Methods and uses of cell therapies engineered with chimeric antigen receptors targeting B cell maturation antigens

Abstract

This invention provides a method for treating subjects who have or are suspected of having a disease or disorder related to B cell maturation antigen (BCMA) expression. [Solution] A method is provided for administering a cell therapy to a subject comprising at least two doses of an interleukin-1 receptor antagonist (IL-1Ra) and a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA, wherein at least one dose of IL-1Ra is administered within approximately 24 hours prior to or approximately 24 hours prior to the administration of the dose of engineered T cells, and at least one dose of IL-1Ra is administered after the administration of the dose of engineered T cells.

Claims

1. A method for treating subjects with or suspected of having a disease or disorder related to B-cell maturation antigen (BCMA) expression, comprising the following steps: A step of administering to a subject a cell therapy comprising at least two doses of an interleukin-1 receptor antagonist (IL-1Ra) and a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA, wherein at least one dose of IL-1Ra is administered within approximately 24 hours prior to or approximately 24 hours prior to the administration of the dose of engineered T cells, and at least one dose of IL-1Ra is administered after the administration of the dose of engineered T cells.

2. A method for treating subjects with or suspected of having a disease or disorder related to B-cell maturation antigen (BCMA) expression, comprising the following steps: A cell therapy comprising administering a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA to a subject who has received at least one dose of an interleukin-1 receptor antagonist (IL-1Ra) within approximately 24 hours prior to administration of the engineered T cell dose or within approximately 24 hours prior to administration, and A step of administering at least one dose of IL-1Ra after administering the dose of the manipulated T cells.

3. A method for reducing the severity of, attenuating, and / or preventing the occurrence of toxicity in subjects having or suspected to have a disease or disorder related to B-cell maturation antigen (BCMA) expression treated by cell therapy, comprising the following steps: A step of administering to a subject a cell therapy comprising at least two doses of an interleukin-1 receptor antagonist (IL-1Ra) and a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA, wherein at least one dose of IL-1Ra is administered within approximately 24 hours prior to or approximately 24 hours prior to the administration of the dose of engineered T cells, and at least one dose of IL-1Ra is administered after the administration of the dose of engineered T cells.

4. A method for reducing the severity of, attenuating, and / or preventing the occurrence of toxicity in subjects having or suspected to have a disease or disorder related to B-cell maturation antigen (BCMA) expression treated by cell therapy, comprising the following steps: A cell therapy comprising administering a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA to a subject who has received at least one dose of an interleukin-1 receptor antagonist (IL-1Ra) within approximately 24 hours prior to administration of the engineered T cell dose or within approximately 24 hours prior to administration, and A step of administering at least one dose of IL-1Ra after administering the dose of the manipulated T cells.

5. The method according to any one of claims 1 to 4, wherein at least one dose of IL-1Ra administered prior to the administration of the dose of manipulated T cells is administered within approximately 21, 18, 15, or 12 hours before or approximately 21, 18, 15, or 12 hours before the administration of the dose of manipulated T cells.

6. The method according to any one of claims 1 to 5, wherein at least one dose of IL-Ra administered prior to the administration of the dose of manipulated T cells comprises at least two doses of IL-1Ra administered prior to the administration of the dose of manipulated T cells.

7. The method according to claim 6, wherein one of at least two doses of IL-1Ra administered prior to the administration of the dose of manipulated T cells is administered within 6, 5, 4, 3, or 2 hours prior to the administration of the dose of manipulated T cells, or within approximately 6, 5, 4, 3, or 2 hours prior to the administration of the dose of manipulated T cells.

8. The method according to claim 6 or 7, wherein one of at least two doses of IL-1Ra administered prior to the administration of the dose of manipulated T cells is administered within 3 hours or about 3 hours prior to the administration of the dose of manipulated T cells.

9. The method according to any one of claims 6 to 8, wherein one of at least two doses of IL-1Ra is administered within approximately 24 hours or within approximately 24 hours prior to the administration of the dose of manipulated T cells, and one of at least two doses of IL-1Ra is administered within approximately 3 hours or within approximately 3 hours prior to the administration of the dose of manipulated T cells.

10. The method according to any one of claims 1 to 9, wherein at least one dose of IL-1Ra administered after the administration of the dose of engineered T cells comprises at least two, three, four, five, six, seven, or eight doses of IL-1Ra administered after the administration of the dose of engineered T cells.

11. The method according to any one of claims 1 to 10, wherein at least one dose of IL-1Ra administered after the administration of the dose of engineered T cells comprises three, four, five, six, or seven doses of IL-1Ra administered after the administration of the dose of engineered T cells.

12. The method according to any one of claims 1 to 11, wherein at least one dose of IL-1Ra administered after the administration of the dose of manipulated T cells comprises four doses of IL-1Ra administered after the administration of the dose of manipulated T cells.

13. The method according to any one of claims 1 to 12, wherein at least one dose of IL-1Ra administered after the administration of the aforementioned dose of manipulated T cells is administered daily over consecutive days.

14. The method according to any one of claims 1 to 13, wherein at least one dose of IL-1Ra administered after the administration of the dose of engineered T cells is four doses, and one of the four doses is administered daily for four consecutive days after the administration of the dose of engineered T cells.

15. The method according to any one of claims 1 to 14, wherein a certain dose of IL-1Ra is administered every 24 hours (q24h) on days 2 to 5.

16. A method for reducing the severity of, attenuating, and / or preventing the occurrence of toxicity in subjects having or suspected to have a disease or disorder related to B-cell maturation antigen (BCMA) expression treated by cell therapy, comprising the following steps: A step of administering to a subject a cell therapy comprising at least six doses of an interleukin-1 receptor antagonist (IL-1Ra) and a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA, The cell therapy is administered on day 1, and (a) One dose of IL-1Ra is administered within approximately 24 hours prior to the administration of the dose of manipulated T cells, or within approximately 24 hours prior to the administration, or optionally on the night before the administration of the dose of manipulated T cells. (b) One dose of IL-1Ra is administered within approximately 3 hours prior to the administration of the dose to the manipulated T cells on day 1, (c) Four doses of IL-1Ra are administered after the administration of the dose of the manipulated T cells, with one of the four doses being administered daily on days 2, 3, 4, and 5. Process.

17. The method according to any one of claims 1 to 16, further comprising the step of administering at least one additional dose of IL-1Ra after the administration of the aforementioned dose of manipulated T cells if the subject exhibits symptoms or signs of cytokine release syndrome (CRS).

18. The method according to claim 17, wherein the additional dose of IL-1Ra comprises administering at least one additional dose of IL-1Ra daily for consecutive days until the symptoms or signs of CRS subside.

19. The method according to claim 18, wherein at least one additional dose of IL-1Ra is an additional dose administered daily over consecutive days until the symptoms or signs of CRS have subsided.

20. The method according to any one of claims 13 to 19, wherein if the subject exhibits symptoms or signs of cytokine release syndrome (CRS), a certain dose of IL-1Ra is administered every 12 hours (q12h) until the symptoms or signs of CRS subside.

21. The method according to any one of claims 13 to 20, wherein the daily administration of IL-1Ra is performed at the same time or approximately the same time each day.

22. The method according to any one of claims 1 to 21, wherein IL-1Ra is recombinant IL-1Ra.

23. The method according to any one of claims 1 to 22, wherein IL-1Ra includes the sequence shown in SEQ ID NO:256, or a sequence that retains the function of IL-1Ra and has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more sequence identity with respect to SEQ ID NO:

256.

24. The method according to any one of claims 1 to 23, wherein IL-1Ra is anakinra.

25. The method according to any one of claims 1 to 24, wherein each dose of IL-1Ra is 500 mg or about 500 mg, 400 mg or about 400 mg, 300 mg or about 300 mg, 200 mg or about 200 mg, 100 mg or about 100 mg, or 50 mg or about 50 mg, or within the range defined by any of the foregoing, and optionally, each dose of recombinant IL-1Ra is between 50 mg or about 50 mg and 200 mg or about 200 mg.

26. The method according to any one of claims 1 to 25, wherein each dose of IL-1Ra is 100 mg or about 100 mg.

27. The method according to any one of claims 1 to 26, wherein IL-1Ra is administered subcutaneously.

28. A method according to any one of claims 1 to 27, for reducing the severity of the occurrence of toxicity associated with the administration of cell therapy, attenuating the occurrence of toxicity, and / or preventing it.

29. The method according to any one of claims 3 to 28, wherein the toxicity is cytokine release syndrome (CRS).

30. The method according to claim 29, wherein the CRS is a severe CRS or a CRS of grade 3 or higher.

31. The method according to any one of claims 3 to 28, wherein the toxicity is neurotoxic (NT).

32. The method according to claim 31, wherein NT is severe NT, or NT of grade 2 or higher, or NT of grade 3 or higher.

33. The method according to any one of claims 3 to 28, wherein the toxicity is macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH).

34. At the time of administration of the aforementioned dose of manipulated T cells or before administration, A prior dose of engineered T cells containing a second CAR specific to BCMA, Prior administration of BCMA-targeted T cell engagers (TCEs), and Prior administration of BCMA-targeted antibody-drug conjugate (ADC) The method according to any one of claims 1 to 33, wherein one or more prior BCMA-targeted therapies selected from among are administered to the target.

35. A method for treating subjects with or suspected of having a disease or disorder related to B-cell maturation antigen (BCMA) expression, comprising the following steps: A step of administering a cell therapy to a subject comprising a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA, wherein at the time of or prior to the administration of the engineered T cells, A prior dose of engineered T cells containing a second CAR specific to BCMA, Prior administration of BCMA-directed T cell engagers (TCEs), and Prior administration of BCMA-targeted antibody-drug conjugate (ADC) A step in which one or more prior BCMA-targeted therapies selected from among are administered to the subject.

36. A method for treating subjects with or suspected of having a disease or disorder related to B-cell maturation antigen (BCMA) expression, comprising the following steps: Cell therapy including a certain dose of engineered T cells containing a first chimeric antigen receptor (CAR) specific to BCMA, A prior dose of engineered T cells containing a second CAR specific to BCMA, Prior administration of BCMA-directed T cell engagers (TCEs), and Prior administration of BCMA-targeted antibody-drug conjugate (ADC) A step of administering to subjects who have previously received one or more prior BCMA-targeted therapies selected from the following.

37. The method according to any one of claims 34 to 36, wherein the subject has relapsed after one or more prior BCMA-targeted therapies, or has become refractory to said one or more prior BCMA-targeted therapies.

38. The method according to any one of claims 34 to 37, wherein the subject has relapsed or become refractory to the one or more preceding BCMA-targeted therapies within approximately one year prior to or within approximately one year prior to the administration of the dose of manipulated T cells containing the first CAR.

39. The method according to any one of claims 34 to 38, wherein the subject has relapsed after one or more preceding BCMA-targeted therapies, or has become refractory to one or more preceding BCMA-targeted therapies, within approximately six months prior to or within approximately six months prior to administration of the dose of manipulated T cells containing the first CAR.

40. The method according to any one of claims 34 to 39, wherein the subject has relapsed after one or more preceding BCMA-targeted therapies, or has become refractory to one or more preceding BCMA-targeted therapies, within approximately three months prior to or within approximately three months prior to administration of the dose of manipulated T cells containing the first CAR.

41. The method according to any one of claims 34 to 40, wherein the BCMA-targeted TCE is a bispecific antibody or a bispecific T cell engager (BiTE), or comprises a bispecific antibody or a bispecific T cell engager (BiTE).

42. The method according to any one of claims 34 to 41, wherein the BCMA directional TCE is selected from one or more of AMG 420 / BI 836909, AMG 701, CC-93269, JNJ-64007957, PF-06863135, and REGN5458.

43. The method according to any one of claims 34 to 42, wherein the BCMA directional ADC is selected from one or more of verantamab mafodotin (GSK2857916), MEDI2228, CC-99712, and AMG 224.

44. The first car, Variable heavy chain (V) containing heavy chain complementarity determination region 1 (CDR-H1), heavy chain complementarity determination region 2 (CDR-H2), and heavy chain complementarity determination region 3 (CDR-H3) within the sequence shown in SEQ ID NO:116 H ), as well as variable light chain (V) containing light chain complementarity determination region 1 (CDR-L1), light chain complementarity determination region 2 (CDR-L2), and light chain complementarity determination region 3 (CDR-L3) within the sequence shown in SEQ ID NO:119 L ); V containing the CDR-H1, CDR-H2, and CDR-H3 sequences shown in SEQ ID NO: 97, 101, and 103, respectively. H , and V containing the CDR-L1, CDR-L2, and CDR-L3 sequences shown in SEQ ID NO: 105, 107, and 108, respectively. L ; V containing the CDR-H1, CDR-H2, and CDR-H3 sequences shown in SEQ ID NO: 96, 100, and 103, respectively. H , and V containing the CDR-L1, CDR-L2, and CDR-L3 sequences shown in SEQ ID NO: 105, 107, and 108, respectively. L ; V containing the CDR-H1, CDR-H2, and CDR-H3 sequences shown in SEQ ID NO: 95, 99, and 103, respectively. H , and V containing the CDR-L1, CDR-L2, and CDR-L3 sequences shown in SEQ ID NO: 105, 107, and 108, respectively. L ; and / or V comprising the CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NO: 94, 98 and 102, respectively H and V comprising the CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NO: 104, 106 and 108, respectively L The method according to any one of claims 1 to 43, comprising an extracellular antigen-binding domain.

45. V H is the amino acid sequence of SEQ ID NO:116 or contains the amino acid sequence of SEQ ID NO:116, V L The method according to claim 44, wherein is the amino acid sequence of SEQ ID NO:119 or comprises the amino acid sequence of SEQ ID NO:

119.

46. The method according to claim 44 or claim 45, wherein the extracellular antigen-binding domain comprises the amino acid sequence of SEQ ID NO:114 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO:

114.

47. The method according to any one of claims 44 to 46, wherein the nucleic acid encoding the extracellular antigen-binding domain comprises (a) the sequence of a nucleotide with SEQ ID NO:113, (b) the sequence of a nucleotide having at least 90% sequence identity thereto, (c) a degenerate sequence of (a) or (b), and / or (d) the sequence of a nucleotide with SEQ ID NO:

115.

48. The first car, (a) IgG4 / 2 chimeric hinge or modified IgG4 hinge, IgG2 / 4 chimeric C H 2 regions, and IgG4 C H A spacer containing 3 regions and optionally approximately 228 amino acid lengths, or the spacer shown in SEQ ID NO:

174. (b) Transmembrane domain, optionally human CD28-derived transmembrane domain, and (c) An intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and a costimulatory signaling region that includes the intracellular signaling domain or signaling portion of a T cell costimulatory molecule. including, The method according to any one of claims 1 to 47.

49. The method according to any one of claims 44 to 48, wherein the transmembrane domain is a transmembrane domain derived from human CD28 or comprises a transmembrane domain derived from human CD28.

50. The method according to any one of claims 44 to 49, wherein the transmembrane domain is the sequence shown in SEQ ID NO:138 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:138, or comprises the sequence shown in SEQ ID NO:138 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:

138.

51. The first car, Variable heavy chain (V) containing heavy chain complementarity determination region 1 (CDR-H1), heavy chain complementarity determination region 2 (CDR-H2), and heavy chain complementarity determination region 3 (CDR-H3) within the sequence shown in SEQ ID NO:125 H ), as well as variable light chain (V) containing light chain complementarity determination region 1 (CDR-L1), light chain complementarity determination region 2 (CDR-L2), and light chain complementarity determination region 3 (CDR-L3) within the sequence shown in SEQ ID NO:127 L ); and / or V containing the CDR-H1, CDR-H2, and CDR-H3 sequences shown in SEQ ID NO: 260, 261, and 262, respectively. H , and V containing the CDR-L1, CDR-L2, and CDR-L3 sequences shown in SEQ ID NO: 257, 258, and 259, respectively. L The method according to any one of claims 1 to 43, comprising an extracellular antigen-binding domain.

52. V H is the amino acid sequence of SEQ ID NO:125 or contains the amino acid sequence of SEQ ID NO:125, V L The method according to claim 51, wherein is the amino acid sequence of SEQ ID NO:127 or comprises the amino acid sequence of SEQ ID NO:

127.

53. The method according to claim 51 or claim 52, wherein the extracellular antigen-binding domain comprises the amino acid sequence of SEQ ID NO:128 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO:

128.

54. The first car, (a) Spacer including CD8 hinge area, (b) Transmembrane domain, optionally human CD8-derived transmembrane domain, and (c) An intracellular signaling region comprising the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain and a costimulatory signaling region that includes the intracellular signaling domain or signaling portion of a T cell costimulatory molecule. A method according to any one of claims 1 to 43 and 51 to 53, including the method described in any one of claims 1 to 43.

55. The method according to any one of claims 44 to 54, wherein the cytoplasmic signaling domain is the sequence shown in SEQ ID NO:143 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:143, or comprises the sequence shown in SEQ ID NO:143 or an amino acid sequence having at least 90% sequence identity to SEQ ID NO:

143.

56. The method according to any one of claims 44 to 59, wherein the co-stimulatory signaling region includes an intracellular signaling domain or signaling portion of CD28, 4-1BB, or ICOS.

57. The method according to any one of claims 44 to 56, wherein the co-stimulatory signaling region comprises an intracellular signaling domain of 4-1BB, optionally human 4-1BB.

58. The method according to any one of claims 44 to 57, wherein the co-stimulatory signaling region is the sequence shown in SEQ ID NO:4 or an amino acid sequence having at least 90% sequence identity with the sequence shown in SEQ ID NO:4, or includes the sequence shown in SEQ ID NO:4 or an amino acid sequence having at least 90% sequence identity with the sequence shown in SEQ ID NO:

4.

59. The method according to any one of claims 44 to 58, wherein the co-stimulatory signaling region is located between the transmembrane domain and the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain.

60. The method according to any one of claims 1 to 50 and 55 to 59, wherein the first CAR comprises the sequence shown in SEQ ID NO:

19.

61. The method according to any one of claims 1 to 43 and 51 to 59, wherein the first CAR comprises the sequence shown in SEQ ID NO:

312.

62. The method according to any one of claims 34 to 61, wherein the first CAR and the second CAR bind to the same epitope of BCMA.

63. The method according to any one of claims 34 to 61, wherein the first CAR and the second CAR bind to different epitopes of BCMA.

64. The method according to any one of claims 34 to 63, wherein the first CAR and the second CAR are different.

65. The method according to any one of claims 34 to 62, wherein the first CAR and the second CAR are the same.

66. The method according to any one of claims 34 to 65, wherein the dose of engineered T cells containing the first CAR is generated from a sample containing T cells obtained from the same subject that has been previously administered a preceding dose of engineered T cells containing the second CAR.

67. The method according to any one of claims 34 to 66, wherein the dose of engineered T cells containing the first CAR is generated from a sample containing T cells obtained from a subject after a preceding dose of engineered T cells containing the second CAR has been administered to the subject.

68. The method according to any one of claims 44 to 67, wherein the binding of the extracellular antigen-binding domain and / or the first CAR, or a measure of the function or activity of the first CAR, following exposure to cells expressing surface BCMA, is not reduced or blocked, or substantially not reduced or blocked, in the presence of soluble or detached BCMA.

69. The dose of the engineered T cells containing the first CAR is 1 × 10⁻⁶ 7 pieces or approximately 1 x 10 7 From individual CAR+ T cells, 1 × 10 9 pieces or approximately 1 x 10 9 The method according to any one of claims 1 to 68, comprising CAR+ T cells.

70. The dose of the engineered T cells containing the first CAR is 1 × 10⁻⁶ 8 pieces or approximately 1 x 10 8 From individual CAR+ T cells, 8 × 10 8 pc or approximately 8 x 10 8 The method according to any one of claims 1 to 69, comprising CAR+ T cells.

71. The aforementioned dose of engineered T cells containing the first CAR is 1.5 × 10⁻⁶ 8 pc or approximately 1.5 × 10 8 The method according to any one of claims 1 to 70, comprising a single cell or a CAR+ T cell.

72. The aforementioned dose of engineered T cells containing the first CAR is 3 × 10 8 pieces or approximately 3 x 10 8 The method according to any one of claims 1 to 70, comprising a single cell or a CAR+ T cell.

73. The aforementioned dose of engineered T cells containing the first CAR is 4.5 × 10 8 pc or approximately 4.5 × 10 8 The method according to any one of claims 1 to 70, comprising a single cell or a CAR+ T cell.

74. The aforementioned dose of engineered T cells containing the first CAR is 6 × 10 8 pc or approximately 6 x 10 8 The method according to any one of claims 1 to 70, comprising a single cell or a CAR+ T cell.

75. The aforementioned dose of engineered T cells containing the first CAR is CD4 ＋ T cells and CD8 ＋ Combination with T cells, optionally CD4 ＋ CAR+ T cells and CD8 ＋ The method according to any one of claims 1 to 74, including a combination with CAR+ T cells.

76. Prior to administering the aforementioned dose of engineered T cells containing the first CAR, 20–40 or approximately 20–40 mg / m² 2 Target body surface area: 30 or approximately 30 mg / m² (optional). 2 Daily administration of fludarabine for 2 to 4 days, and / or 200 to 400 mg / m² or approximately 200 to 400 mg / m² 2 Target body surface area: 300 or approximately 300 mg / m² (optional). 2 The method according to any one of claims 1 to 75, wherein lymphocyte depletion therapy, comprising daily administration of cyclophosphamide over a period of 2 to 4 days, is administered to the target.

77. Lymphocyte depletion therapy involves administering 30 or approximately 30 mg / m² daily for three days. 2 Fludarabine for the target body surface area, and 300 or approximately 300 mg / m² 2 The method according to claim 76, comprising administering cyclophosphamide to a target body surface area.

78. The method according to any one of claims 1 to 77, wherein the disease or disorder associated with BCMA expression is an autoimmune disease or autoimmune disorder.

79. The method according to any one of claims 1 to 78, wherein the disease or disorder associated with BCMA expression is cancer, optionally BCMA-expressing cancer.

80. The method according to claim 79, wherein the cancer is a B-cell malignant tumor.

81. The method according to claim 79 or 80, wherein the cancer is lymphoma, leukemia, or plasma cell malignancy.

82. The method according to any one of claims 79 to 81, wherein the cancer is a lymphoma, and the lymphoma is Burkitt lymphoma, non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, Waldenström hypergammaglobulinemia, follicular lymphoma, small non-incisional nuclear cell lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), marginal zone lymphoma, splenic lymphoma, nodular monocytic B-cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, pulmonary B-cell angiocentral lymphoma, small lymphocytic lymphoma, mediastinal primary B-cell lymphoma, lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL).

83. The method according to any one of claims 79 to 81, wherein the cancer is leukemia, and the leukemia is chronic lymphocytic leukemia (CLL), plasma cell leukemia, or acute lymphoblastic leukemia (ALL).

84. The method according to any one of claims 79 to 81, wherein the cancer is a plasma cell malignancy, and the plasma cell malignancy is multiple myeloma (MM) or plasmacytoma.

85. The method according to any one of claims 79 to 81 and 84, wherein the cancer is multiple myeloma (MM), optionally relapsed or refractory multiple myeloma (R / R MM).

86. Three or more prior therapies, optionally four or more prior therapies, are being administered for a disease or disorder. Optionally, the preceding therapy is autologous stem cell transplantation (ASCT), Immunomodulators, Proteasome inhibitors, and Anti-CD38 antibody Selected from among The method according to any one of claims 1 to 85.

87. The method according to claim 86, wherein the immunomodulator is selected from thalidomide, lenalidomide, and pomalidomide.

88. The method according to claim 86 or claim 87, wherein the proteasome inhibitor is selected from bortezomib, carfilzomib, and ixazomib.

89. The method according to any one of claims 86 to 88, wherein the anti-CD38 antibody is daratumumab or comprises daratumumab.

90. The method according to any one of claims 1 to 89, wherein the subject has been administered 3 to 15 or 4 to 15 prior therapies, or approximately 10 prior therapies.

91. The method according to any one of claims 86 to 90, wherein the subject has relapsed after one or more of the three or more prior therapies, or has become refractory to one or more of the three or more prior therapies.

92. The method according to any one of claims 86 to 91, wherein the subject has relapsed after at least three or at least four of the three or more prior therapies, or has become refractory to at least three or at least four of the three or more prior therapies.

93. The method according to claim 91 or 92, wherein the subject is refractory or unresponsive to bortezomib, carfilzomib, lenalidomide, pomalidomide, and / or an anti-CD38 monoclonal antibody.

94. The method according to any one of claims 1 to 93, wherein the subject has previously undergone autologous stem cell transplantation.

95. The method according to any one of claims 1 to 93, wherein the subject has not undergone prior autologous stem cell transplantation.

96. The method according to any one of claims 1 to 95, wherein the subject does not have active plasma cell leukemia (PCL) or a history of plasma cell leukemia (PCL).

97. The method according to any one of claims 1 to 96, wherein the subject has developed secondary plasma cell leukemia (PCL).

98. The method according to any one of claims 1 to 97, wherein the subject is an adult, or 25 or 35 years of age or older.

99. The method according to any one of claims 1 to 98, wherein the subject has been diagnosed with a disease or disability for approximately 4 years, or 2 to 15 years, or 2 to 12 years.

100. The method according to any one of claims 1 to 99, wherein the subject has IMWG high-risk cytogenetics.

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