#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Monoclonal antibodies in the treatment of multiple myeloma


Authors: T. Jelínek 1;  P. Všianská 2;  R. Hájek 1
Authors‘ workplace: Klinika hematoonkologie, Fakultní nemocnice Ostrava 1;  Oddělení klinické hematologie, Fakultní nemocnice Brno 2
Published in: Transfuze Hematol. dnes,21, 2015, No. 2, p. 74-83.
Category: Comprehensive Reports, Original Papers, Case Reports

Overview

Monoclonal antibodies (MoAbs) are currently the most investigated and the most developed therapeutic compounds not only in oncology but also in other medical fields. The first monoclonal antibody introduced into haematology practise was rituximab. The use of this anti-CD20 antibody in the treatment of B-lymphocytic malignancies meant significant improvement in treatment outcomes, but its activity in multiple myeloma (MM) was low. At the moment, there is no monoclonal antibody approved for the treatment of MM, nevertheless several truly promising molecules are under investigation in phase III clinical trials. Daratumumab (anti-CD38) and elotuzumab (anti-CS1) have especially shown exceptional efficacy in phase I/II clinical trials. Their toxicity was acceptable, which is important if they are to be added to standard anti-myeloma agents such as proteasome inhibitors and immunomodulatory agents in combinational treatment. In this review, we focus on the most promising monoclonal antibodies currently under investigation. The mechanism of action and the rationale for using each monoclonal antibody in MM are explained and practically all available results are described. If the results of phase III trials confirm the efficacy of monoclonal antibodies, they could become an important part in the treatment of multiple myeloma that would translate into further improvement of therapeutic outcomes.

Key words.
monoclonal antibodies, multiple myeloma, daratumumab, elotuzumab, siltuximab, lorvotuzumab


Sources

1. Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood 2010;116(19): 3724–3734.

2. UK CR. Myeloma incidence statistics [online]. 2014 [cited 2015 Jan 11]. Available from: http://www.cancerresearchuk.org/cancer-info/cancerstats/types/myeloma/incidence/uk-multiple-myeloma-incidence-statistics.

3. San-Miguel JF, Mateos M-V. Can multiple myeloma become a curable disease? Haematologica 2011; 96(9): 1246–1248.

4. Hajek R. Strategies for the Treatment of Multiple Myeloma in 2013: Moving Toward the Cure. In: Hajek R, editor. Multiple Myeloma - A Quick Reflection on the Fast Progress [online]. InTech; 2013 [cited 2015 Jan 12]. Available from: http://www.intechopen.com/books/multiple-myeloma-a-quick-reflection-on-the-fast-progress/strategies-for-the-treatment-of-multiple-myeloma-in-2013-moving-toward-the-cure.

5. Rajkumar SV. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and management. Am J Hematol 2014; 89(10): 998–1009.

6. Kumar SK, Lee JH, Lahuerta JJ, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study. Leukemia 2012; 26(1): 149–157.

7. Van de Donk NWCJ, Lokhorst HM. New developments in the mana-gement and treatment of newly diagnosed and relapsed/refractory multiple myeloma patients. Expert Opin Pharmacother 2013; 14(12): 1569–1573.

8. Laubach JP, Tai Y-T, Richardson PG, Anderson KC. Daratumumab granted breakthrough drug status. Expert Opin Investig Drugs 2014; 23(4): 445–452.

9. Deckert J, Wetzel M-C, Bartle LM, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res Off J Am Assoc Cancer Res 2014; 20(17): 4574–4583.

10. Malavasi F, Funaro A, Roggero S, Horenstein A, Calosso L, Mehta K. Human CD38: a glycoprotein in search of a function. Immunol Today 1994; 15(3): 95–97.

11. Deaglio S, Zubiaur M, Gregorini A, et al. Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells. Blood 2002; 99(7): 2490–2498.

12. Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and receptors. Leuk Res 2001; 25(1): 1–12.

13. Han X, Jorgensen JL, Brahmandam A, et al. Immunophenotypic study of basophils by multiparameter flow cytometry. Arch Pathol Lab Med 2008; 132(5): 813–819.

14. Tedder TF, Clement LT, Cooper MD. Discontinuous expression of a membrane antigen (HB-7) during B lymphocyte differentiation. Tissue Antigens 1984; 24(3): 140–149.

15. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol 2004; 121(4): 482–488.

16. Teillaud J-L. Antibody-dependent Cellular Cytotoxicity (ADCC). eLS [online]. John Wiley & Sons, Ltd; 2001 [cited 2015 Jan 19]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/9780470015902.a0000498.pub2/abstract.

17. De Weers M, Tai Y-T, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol Baltim Md 1950 2011; 186(3): 1840–1848.

18. Van der Veer MS, de Weers M, van Kessel B, et al. The therapeutic human CD38 antibody daratumumab improves the anti-myeloma effect of newly emerging multi-drug therapies. Blood Cancer J 2011; 1(10): e41.

19. Plesner T, Lokhorst H, Gimsing P, Nahi H, Lisby S, Richardson PG. Daratumumab, a CD38 Monoclonal antibody in patients with multiple myeloma – data from a dose-escalation phase I/II Study. ASH Ann Meet Abstr 2012; 120(21): 73.

20. Lokhorst HM, Plesner T, Gimsing P, et al. Phase I/II dose-escalationstudy of daratumumab in patients with relapsed or refractory multiple myeloma. J Clin Oncol [online]. 2013 [cited 2015 Jan 21];31(suppl; abstr 8512). Available from: http://meetinglibrary.asco.org/content/109895-132.

21. Plesner T, Arkenau H-T, Lokhorst HM, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma. Blood 2014; 124(21): 84.

22. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res 2008; 14(9): 2775–2784.

23. Tai Y-T, Dillon M, Song W, et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 2008; 112(4): 1329–1337.

24. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother CII 2013; 62(12): 1841–1849.

25. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 2012; 120(3): 552–559.

26. Jakubowiak AJ, Benson DM, Bensinger W, et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J Clin Oncol 2012; 30(16): 1960–1965.

27. Lonial S, Vij R, Harousseau J-L, et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol 2012; 30(16): 1953–1959.

28. Richardson PG, Jagannath S, Moreau P, et al. Final Results for the 1703 phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood 2014; 124(21): 302–312.

29. Van Zaanen HC, Lokhorst HM, Aarden LA, et al. Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced multiple myeloma: a phase I dose-escalating study. Br J Haematol 1998; 102(3): 783–790.

30. Trikha M, Corringham R, Klein B, Rossi J-F. Targeted anti-Interleukin-6 monoclonal antibody therapy for cancer a review of the rationale and clinical evidence. Clin Cancer Res 2003; 9(13): 4653–4665.

31. Rawstron AC, Fenton JA, Ashcroft J, et al. The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells. Blood 2000; 96(12): 3880–3886.

32. Hong DS, Angelo LS, Kurzrock R. Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 2007; 110(9): 1911–1928.

33. Kawano M, Hirano T, Matsuda T, et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332(6159): 83–85.

34. Voorhees PM, Chen Q, Small GW, et al. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 2009; 145(4): 481–490.

35. Juge-Morineau N, François S, Puthier D, Godard A, Bataille R, Amiot M. The gp 130 family cytokines IL-6, LIF and OSM but not IL-11 can reverse the anti-proliferative effect of dexamethasone on human myeloma cells. Br J Haematol 1995; 90(3): 707–710.

36. Voorhees PM, Manges RF, Sonneveld P, et al. A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol 2013; 161(3): 357–366.

37. Orlowski RZ, Gercheva L, Williams C, et al. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol 2015; 90(1): 42–49.

38. San-Miguel J, Bladé J, Shpilberg O, et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 2014; 123(26): 4136–4142.

39. Deisseroth A, Ko C-W, Nie L, et al. FDA Approval: siltuximab for the treatment of patients with multicentric castleman disease. Clin Cancer Res Off J Am Assoc Cancer Res 2015; 21(5): 950–954.

40. Tassone P, Gozzini A, Goldmacher V, et al. In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ multiple myeloma cells. Cancer Res 2004; 64(13): 4629–4636.

41. Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumor inhibitor maytansine. Science 1975; 189(4207): 1002–1005.

42. Lanier LL, Testi R, Bindl J, Phillips JH. Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J Exp Med 1989; 169(6): 2233–2238.

43. Berdeja JG. Lorvotuzumab mertansine: antibody-drug-conjugate for CD56+ multiple myeloma. Front Biosci Landmark Ed. 2014; 19: 163–170.

44. Sahara N, Takeshita A, Shigeno K, et al. Clinicopathological and prognostic characteristics of CD56-negative multiple myeloma. Br J Haematol 2002; 117(4): 882–885.

45. Chanan-Khan A, Wolf JL, Garcia J, et al. Efficacy analysis from phase I study of lorvotuzumab mertansine (IMGN901), used as monotherapy, in patients with heavily pre-treated CD56-positive multiple myeloma – a preliminary efficacy analysis. ASH Ann Meet Abstr 2010; 116(21): 1962.

46. Berdeja JG, Hernandez-Ilizaliturri F, Chanan-Khan A, et al. Phase I study of lorvotuzumab mertansine (LM, IMGN901) in combination with lenalidomide (Len) and dexamethasone (Dex) in patients with CD56-positive relapsed or relapsed/refractory multiple myeloma (MM). ASH Ann Meet Abstr 2012; 120(21): 728.

47. Hussein M, Berenson JR, Niesvizky R, et al. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica 2010; 95(5): 845–848.

48. Bensinger W, Maziarz RT, Jagannath S, et al. A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol 2012; 159(1): 58–66.

49. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341(21): 1565–1571.

50. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352(24): 2487–2498.

51. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120(14): 2817–2825.

52. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 2006; 108(10): 3458–3464.

53. Richardson PG, Siegel DS, Vij R, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood 2014; 123(12): 1826–1832.

54. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357(21): 2133–2142.

55. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14(11): 1055–1066.

56. Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood 2014; 123(10): 1461–1469.

57. Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 2013; 122(18): 3122–3128.

58. Lentzsch S, O’Sullivan A, Kennedy RC, et al. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood 2012; 119(20): 4608–4613.

Labels
Haematology Internal medicine Clinical oncology
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#