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1. WO2020113263 - PROCÉDÉ DE TRAITEMENT

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CLAIMS:

1. A method of treating multiple myeloma in a subject in need thereof, the method comprising administering to the subject an anti-KMA antibody and a proteasome inhibitor.

2. A therapeutic combination comprising a proteasome inhibitor and an anti-KMA antibody, the combination being provided for simultaneous or sequential administration.

3. The method according to claim 1 or the therapeutic combination according to claim 2, wherein the proteasome inhibitor is selected from the group consisting of marizomib, oprozomib, epoxomicin, salinosporamide A, carfilzomib, ixazomib and bortezomib.

4. The method or therapeutic combination according to claim 3, wherein the proteasome inhibitor is bortezomib.

5. The method or therapeutic combination according to any one of claims 1 to 4, wherein the anti-KMA antibody binds to or specifically binds to an epitope of KMA that is specifically bound by kappamab or that competes with kappamab for binding to KMA, wherein kappamab has a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 2.

6. The method or therapeutic combination according to claim 5, wherein the epitope of KMA comprises a sequence set forth in SEQ ID NO: 5.

7. The method or therapeutic combination according to any one of claims 1 to 6, wherein the anti-KMA antibody comprises a VH and a VL, the VH comprising a complementarity determining region (CDR) 1 comprising an amino acid sequence as shown in SEQ ID NO: 6, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 7 and a CDR3 comprising a sequence as shown in SEQ ID NO: 8 and the VL comprising a CDR 1 comprising an amino acid sequence as shown in SEQ ID NO: 9, a CDR2 comprising an amino acid sequence as shown in SEQ ID NO: 10 and a CDR3 comprising a sequence as shown in SEQ ID NO: 11.

8. The method or therapeutic combination according to claim 7, wherein the VH comprises an amino acid sequence at least about 95% identical to the amino acid sequence shown in SEQ ID NO: 1.

9. The method or therapeutic combination according to claims 7 or 8, wherein the VL comprises an amino acid sequence at least about 95% identical to the amino acid sequence shown in SEQ ID NO: 2.

10. The method or therapeutic combination according to claims 7 or 9 wherein the

VH comprises an amino acid sequence as shown in SEQ ID NO: 1.

11. The method or therapeutic combination according to any one of claims 7 or 8, wherein the VL comprises an amino acid sequence as shown in SEQ ID NO: 2.

12. The method or therapeutic combination according to any one of claims 1 to 6, wherein the VH comprises an amino acid sequence as shown in SEQ ID NO: 1 and the VL comprises an amino acid sequence as shown in SEQ ID NO: 2.

13. The method according to any one of claims 1 to 12, wherein the anti-KMA antibody is administered at a dosage ranging from about 0.3 mg/kg to 30 mg/kg.

14. The method according to any one of claims 1 to 12, wherein the anti-KMA antibody is administered at a dosage ranging from about 1 mg/kg to 10 mg/kg.

15. The method according to any one of claims 1 to 12, wherein the anti-KMA antibody is administered at about 10 mg/kg.

16. The method according to any one of claims 4 to 15, wherein the proteasome inhibitor is administered at a dose ranging from about 0.5 mg/m2 to about 1.5 mg/m2.

17. The method according to any one of claims 1 or 3 to 15, further comprising administering one or more additional anti-cancer agents.

18. The therapeutic combination according to claim 2, further comprising one or more additional anti-cancer agents.

19. The method according to claim 17 or the therapeutic combination according to claim 18, wherein the one or more additional anti-cancer agent(s) is/are selected from the group consisting of a chemotherapy, an immunomodulatory drug (thalidomide, lenalidomide, pomalidomide), a histone deacetylase inhibitor (panobinostat), an antibody (elotuzumab, daratumumab, isatuximab), a steroid (dexamethasone).

20. The method according to claim 17 or the therapeutic combination according to claim 19, wherein the additional anti-cancer agent is dexamethasone.

21. The method according to claim 17 or the therapeutic combination according to claim 19, wherein the additional anti-cancer agents are dexamethasone and lenalidomide.

22. The method according to any one of claims 1 or 3 to 17 or 19 to 21, wherein the anti-KMA antibody and proteasome inhibitor are administered simultaneously or sequentially.

23. The method according to any one of claims 1 or 3 to 17 or 19 to 22, wherein the anti-KMA antibody is administered monthly.

24. The method according to any one of claims 1 or 3 to 17, 19 or 22, wherein the subject has received at least one, at least two, at least three, at least four, at least five, at least six prior lines of therapy.

25. The method according to claim 24, wherein the subject achieved at least a minimal response (25% reduction in M protein) to their most recent line of therapy.

26. The method according to any one of claims 1 or 3 to 17 or 19 to 25, wherein the subject is refractory to at least one, at least two, at least three, at least four prior lines of therapy.

27. The method according to any one of claims 1 or 3 to 17 or 19 to 26, wherein the subject is refractory to at least one proteasome inhibitor.

28. The method according to claim 27, wherein the subject is refractory to bortezomib.

29. The method according to any one of claims 1 or 3 to 17 or 19 to 28, wherein the subject has relapsed myeloma.

30. The method according to any one of claims 1 or 3 to 17 or 19 to 28, wherein the subjects multiple myeloma has relapsed and is refractory to at least one proteasome inhibitor.

31. The method according to any one of claims 1 or 3 to 17 or 19 to 30, wherein the serum level of kappa free light chain in a sample obtained from the subject is less than about 250 mg/ml.

32. The method according to any one of claims 1 or 3 to 17 or 19 to 31, wherein the serum level of HGF in a sample obtained from the subject is between about 0.18 ng/ml and 1.6 ng/ml.

33. The method according to any one of claims 1 or 3 to 17 or 19 to 31, wherein the serum level of MIF in a sample obtained from the subject is between about 414 pg/ml and 4707 pg/ml.

34. The method according to any one of claims 1 or 3 to 17 or 19 to 31, wherein the serum level of CCL27 in a sample obtained from the subject is between about 150 pg/ml and 600 pg/ml.

35. The method according to any one of claims 1 or 3 to 17 or 19 to 31, wherein the serum level of G-CSF in a sample obtained from the subject is between about 20 pg/ml and 65 pg/ml.

36. The method according to any one of claims 1 or 3 to 17 or 19 to 31, wherein the serum level of CXCL9 in a sample obtained from the subject is between about 70 pg/ml and 550 pg/ml.

37. The method according to any one of claims 1 or 3 to 17 or 19 to 31, wherein the serum level of CXCL10 in a sample obtained from the subject is between about 300 pg/ml and 900 pg/ml.

38. A method of treating multiple myeloma in a subject, the method comprising selecting a subject who has high serum levels of one or more of the following factors relative to control serum levels: hepatocyte growth factor (HGF), macrophage inhibitory factor (MIF), CCL27, G-CSF, CXCL9, and CXCL10; and

administering to the subject an anti-KMA antibody.

39. The method according to claim 38, wherein the serum level of HGF in a sample obtained from the subject is above about 0.5 ng/ml.

40. The method according to claims 38, wherein the serum level of MIF in a sample obtained from the subject is above about 5000 pg/ml.

41. The method according to claims 38, wherein the serum level of CCL27 in a sample obtained from the subject is above about 500 pg/ml.

42. The method according to claims 38, wherein the serum level of G-CSF in a sample obtained from the subject is above about 55 pg/ml.

43. The method according to claims 38, wherein the serum level of CXCL9 in a sample obtained from the subject is above about 550 pg/ml.

44. The method according to claims 38, wherein the serum level of CXCL10 in a sample obtained from the subject is above about 850 pg/ml.

45. The method according to any one of claims 38 to 44, further comprising administering a proteasome inhibitor.

46. The method according to claim 45, wherein the proteasome inhibitor is selected from the group consisting of marizomib, oprozomib, epoxomicin, salinosporamide A, carfilzomib, ixazomib and bortezomib.

47. The method of claim 46, wherein the proteasome inhibitor is bortezomib.

48. Use of a proteasome inhibitor and an anti-KMA antibody defined by any one of the preceding claims in the manufacture of a medicament for the treatment of multiple myeloma.

49. A proteasome inhibitor and an anti-KMA antibody defined by any one of the preceding claims for use in the treatment of multiple myeloma.