino - 5 - oxopentanoate hydrochloride as a white solid (130 g, 95% yield). 1 1H NMR: 400 MHz in CD3OD δ: 4.00 - 3.96 (m, 1H), 3.70 (s, 3H), 2.59 - 2.52 (m, 2H), 2.22 - 2.13 (m, 2H).

[0507] Methyl 3-hydroxy-2-methylbenzoate. Four batches (200 g each) were run in parallel. Concentrated sulfuric acid (47.7 g, 486 mmol) was added to a solution of 3-hydroxy-2-methylbenzoic acid (200 g, 1.31 mol) in methanol (4.0 L). The reaction mixture was stirred at 60 °C for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20 °C and slowly poured into water (400 mL) over 30 min. Water (1200 mL) was added over 3 h at 20 °C and the resulting mixture was stirred at 20 °C for 1 h. The precipitated solid was collected by vacuum filtration (combining four batches) and washed three times with water / methanol (1000 mL, 9:1) until pH > 3. The solid was dried in vacuo at 45 °C to give methyl 3-hydroxy-2-methylbenzoate as a grey solid (700 g, 80.4% yield). 1 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J = 6.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H).

[0508] Methyl 3-[(tert-butyl(dimethyl)silyl)oxy]-2-methylbenzoate. Two batches (240 g each) were run in parallel. Imidazole (246 g, 3.61 mol) and tert-butyldimethylchlorosilane (238 g, 1.58 mol) were added to a solution of methyl 3-hydroxy-2-methylbenzoate (240 g, 1.44 mol) in N,N-dimethylformamide (1.40 L) at 5 °C. After addition, the mixture was warmed to 20 °C and stirred for 6 h. Isopropyl acetate (1700 mL) was added, then water (2000 mL) was added slowly while maintaining the temperature below 30 °C. The resulting mixture was stirred and the organic phase was separated. The combined organic phases (combining two batches) were washed with water (1700 mL x 3) and concentrated to approximately 1500 mL (KF < 0.05%). The product was stored as an isopropyl acetate solution and was used in the next step without further purification.

[0509] Methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-benzoate. Two batches (each approximately 375 g) were run in parallel. To a solution of methyl 3-[tert-butyl(dimethyl)silyl]oxy-2-methyl-benzoate in isopropyl acetate (approx. 375 g, 1.34 mol) was added N-bromosuccinimide (274 g, 1.54 mol) and azobisisobutyronitrile (4.40 g, 26.8 mmol). The reaction mixture was heated to 70 °C over at least 1 hour and stirred at 70 °C for 4 hours. The reaction mixture was cooled to 20 °C and held at 20 °C for at least 1 hour. The solids (succinimide) from both batches were removed by filtration and washed with isopropyl acetate (700 mL). The filtrate was washed with a solution of sodium sulfite (700 g) in water (6000 mL), then with water (1500 mL). The organic layer was distilled to dryness under vacuum at 45 °C to give methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-benzoate as a dark orange oil (920 g, 95.5% yield). 1 H NMR: 400 MHz DMSO-d6 δ: 7.45 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 4.95 (s, 2H), 1.02 (s, 9H), 0.29 (s, 6H).

[0510] Methyl 5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate. To a stirred solution of methyl 4,5-diamino-5-oxo-pentanoate hydrochloride (74.5 g, 379 mmol) in acetonitrile (2.50 L) was added methyl 2-(bromomethyl)-3-[tert-butyl(dimethyl)silyl]oxy-benzoate (125 g, 348 mmol). Diisopropylethylamine (89.9 g, 696 mmol) was added to the suspension via an addition funnel over 10 minutes, then the mixture was stirred at 60 °C for 16 hours. The reaction mixture was diluted with ethyl acetate (1.0 L) and washed successively with HCl (1 N, 1.0 L), sodium bicarbonate (saturated 1.0 L) and brine (1.0 L). The organic layer was concentrated to give crude methyl 5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate as a pale yellow solid (108 g, crude). LCMS: m / z 407.3 [M+1] + 。

[0511] Methyl 5-amino-4-(4-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate. Potassium carbonate (14.7 g, 106 mmol) in water (40 mL) was added portionwise to a stirred cold solution of methyl 5-amino-4-[4-[tert-butyl(dimethyl)silyl]oxy-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (108 g, 266 mmol) in N,N-dimethylformamide (350 mL) over 5 minutes. The resulting reaction mixture was stirred at 15 °C for 15 h. The reaction mixture was cooled in an ice bath and HCl (12 M, 15 mL) was added slowly at 0 °C - 5 °C. Acetonitrile (200 mL) was added to the mixture and the solid formed was precipitated. The suspension was stirred at room temperature for 10 minutes and filtered. The filter cake was washed with ethyl acetate (200 mL x 5) to give the product (55 g). The filtrate was concentrated under high vacuum to give the crude product (100 g), which was dissolved in dichloromethane (1.0 L) and allowed to stand at 15 °C for 16 h. A white solid formed, which was filtered to give 5 g of product. The solids were combined to give methyl 5-amino-4-(4-hydroxy-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate as a white solid (60 g, 77% yield). 1 H NMR: 400 MHz DMSO-d6 δ: 7.58 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.19 - 7.14 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 4.75 - 4.71 (m, 1H), 4.50 (d, J = 17.6 Hz, 1H), 4.32 (d, J = 17.6 Hz, 1H), 3.51 (s, 3H), 2.29 - 2.18 (m, 3H), 2.09 - 1.99 (m, 1H).

[0512] Methyl 5-amino-4-[4-[[4-(bromomethyl)phenyl]methoxy]-1-oxoisoindolin-2-yl]-5-oxopentanoate. Two reactions were carried out in parallel (25 g, 85.5 mmol). A mixture of 1,4-bis(bromomethyl)benzene (67.7 g, 257 mmol), potassium carbonate (11.8 g, 85.5 mmol) and methyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (25 g, 85.5 mmol) in acetonitrile (1 L) was stirred at 60 °C for 16 h. The two batches were combined and the mixture was cooled to 15 °C and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluting with 50% petroleum ether in ethyl acetate to 100% ethyl acetate) to give methyl 5-amino-4-[4-[[4-(bromomethyl)phenyl]methoxy]-1-oxoisoindolin-2-yl]-5-oxopentanoate as a white solid (52 g, 63% yield). 1 1H NMR: 400 MHz DMSO-d6 δ: 7.59 (s, 1H), 7.50 - 7.44 (m, 5H), 7.32 - 7.28 (m, 2H), 7.19 (s, 1H), 5.26 (s, 2H), 4.79 - 4.71 (m, 3H), 4.55 (d, J = 17.6 Hz, 1H), 4.43 (d, J = 17.6 Hz, 1H), 3.52 (s, 3H), 2.30 - 2.19 (m, 3H), 2.10 - 2.08 (m, 1H).

[0513] 3-[4-[[4-(Bromomethyl)phenyl]methoxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione. Two reactions were run in parallel (28.5 g, 60.0 mmol). Methyl 5-amino-4-[4-[[4-(bromomethyl)phenyl]methoxy]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (28.5 g, 60.0 mmol) was dissolved in tetrahydrofuran (720 mL), and the solution was cooled to -70 °C in a dry ice / acetone bath. With stirring, potassium tert-butoxide (7.4 g, 66.0 mmol) was added in one portion to the clear solution. The reaction mixture turned light yellow and was stirred at -70 °C for an additional 2 h. A cooled solution of HCl (1 N, 260 mL) was rapidly transferred to the reaction mixture while maintaining the temperature at -70 °C. The mixture immediately turned milky white, and the dry ice / acetone bath was removed. The mixture was concentrated to remove most of the tetrahydrofuran. After concentration of the reaction mixture, a white solid precipitated. The white slurry was diluted with water (500 mL) and then filtered. The filter cake was washed with water (500 mL) and dried in a vacuum oven at 40 °C for 12 h and then washed with ethyl acetate (500 mL). The batches were combined to give 3-[4-[[4-(bromomethyl)phenyl]methoxy]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione as a yellow solid (49.85 g, 93%). 1 1H NMR: 400 MHz DMSO-d6 δ: 10.95 (s, 1H), 7.51 - 7.41 (m., 5H), 7.35 - 7.28 (m, 2H), 5.23 (s, 2H), 5.12 - 5.07 (m, 1H), 4.70 (s, 2H), 4.41 (d, J = 17.6 Hz, 1H), 4.25 (d, J = 17.6 Hz, 1H), 2.90 - 2.84 (m, 1H), 2.58 - 2.53 (m, 1H), 2.44 - 2.41 (m, 1H), 1.98 - 1.95 (m, 1H).

[0514] 4-(4-(4-(((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 3-(4-((4-(Bromomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.0 g, 11.28 mmol) was placed in a flask containing 3-fluoro-4-(piperazin-1-yl)benzonitrile (2.315 g, 11.28 mmol), diisopropylethylamine (5.91 ml, 33.8 mmol) and acetonitrile (100 ml). The reaction mixture was stirred at 40 °C for 18 h. Volatile organic compounds were removed under reduced pressure and purified by standard methods to give 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 7.68 (dd, J = 1.96, 13.45 Hz, 1H), 7.56 (dd, J = 1.77, 8.38 Hz, 1H), 7.43 - 7.52 (m, 3H), 7.30 - 7.38 (m, 4H), 7.11 (t, J = 8.80 Hz, 1H), 5.24 (s, 2H), 5.11 (dd, J = 5.14, 13.33 Hz, 1H), 4.37 - 4.46 (m, 1H), 4.22 - 4.30 (m, 1H), 3.54 (s, 2H), 3.12 - 3.23 (m, 4H), 2.84 - 2.98 (m, 1H), 2.52 - 2.62 (m, 5H), 2.36 - 2.48 (m, 1H), 1.92 - 2.04 (m, 1H). MS (ESI) m / z 568.2 [M+1] + 。C 32 H 30 Calculated for C29H28FN5O4: C, 67.71; H, 5.33; N, 12.34. Found: C, 67.50; H, 5.44; N 12.34.

[0515] Example 2: Synthesis of (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (Compound 2).

[0516]

[0517] (4S)-tert-Butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate. To a solution of (2S)-2-(benzyloxycarbonylamino)-5-tert-butoxy-5-oxopentanoic acid (150 g, 445 mmol) in 1,4-dioxane (1.50 L) was added di-tert-butyl dicarbonate (155 g, 711 mmol), pyridine (70.3 g, 889 mmol) and ammonium bicarbonate (105 g, 1.33 mol). The reaction mixture was stirred at 18 °C for 16 h and then concentrated. The residue was dissolved in ethyl acetate (5.0 L) and water (5.0 L), the organic layer was separated and washed with HCl (3.0 mL, 1 N), saturated sodium bicarbonate (3.0 L), brine (3.0 L), dried over anhydrous sodium sulfate, filtered and concentrated to give crude (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate as a white solid (450 g, crude), which was used in the next step without further purification. 1 H NMR 400 MHz DMSO-d6 δ: 7.35 - 7.30 (m, 5H), 7.02 (s, 1H), 5.01 (d, J = 3.2 Hz, 1H), 3.93 - 3.90 (m, 1H), 2.20 (t, J = 8.0 Hz, 2H), 1.88 - 1.84 (m, 1H), 1.72 - 1.69 (m, 1H), 1.35 (s, 9H).

[0518] (4S)-tert-Butyl 4,5-diamino-5-oxopentanoate. Under nitrogen, to a solution of (4S)-tert-butyl 5-amino-4-(benzyloxycarbonylamino)-5-oxopentanoate (112 g, 333 mmol) in methanol (1.0 L) was added 10% palladium on carbon (15 g). The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 30 °C under hydrogen (40 psi) for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give crude (4S)-tert-butyl 4,5-diamino-5-oxopentanoate as a colorless oil. 1 H NMR 400 MHz DMSO-d6 δ: 7.30 (s, 1H), 6.95 (s, 1H), 3.10 - 3.07 (m, 1H), 2.27 - 2.23 (m, 2H), 1.69 - 1.78 (m, 1H), 1.59 - 1.55 (m, 1H), 1.38 (s, 9H).

[0519] Methyl 3-hydroxy-2-methylbenzoate. Four batches (200 g each) were run in parallel. Concentrated sulfuric acid (47.7 g, 486 mmol) was added to a solution of 3-hydroxy-2-methylbenzoic acid (200 g, 1.31 mol) in methanol (4.0 L). The reaction mixture was stirred at 60 °C for 17 h. The reaction mixture was concentrated to 800 mL. The resulting mixture was cooled to 20 °C and slowly poured into water (400 mL) over 30 min. Water (1200 mL) was added over 3 h at 20 °C and the resulting mixture was stirred at 20 °C for 1 h. The precipitated solid was collected by vacuum filtration (combining four batches) and washed three times with water / methanol (1000 mL, 9:1) until pH > 3. The solid was dried under vacuum at 45 °C to give methyl 3-hydroxy-2-methylbenzoate as a grey solid (700 g, 80.4% yield). 1 1H NMR: 400 MHz DMSO-d6 δ: 9.70 (s, 1H), 7.18 (t, J = 6.8 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H).

[0520] Methyl 3-[tert-butyl(dimethyl)silyl]oxy-2-methylbenzoate. Two batches (240 g each) were run in parallel. Imidazole (246 g, 3.61 mol) and tert-butyldimethylchlorosilane (238 g, 1.58 mol) were added to a solution of methyl 3-hydroxy-2-methylbenzoate (240 g, 1.44 mol) in N,N-dimethylformamide (1.40 L) at 5 °C. After addition, the mixture was warmed to 20 °C and stirred for 6 h. Isopropyl acetate (1700 mL) was added, then water (2000 mL) was added slowly while maintaining the temperature below 30 °C. The resulting mixture was stirred and the organic phase was separated. The combined organics (combining two batches) were washed with water (1700 mL x 3) and concentrated to approximately 1500 mL (KF < 0.05%). The product was stored as an isopropyl acetate solution and used in the next step without further purification.

[0521] Methyl 2-(bromomethyl)-3-[(tert-butyl(dimethyl)silyl)oxy]benzoate. Two batches (each approximately 375 g) were run in parallel. To a solution of methyl 3-[(tert-butyl(dimethyl)silyl)oxy]-2-methylbenzoate in isopropyl acetate (approximately 375 g, 1.34 mol) was added N-bromosuccinimide (274 g, 1.54 mol) and azobisisobutyronitrile (4.40 g, 26.8 mmol). The reaction mixture was heated to 70 °C over at least 1 hour and stirred at 70 °C for 4 hours. The reaction mixture was cooled to 20 °C and held at 20 °C for at least 1 hour. The solids (succinimide) from both batches were removed by filtration and washed with isopropyl acetate (700 mL). The filtrate was washed with a solution of sodium sulfite (700 g) in water (6000 mL), then with water (1500 mL). The organic layer was distilled to dryness under vacuum at 45 °C to give methyl 2-(bromomethyl)-3-[(tert-butyl(dimethyl)silyl)oxy]benzoate as a dark orange oil (920 g, 95.5% yield). 1 H NMR: 400 MHz DMSO-d6 δ: 7.45 (d, J = 6.8 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 4.95 (s, 2H), 1.02 (s, 9H), 0.29 (s, 6H).

[0522] (4S)-tert-Butyl 5-amino-4-[4-[(tert-butyl(dimethyl)silyl)oxy]-1-oxoisoindolin-2-yl]-5-oxopentanoate. To a solution of (4S)-tert-butyl 4,5-diamino-5-oxopentanoate (130 g, 643 mmol) in acetonitrile (4.0 L) was added methyl 2-(bromomethyl)-3-[(tert-butyl(dimethyl)silyl)oxy]benzoate (210 g, 584 mmol) and diisopropylethylamine (113 g, 877 mmol). The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was concentrated to remove most of the acetonitrile, the residue was dissolved in methyl tert-butyl ether (2.0 L) and water (1.5 L), the organic layer was washed with saturated monopotassium phosphate (1.0 L x 2), brine (1.0 L), dried over anhydrous sodium sulfate, filtered and concentrated to give crude (4S)-tert-butyl 5-amino-4-[4-[(tert-butyl(dimethyl)silyl)oxy]-1-oxoisoindolin-2-yl]-5-oxopentanoate (524 g), which was used in the next step without further purification.

[0523] (4S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate. To a solution of (4S)-tert-butyl 5-amino-4-[4-(tert-butyl(dimethyl)silyl)oxy-1-oxoisoindolin-2-yl]-5-oxopentanoate (275 g, 613 mmol) in methanol (2.0 L) was added tetrabutylammonium fluoride trihydrate (38.7 g, 123 mmol). The mixture was stirred at 18 °C for 16 h. The reaction mixture was concentrated to remove most of the methanol, the residue was dissolved in dichloromethane / water (3 L / 2 L), the organic layer was washed with brine (1.0 L), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography to give the product (260 g). The product was added to acetonitrile (750 mL) and the mixture was stirred at 60 °C for 2 h, cooled to 18 °C and stirred for another 2 h. The solid was filtered and the cake was dried to give (4S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate as a grey solid (248 g, 60.5% yield). 1 1H NMR 400 MHz DMSO-d6 δ: 10.00 (s, 1H), 7.54 (s, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 4.8 Hz, 2H), 4.72 - 4.68 (m, 1H), 4.49 - 4.28 (m, 2H), 2.17 - 1.97 (m, 4H), 1.31 (s, 9H).

[0524] 4-(4-(4-(Chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. 1,4-Bis(chloromethyl)benzene (51.2 g, 292 mmol) was placed in a flask containing acetonitrile (195 mL) and N,N-dimethylformamide (195 mL). The reaction mixture was stirred at ambient temperature until all solids had dissolved. Diisopropylamine (51.1 mL, 292 mmol) and 3-fluoro-4-(piperazin-1-yl)benzonitrile (20 g, 97 mmol) were then added. The reaction mixture was heated to 60 °C for 1 h. Acetonitrile was removed under reduced pressure. The remaining mixture was partitioned between ethyl acetate (1.0 L), water (700 mL) and brine (300 mL). The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The volatile organics were combined and removed under reduced pressure. The solid was dissolved in the minimum amount of dichloromethane and purified on a silica gel column (0%-100% ethyl acetate in hexane in 3 L). The fractions containing the desired product were combined and the volatile organics were removed under reduced pressure. The residue was dissolved in the minimum amount of dichloromethane and purified a second time on a silica gel column (10% ethyl isovalerate in hexane in 800 mL, followed by 20%-80% ethyl acetate in hexane in 4 L). The fractions containing the desired product were combined and the volatile organics were removed under reduced pressure to afford 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile as an off-white solid (22.7 g, 66.0 mmol, 67.7% yield). 1 HNMR(400MHz,CDCl3)δppm 7.33 - 7.39(m,5H)7.29(d,J=1.96Hz,1H)7.25(d,J=1.96Hz,1H)6.91(t,J=8.56Hz,1H)4.60(s,2H)3.58(s,2H)3.19 - 3.27(m,4H)2.58 - 2.66(m,4H).MS(ESI)m / z 344.2[M + 1] + 。

[0525] (S)-tert-Butyl 5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate. (S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (22.05 g, 65.9 mmol) was placed in a flask containing 4-(4-(4-(chloromethyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile (22.67 g, 65.9 mmol), potassium carbonate (18.23 g, 132 mmol), and N,N-dimethylformamide (330 mL). The reaction mixture was heated to 45 °C and maintained for 16 h. The reaction product was diluted with ethyl acetate (50 mL) and filtered. The filtrate was partitioned between ethyl acetate (900 mL) and water (600 mL) and brine (200 mL). The organic layer was separated and partitioned with water (600 mL). The organic layer was separated, and all the organic layers were combined, dried over sodium sulfate, and the volatiles were removed under reduced pressure. The residue was treated with 20% ethyl acetate in hexane, and the volatiles were removed under reduced pressure to give (S)-tert-Butyl 5-amino-4-(4-((4-((4-(4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as an off-white solid (44.02 g, 68.6 mmol, 104% yield). The yield was slightly higher than quantitative due to some remaining N,N-dimethylformamide. 1 H NMR (400 MHz, CDCl3) δ ppm 7.43 - 7.49 (m, 2H) 7.40 (s, 4H) 7.36 (dd, J = 8.38, 1.28 Hz, 1H) 7.29 (d, J = 1.96 Hz, 1H) 7.26 (d, J = 1.83 Hz, 1H) 7.11 (dd, J = 7.64, 1.16 Hz, 1H) 6.92 (t, J = 8.50 Hz, 1H) 6.23 (br s, 1H) 5.24 - 5.32 (m, 1H) 5.15 (s, 2H) 4.86 - 4.94 (m, 1H) 4.38 - 4.55 (m, 2H) 3.61 (s, 2H) 3.18 - 3.32 (m, 4H) 2.58 - 2.70 (m, 4H) 2.09 - 2.47 (m, 4H) 1.43 (s, 8H). MS (ESI) m / z 642.4 [M+1] + 。

[0526] (S)-4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile. (S)-tert-Butyl 5-amino-4-(4-((4-((4-((4-cyano-2-fluorophenyl)piperazin-1-yl)methyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate (12.1 g, 18.86 mmol) was placed in a vial containing acetonitrile (189 mL) and benzenesulfonic acid (3.96 g, 24.51 mmol). The reaction mixture was placed under vacuum and purged with nitrogen. This was repeated once, and then the mixture was heated to 85 °C overnight under a nitrogen atmosphere. The reaction mixture was poured directly while warm into two separatory funnels containing dichloromethane (1000 mL) and ethyl acetate (300 mL). A saturated solution of sodium bicarbonate (900 mL), water (100 mL), and brine (450 mL) was added to this mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (800 mL) and ethyl acetate (200 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. Purification by standard methods afforded the title compound. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (s, 1H) 7.68 (dd, J = 13.45, 1.83 Hz, 1H) 7.56 (dd, J = 8.44, 1.83 Hz, 1H) 7.43 - 7.52 (m, 3H) 7.29 - 7.39 (m, 4H) 7.11 (t, J = 8.80 Hz, 1H) 5.24 (s, 2H) 5.11 (dd, J = 13.20, 5.14 Hz, 1H) 4.22 - 4.46 (m, 2H) 3.54 (s, 2H) 3.12 - 3.22 (m, 4H) 2.85 - 2.97 (m, 1H) 2.53 - 2.62 (m, 2H) 2.38 - 2.48 (m, 2H) 1.93 - 2.03 (m, 1H). MS (ESI) m / z 568.2 [M+1] + 。

[0527] Example 3: Anti-CD3 antibody

[0528] Preferably, the anti-CD3 antibody comprises a variable domain VH, which contains heavy chain CDRs of SEQ ID NO:1, 2, and 3 as heavy chain CDR1, CDR2, and CDR3, respectively; and a variable domain VL, which contains light chain CDRs of SEQ ID NO:4, 5, and 6 as light chain CDR1, CDR2, and CDR3, respectively. Preferably, the antibody comprises variable domains of SEQ ID NO:7 (VH) and SEQ ID NO:8 (VL). The anti-CD3 antibody as described above is used to generate T cell bispecific antibodies according to the following examples.

[0529] Example 4: Generation of Fc-containing 2+1 form anti-BCMA / anti-CD3 T cell bispecific antibody

[0530] The cDNAs encoding the complete heavy and light chains of the corresponding anti-BCMA IgG1 antibody and the anti-CD3 VH and VL cDNAs were used as starting materials. For each bispecific antibody, four protein chains are involved, which respectively contain the heavy and light chains of the corresponding anti-BCMA antibody and the heavy and light chains of the above anti-CD3 antibody. To minimize the formation of by-products with mismatched heavy chains (e.g., two heavy chains with anti-CD3 antibody), a mutated heterodimeric Fc region carrying "button-in-hole mutations" and engineered disulfide bonds was used, as described in WO2009080251 and WO2009080252. To minimize the formation of by-products with mismatched light chains (e.g., two light chains with anti-BCMA antibody), the method described in WO2009080251 and WO2009080252 was used to make CH1x constant κ cross for the heavy and light chains of the anti-CD3 antibody.

[0531] a) The anti-BCMA / anti-CD3 T cell bispecific antibody in 2+1 form, i.e., a bispecific (Fab)2x(Fab) antibody that is bivalent for BCMA and monovalent for CD3, will have advantages in terms of potency, predictability of efficacy, and safety, because it will preferentially bind to the tumor target BCMA and avoid CD3 antibody precipitation, thus having a higher possibility of drug exposure concentrated in the tumor.

[0532] For the previously selected anti-BCMA antibodies, anti-BCMA / anti-CD3 T cell bispecifics of the 2+1 format, which are bivalent for BCMA and monovalent for CD3 with an Fc, were generated (i.e., bispecific (Fab)2x(Fab) antibodies). The cDNA encoding the complete Fab (heavy chain VH and CH1 domains plus light chain VL and CL domains) of the corresponding anti-BCMA IgG1 antibody and the anti-CD3 VH and VL cDNAs were used as starting materials. For each bispecific antibody, four protein chains are involved with the Fc region, the four protein chains comprising respectively the heavy and light chains of the corresponding anti-BCMA antibody and the heavy and light chains of the above anti-CD3 antibody.

[0533] Briefly, each bispecific antibody was generated by co-transfecting four mammalian expression vectors simultaneously, the expression vectors encoding respectively: a) the complete light chain cDNA of the corresponding BCMA antibody, b) a fusion cDNA generated by standard molecular biology methods such as splicing-overlap-extension PCR, the fusion cDNA encoding a fusion protein consisting of (in N- to C-terminal order) a secretion leader sequence, Fab (VH, followed by the CH1 domain) of the above corresponding anti-BCMA antibody, a flexible glycine (Gly)-serine (Ser) linker having the sequence Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser, Fab (VH, followed by the CH1 domain) of the above corresponding anti-BCMA antibody, a flexible glycine (Gly)-serine (Ser) linker having the sequence Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser, the VH of the above anti-CD3 antibody and the constant κ domain of the human light chain cDNA, c) a fusion cDNA generated by standard molecular biology methods such as splicing-overlap-extension PCR, the fusion cDNA encoding a fusion protein consisting of (in N- to C-terminal order) a secretion leader sequence, the VL of the above anti-CD3 antibody, the constant CH1 domain of the human IgG1 cDNA. Co-transfection of mammalian cells and antibody production and purification were carried out using the methods for generating human or humanized IgG1 antibodies described above, with one modification: for the purification of the antibody, the first capture step was not carried out using protein A, but using an affinity chromatography column packed with a resin that binds to the constant region of the human κ light chain, such as KappaSelect (GE Healthcare Life Sciences). In addition, disulfide bonds may be included to increase stability and yield and additional residues that form ionic bridges and increase heterodimerization yield (EP 1870459 A1).

[0534] To generate a BCMAxCD3 bispecific antibody construct, the IgG1-derived bispecific molecule consists of at least two antigen-binding portions capable of specifically binding to two different epitopes, CD3 and BCMA. The antigen-binding portions are Fab fragments composed of a heavy chain and a light chain, each containing a variable region and a constant region. At least one Fab fragment is a "Crossfab" fragment in which the constant domains of the Fab heavy and light chains are exchanged. The exchange of the heavy and light chain constant domains within the Fab fragment ensures that Fab fragments with different specificities do not have the same domain arrangement and thus do not exchange light chains. The bispecific molecule is designed to be monovalent for CD3 and bivalent for BCMA, with one Fab fragment fused to the N-terminus of an internal CrossFab (2+1). The bispecific molecule contains an Fc portion to have a longer half-life. In Figure 1A 、 1B 、schematic diagrams of the constructs are given in 2A to 2D and 3A to 3D; the sequences of the preferred constructs are shown in Table 2A. The molecules are generated by co-transfecting suspension-grown HEK293 EBNA cells with a mammalian expression vector using a polymer-based solution. To prepare the 2+1 CrossFab-IgG construct, cells are transfected with the corresponding expression vectors at a ratio of 1:2:1:1 ("vector Fc (button)": "vector light chain": "vector light chain CrossFab": "vector heavy chain-CrossFab").

[0535] Example 5: Use of anti-BCMA / anti-CD3 T cell bispecific antibody in combination with a compound

[0536] T cell activation and cytokine release. Purified T cells are thawed in RPMI 1640 medium containing 10% FBS and 1 ng / mL human IL-7. Cells are counted in a Vi-CELL cell counter and diluted to 2x10 6 cells / mL with cell medium. The T cells are allowed to recover overnight in a 37 °C, 5% CO2 incubator. The T cells are treated with the bispecific antibody specifically binding to human B cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein or Compound 1, Compound 2, or Compound 3 as a single agent alone or in combination for 24, 48, and 72 hours. Cells are collected at each time point and profiled for T cell activation markers (CD25, CD69, and HLA-DR) on the CD3+CD4+ and CD3+CD8+ subsets by FACS analysis. The medium is also collected at each time point and the cytokines are analyzed by MesoScale Discovery or Luminex platform.

[0537] Co - culture of effector T cells (E) and tumor cells (T). The pre - treated T cells and / or tumor cells are co - cultured together at different E:T ratios with a bispecific antibody or Compound 1, Compound 2, or Compound 3 that specifically binds to human B - cell maturation antigen (BCMA) and human CD3ε (CD3) provided herein, at 37 °C, 5% CO2, and the T - cell - induced tumor killing is evaluated by FACS at 24, 48, or 72 hours. Just before the start of the co - culture assay, the tumor cells are labeled with CFSE (5(6) - carboxyfluorescein N - hydroxysuccinimide ester) according to the manufacturer's instructions. Additionally, T - cell activation markers (CD25, CD69, HLA - DR) are monitored by FACS on CD3+CD4+ and CD3+CD8+ subsets.

[0538] In one embodiment, the combination therapy will show enhanced response depth in lenalidomide - and / or pomalidomide - resistant cells compared to either single agent alone. In another embodiment, the combination therapy will show synergistic and / or additive cell - killing activity in myeloma cells with low to no BCMA expression. Furthermore, the combination therapy will show an increase in T - cell activation and cytokine (such as IL - 2, IFN - γ, and TNF - α) production compared to either single agent alone.

[0539] Example 6: Combined use of anti - BCMA / anti - CD3 T - cell bispecific antibody and compounds

[0540] Co - culture of effector T cells (E) and target cells (T) after pretreatment with compounds. CD3+ T cells are isolated from the peripheral blood mononuclear cell fraction of healthy donors using magnetic - activated cell sorting. The cells are thawed in RPMI 1640 medium supplemented with 10% (v / v) fetal bovine serum (FBS), non - essential amino acids, and sodium pyruvate. All cell cultures and cell treatments are carried out in a 37 °C, 5% CO2 incubator for the indicated time periods. Then the T cells are labeled with CFSE (carboxyfluorescein succinimide ester) according to the manufacturer's instructions and allowed to recover overnight in the presence of 1 ng / mL human IL - 7. Before co - culture, the T cells are treated with DMSO (control) or Compound 2 as a single agent for 16 hours. With CellTrace TMViolet was used to label multiple myeloma H929 and OPM-2 cell lines or plasma cell leukemia (PCL) cell line L363, and then pretreated with DMSO (control) or compound 2 as a single agent for 72 hours. Then, T cells and target cells were washed to remove the compound, and co-cultured for 72 hours at different effector T cell (E) to target cell (T) ratios in the presence of increasing concentrations of a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) as provided herein. At the end of the co-culture, cells were collected and target cell apoptosis and necrosis were analyzed by flow cytometry using an APC annexin V apoptosis detection kit with 7-AAD according to the manufacturer's instructions (BioLegend). The results showed that pretreatment of target cells with compound 2 significantly enhanced the potency of the bispecific antibody (for both H929 and L363 cells), as well as the maximum target cell killing induced by the tested bispecific antibody (for H929 cells)( Figure 4A and 4B ). In the cytotoxicity assay using OPM-2 cells, the results showed that treatment of effector T cells or target cells alone with compound 2 enhanced the potency and efficacy of the tested bispecific antibody for target cell killing( Figure 4C ). For the OPM-2 cytotoxicity assay, the combination of pretreatment of effector T cells and target cells with compound 2 produced the greatest synergy and increase in the efficacy of the tested bispecific antibody( Figure 4C ).

[0541] Co-culture of effector T cells (E) and target cells (T) with simultaneous compound treatment. CD3+ T cells were isolated from the peripheral blood mononuclear cell fraction from three different healthy donors (donors A, B, and C) using magnetic-activated cell sorting. Cells were thawed in RPMI 1640 medium supplemented with 10% (v / v) FBS, non-essential amino acids, sodium pyruvate, and penicillin / streptomycin. All cell culture and treatments were carried out in a 37 °C, 5% CO2 incubator for the indicated time periods. Then, T cells were labeled with CFSE (carboxyfluorescein succinimidyl ester) according to the manufacturer's instructions and recovered overnight in the presence of 1 ng / mL human IL-7. With CellTrace TMViolet-labeled multiple myeloma H929 cell lines and allowed them to recover overnight. Then the T cells and target cells were washed and co-cultured at a fixed effector T cell (E) to target cell (T) ratio of 1:3 for 72 hours in the presence of increasing concentrations of the bispecific antibody provided herein that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3). Co-culture in the presence of the bispecific antibody was carried out in the presence of DMSO (control) or compound 2. Cells were collected at the end of co-culture to analyze target cell apoptosis and necrosis by flow cytometry using an APC Annexin V apoptosis detection kit with 7-AAD. The results showed that for all donors tested, simultaneous exposure of the cells to compound 2 significantly increased the potency of the bispecific antibody tested and also improved the maximum efficacy of target cell killing mediated by the bispecific antibody ( Figure 5 ).

[0542] Example 7: Use of a combination of an anti-BCMA / anti-CD3 T cell bispecific antibody and a compound in lenalidomide-resistant multiple myeloma

[0543] Co-culture of effector T cells (E) and lenalidomide-resistant multiple myeloma target cells (T) after pretreatment with a compound. CD3+ T cells were isolated from the peripheral blood mononuclear cell fraction from three different healthy donors (donors D, E, and F) using magnetic-activated cell sorting. The cells were thawed in RPMI 1640 medium supplemented with 10% (v / v) fetal bovine serum (FBS), non-essential amino acids, sodium pyruvate, and penicillin / streptomycin. All cell cultures and cell treatments were carried out in a 37 °C, 5% CO2 incubator for the indicated time periods. Then the T cells were labeled with CFSE (carboxyfluorescein succinimidyl ester) according to the manufacturer's instructions and allowed to recover overnight in the presence of 1 ng / mL human IL-7. Lenalidomide-resistant multiple myeloma cell line H929-1051 was generated by long-term culture in the presence of increasing concentrations of lenalidomide as previously described (Ghandi et al. Br. J. Haematol. January 2014; 164(2):233-44), using the method described (Lopez-Girona et al. Leukemia. November 2012; 26(11):2326-35). The H929-1051 cells were labeled with CellTrace TMViolet-labeled and then pretreated with DMSO (control), pomalidomide, or Compound 2 as a single agent for 72 hours. Then the T cells and target cells were washed to remove the compound and co-cultured for 72 hours at a fixed effector T cell (E) to target cell (T) ratio of 1:3 in the presence of increasing concentrations of a bispecific antibody that specifically binds to human B cell maturation antigen (BCMA) and human CD3ε (CD3) as provided herein. Cells were collected at the end of the co-culture and analyzed for target cell apoptosis and necrosis by flow cytometry using an APC Annexin V apoptosis detection kit with 7-AAD according to the manufacturer's instructions (BioLegend). The results showed that pretreatment of lenalidomide-resistant H929-1051 target cells with Compound 2 rather than pomalidomide increased the potency and maximum target cell killing induced by the bispecific antibodies tested ( Figure 6 ). The data indicate that the cell line is also pomalidomide-resistant.

[0544] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to determine using only routine experimentation, many equivalents of specific compounds, materials, and procedures. All such equivalents are considered to be within the scope of the present invention and are covered by the appended claims. Sequence Listing <110> Cell Genesys, Inc. <120> Anti-Proliferative Compounds and Bispecific Antibodies Against BCMA and CD3 for Combinatorial Use <130> 10624-451-228 <140> TBA <141> 2019-05-22 <150> 62 / 675,639 <151> 2018-05-23 <160> 57 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> Mus musculus <400> 1 Thr Tyr Ala Met Asn 1 5 <210> 2 <211> 19 <212> PRT <213> House mouse (Mus musculus) <400> 2 Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Ser 1 5 10 15 Val Lys Gly <210> 3 <211> 14 <212> PRT <213> House mouse (Mus musculus) <400> 3 His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe Ala Tyr 1 5 10 <210> 4 <211> 14 <212> PRT <213> House mouse (Mus musculus) <400> 4 Gly Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn 1 5 10 <210> 5 <211> 7 <212> PRT <213> House mouse (Mus musculus) <400> 5 Gly Thr Asn Lys Arg Ala Pro 1 5 <210> 6 <211> 9 <212> PRT <213> House mouse (Mus musculus) <400> 6 Ala Leu Trp Tyr Ser Asn Leu Trp Val 1 5 <210> 7 <211> 125 <212> PRT <213> Mus musculus <400> 7 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 8 <211> 109 <212> PRT <213> Mus musculus <400> 8 Gln Ala Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly 1 5 10 15 Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Thr Ser 20 25 30 Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Gly Gln Ala Phe Arg Gly 35 40 45 Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro Gly Thr Pro Ala Arg Phe 50 55 60 Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Ala 65 70 75 80 Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Ala Leu Trp Tyr Ser Asn 85 90 95 Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 <210> 9 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> 83A10 Heavy Chain Variable Region (VH) <400> 9 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 10 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Mab21 / Mab22 / Mab42 heavy chain variable region <400> 10 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Pro Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 11 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> 83A10 Variable Light Chain (VL) <400> 11 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro 85 90 95 Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 12 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Mab21 / Mab27 / Mab33 / Mab39 light chain variable region <400> 12 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Glu Tyr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Glu His Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro 85 90 95 Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 13 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Mab22 light chain variable region (VL) <400> 13 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Ser Gly Ala Gly Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro 85 90 95 Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 14 <211> 109 <212> PRT <213> Artificial Sequence <220> <223> Mab42 light chain variable region (VL) <400> 14 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asp Glu 20 25 30 Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile His Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro 85 90 95 Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 15 <211> 5 <212> PRT <213> Homo sapiens <220> <223> 83A10 CDR1H <400> 15 Ser Tyr Ala Met Ser 1 5 <210> 16 <211> 17 <212> PRT <213> Homo sapiens <220> <223> 83A10 CDR2H <400> 16 Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 17 <211> 7 <212> PRT <213> Homo sapiens <220> <223> 83A10 / Mab21 / Mab22 / Mab42 / Mab27 / Mab33 / Mab39 CDR3H <400> 17 Val Leu Gly Trp Phe Asp Tyr 1 5 <210> 18 <211> 13 <212> PRT <213> Homo sapiens <220> <223> 83A10 CDR1L <400> 18 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp 1 5 10 <210> 19 <211> 8 <212> PRT <213> Homo sapiens <220> <223> 83A10 CDR2L <400> 19 Tyr Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 20 <211> 10 <212> PRT <213> Homo sapiens <220> <223> 83A10 / Mab21 / Mab22 / Mab42 CDR3L <400> 20 Gln Gln Tyr Gly Tyr Pro Pro Asp Phe Thr 1 5 10 <210> 21 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Mab21 / Mab22 / Mab42 CDR1H <400> 21 Asp Asn Ala Met Gly 1 5 <210> 22 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Mab21 / Mab22 / Mab42 CDR2H <400> 22 Ala Ile Ser Gly Pro Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 23 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Mab21 CDR1L <400> 23 Arg Ala Ser Gln Ser Val Ser Glu Tyr Tyr Leu Ala Trp 1 5 10 <210> 24 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Mab21 CDR2L <400> 24 Glu His Ala Ser Thr Arg Ala Thr 1 5 <210> 25 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Mab22 CDR1L <400> 25 Arg Ala Ser Gln Ser Val Ser Ser Tyr Tyr Leu Ala Trp 1 5 10 <210> 26 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Mab22 CDR2L <400> 26 Ser Gly Ala Gly Ser Arg Ala Thr 1 5 <210> 27 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> Mab42 CDR1L <400> 27 Arg Ala Ser Gln Ser Val Ser Asp Glu Tyr Leu Ser Trp 1 5 10 <210> 28 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Mab42 CDR2L <400> 28 His Ser Ala Ser Thr Arg Ala Thr 1 5 <210> 29 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Mab27 CDR1H <400> 29 Ser Ala Pro Met Gly 1 5 <210> 30 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Mab27 CDR2H <400> 30 Ala Ile Ser Tyr Ile Gly His Thr Tyr Tyr Ala Asp Ser Val Lys Gly 1 5 10 15 <210> 31 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Mab27 / Mab33 / Mab39 CDR1L <400> 31 Arg Ala Ser Gln Ser Val Ser Glu Tyr Tyr Leu Ala 1 5 10 <210> 32 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Mab27 / Mab33 / Mab39 CDR2L <400> 32 His Ala Ser Thr Arg Ala Thr 1 5 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Mab27 / Mab33 / Mab39 CDR3L <400> 33 Gln Gln Tyr Gly Tyr Pro Pro Asp Phe Thr 1 5 10 <210> 34 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Mab33 CDR1H <400> 34 Thr Asn Ala Met Gly 1 5 <210> 35 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Mab33 CDR2H <400> 35 Ala Ile Asn Arg Phe Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 36 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Mab39 CDR1H <400> 36 Gln Asn Ala Met Gly 1 5 <210> 37 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Mab39 CDR2H <400> 37 Ala Ile Ser Pro Thr Gly Phe Ser Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 38 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> Mab27 VH <400> 38 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Ala 20 25 30 Pro Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Tyr Ile Gly His Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser 115 <210> 39 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Mab33 VH <400> 39 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Tyr Thr Asn 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Asn Arg Phe Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 40 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Mab39 VH <400> 40 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Gln Asn 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Pro Thr Gly Phe Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 41 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> 83A10 / Mab21 / Mab22 / Mab42 BCMA CH1 <400> 41 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Glu Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Glu 85 90 95 Lys Val Glu Pro Lys Ser Cys 100 <210> 42 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> 83A10 / Mab21 / Mab22 / Mab42 BCMA CL <400> 42 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg 1 5 10 15 Lys Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 43 <211> 103 <212> PRT <213> Artificial Sequence <220> <223> CD3 CH1 <400> 43 Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys 1 5 10 15 Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30 Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45 Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60 Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr 65 70 75 80 Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95 Lys Val Glu Pro Lys Ser Cys 100 <210> 44 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> CD3 CL <400> 44 Ala Ser Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 1 5 10 15 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 65 70 75 80 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105 <210> 45 <211> 671 <212> PRT <213> Artificial Sequence <220> <223> 83A10 Button HC <400> 45 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Pro Ser Leu 225 230 235 240 Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr 245 250 255 Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro 260 265 270 Gly Gln Ala Phe Arg Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro 275 280 285 Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala 290 295 300 Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys 305 310 315 320 Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu 325 330 335 Thr Val Leu Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 340 345 350 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 355 360 365 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 370 375 380 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 385 390 395 400 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 405 410 415 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 420 425 430 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 435 440 445 Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 450 455 460 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 465 470 475 480 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 485 490 495 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 500 505 510 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 515 520 525 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 530 535 540 Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile 545 550 555 560 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 565 570 575 Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 580 585 590 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 595 600 605 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 610 615 620 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 625 630 635 640 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 645 650 655 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 660 665 670 <210> 46 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> 83A10 pore HC <400> 46 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 47 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> 83A10 LC <400> 47 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro 85 90 95 Asp Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val 100 105 110 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Arg Lys Leu Lys 115 120 125 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 130 135 140 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 145 150 155 160 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 165 170 175 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 180 185 190 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 195 200 205 Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 48 <211> 232 <212> PRT <213> Artificial Sequence <220> <223> CD3 LC <400> 48 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Thr Tyr 20 25 30 Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Val Arg His Gly Asn Phe Gly Asn Ser Tyr Val Ser Trp Phe 100 105 110 Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Val 115 120 125 Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys 130 135 140 Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg 145 150 155 160 Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn 165 170 175 Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser 180 185 190 Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys 195 200 205 Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr 210 215 220 Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <210> 49 <211> 671 <212> PRT <213> Artificial Sequence <220> <223> Mab21 Button HC <400> 49 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Pro Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Gly Gly Gly Gly 210 215 220 Ser Gly Gly Gly Gly Ser Gln Ala Val Val Thr Gln Glu Pro Ser Leu 225 230 235 240 Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Gly Ser Ser Thr 245 250 255 Gly Ala Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro 260 265 270 Gly Gln Ala Phe Arg Gly Leu Ile Gly Gly Thr Asn Lys Arg Ala Pro 275 280 285 Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala 290 295 300 Leu Thr Leu Ser Gly Ala Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys 305 310 315 320 Ala Leu Trp Tyr Ser Asn Leu Trp Val Phe Gly Gly Gly Thr Lys Leu 325 330 335 Thr Val Leu Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 340 345 350 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 355 360 365 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 370 375 380 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 385 390 395 400 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 405 410 415 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 420 425 430 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 435 440 445 Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val 450 455 460 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 465 470 475 480 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 485 490 495 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 500 505 510 Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser 515 520 525 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 530 535 540 Cys Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile 545 550 555 560 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 565 570 575 Pro Cys Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Trp Cys Leu 580 585 590 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 595 600 605 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 610 615 620 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 625 630 635 640 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 645 650 655 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 660 665 670 <210> 50 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> Mab21 hole HC <400> 50 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Asn 20 25 30 Ala Met Gly Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Pro Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Val Leu Gly Trp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Glu Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Glu Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Gly Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Cys Thr Leu Pro Pro 340 345 350 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Ser Cys Ala Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Val Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 51 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Mab21 LC <400> 51 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Glu Tyr 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Glu His Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Pro Pro 85 90 95 Asp Phe Thr Phe Gly Gln Gly Thr Lys ...

Claims

1. Use of a compound of formula 1 or its enantiomer, mixture of enantiomers, tautomer, isotopomer or pharmaceutically acceptable salt in the preparation of a medicament for combination therapy of multiple myeloma with a bispecific antibody; wherein the bispecific antibody comprises a first binding portion that specifically binds to human B-cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε, wherein the first binding portion comprises the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:14; and wherein the second binding portion comprises the VH region of SEQ ID NO:7 and the VL region of SEQ ID NO:

8.

2. Use of a compound of formula 2 or its tautomer, isotopomer or pharmaceutically acceptable salt in the preparation of a medicament for combination therapy of multiple myeloma with a bispecific antibody; wherein the bispecific antibody comprises a first binding portion that specifically binds to human B-cell maturation antigen (BCMA) and a second binding portion that specifically binds to human CD3ε, wherein the first binding portion comprises the VH region of SEQ ID NO:10 and the VL region of SEQ ID NO:14; and wherein the second binding portion comprises the VH region of SEQ ID NO:7 and the VL region of SEQ ID NO:

8.

3. The use according to claim 1, wherein the bispecific antibody comprises the heavy chain of SEQ ID NO:55, the heavy chain of SEQ ID NO:56, the light chain of SEQ ID NO:48 and two light chains of SEQ ID NO.

57.

4. The use according to claim 2, wherein the bispecific antibody comprises the heavy chain of SEQ ID NO:55, the heavy chain of SEQ ID NO:56, the light chain of SEQ ID NO:48 and two light chains of SEQ ID NO.

57.

5. The use according to claim 2, wherein the compound is a compound of formula 2 6. The use according to any one of claims 1 to 5, wherein the multiple myeloma is recurrent, refractory or drug-resistant.

7. The use according to claim 6, wherein the multiple myeloma is lenalidomide-refractory or drug-resistant.

8. The use according to claim 6, wherein the multiple myeloma is pomalidomide-refractory or drug-resistant.

9. The use according to any one of claims 1 to 5, wherein the multiple myeloma is newly diagnosed multiple myeloma.

10. The use according to any one of claims 1 to 5, wherein the multiple myeloma is plasma cell leukemia.

11. The use according to any one of claims 1 to 5, wherein the medicament is prepared for administration before the bispecific antibody.

12. The use according to any one of claims 1 to 5, wherein the medicament is prepared for simultaneous administration with the bispecific antibody.

13. The use according to any one of claims 1 to 5, wherein the medicament is prepared for administration after the bispecific antibody.

14. The use according to any one of claims 1 to 5, wherein the medicament is prepared for further combined administration with an additional active agent.

15. The use according to claim 14, wherein the additional active agent is daratumumab, bortezomib or dexamethasone.

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