proteasome inhibitors

New Possibilities of Treatment for Relapsed/Refractory Multiple Myeloma: A Literature Review

REVIEWS , , ,

OM Votyakova

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Ol’ga Mikhailovna Votyakova, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-92-09; e-mail: omvtk@yandex.ru 24

For citation: Votyakova OM. New Possibilities of Treatment for Relapsed/Refractory Multiple Myeloma: A Literature Review. Clinical oncohematology. 2017;10(4):425–34 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-425-434

ABSTRACT

Despite improvements in the treatment of patients with newly diagnosed multiple myeloma (MM) through the introduction of new drugs and high-dose chemotherapy with autologous hematopoietic stem cell transplantation, relapses are still inevitable in all patients. The use of immunomodulatory agents (thalidomide, lenalidomide) and proteasome inhibitor bortezomib has improved the treatment of relapses. However, the disease progression lead to repeated relapses and eventually refractory MM. For these patients new therapeutic strategies are needed, including the development of more effective drugs within the existing classes and the study of new combinations, as well as searching new targets for the treatment of MM. We present the key clinical data on the efficacy and safety of the most promising proteasome inhibitors (carfilzomib, ixazomib), new generation immunomodulatory drug pomalidomide, and monoclonal antibodies (daratumumab and elotuzumab).

Keywords: proteasome inhibitors, immunomodulatory medication, monoclonal antibodies, multiple myeloma.

Received: March 14, 2017

Accepted: June 20, 2017

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REFERENCES

  1. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28(5):1122–5. doi: 10.1038/leu.2013.313.
  2. Ludwig H, Sonneveld P, Davies F, et al. European Perspective on Multiple Myeloma Treatment Strategies in 2014. Oncologist. 2014;19(8):829–44. doi: 10.1634/theoncologist.2014-0042.
  3. Rajkumar SV, Harousseau J-L, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18):4691–5. doi: 10.1182/blood-2010-10-299487.
  4. Richardson PG, Sonnefeld P, Schuster M, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(11):3557–60. doi: 10.1182/blood-2006-08-036947.
  5. Dimopoulos MA, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123–32. doi: 10.1056/NEJMoa070594.
  6. 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):2133–42. doi: 10.1056/NEJMoa070596.
  7. Weber D, Knight R, Chen C, et al. Prolonged overall survival with lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2007;110(11): Abstract 412.
  8. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79(7):867–74.
  9. Usmani S, Ahmadi T, Ng Y, et al. Analysis of Real-World Data on Overall Survival in Multiple Myeloma Patients With ≥ 3 Prior Lines of Therapy Including a Proteasome Inhibitor (PI) and an Immunomodulatory Drug (IMiD), or Double Refractory to a PI and an IMiD. Oncologist. 2016;21:1355–61. doi: 10.1634/theoncologist.2016-0104.
  10. 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):149–57. doi: 10.1038/leu.2011.196.
  11. Bolli N, Avert-Loiseau H, Wedge DC, et al. Heterogeneity of genomic evolution and mutational profiles in multiple myeloma. Nat Commun. 2014;5:2997. doi: 10.1038/ncomms3997.
  12. Lohr JG, Stojanov P, Carter SL, et al. Multiple Myeloma Research Consortium. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25(1):91–101. doi: 10.1016/j.ccr.2013.12.015.
  13. Egan JB, Shi CH, Tembe W, et al. Whole-genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution, and clonal tides. Blood. 2012;120(5):1060–6. doi: 10.1182/blood-2012-01-405977.
  14. Yee AJ, Raje NS. Sequencing of nontransplant treatments in multiple myeloma patients with active disease. Hematology Am Soc Hematol Educ Program. 2016(1):495–503. doi: 10.1182/asheducation-2016.1.495.
  15. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–52. doi: 10.1056/NEJMoa1411321.
  16. Moreau P, Masszi T, Grzasko N, et al. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;374(17):1621–34. doi: 10.1056/NEJMoa1516282.
  17. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373(7):621–31. doi: 10.1056/NEJMoa1505654.
  18. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(14):1319–31. doi: 10.1056/NEJMoa1607751.
  19. Kuhn DJ, Orlowski RZ, Bjorklund CC. Second generation proteasome inhibitors: carfilzomib and immunoproteasome-specific inhibitors (IPSIs). Curr Cancer Drug Targets. 2011;11(3):285–95. doi: 10.2174/156800911794519725.
  20. 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):2817–25. doi: 10.1182/blood-2012-05-425934.
  21. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2015;17(1):27–38. doi: 10.1016/S1470-2045(15)00464-7.
  22. Avet-Loiseau H, Fonseca R, Siegel D, et al. Efficacy and Safety of Carfilzomib, Lenalidomide, and Dexamethasone Vs Lenalidomide and Dexamethasone in Patients with Relapsed Multiple Myeloma Based on Cytogenetic Risk Status: Subgroup Analysis from the Phase 3 Study Aspire (NCT01080391). Blood. 2015;126(23):731.
  23. Kupperman E, Lee EC, Cao Y, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70(5):1970–80. doi: 10.1158/0008-5472.CAN-09-2766.
  24. Lee EC, Fitzgerald M, Bannerman B, et al. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res. 2011;17(23):7313–23. doi: 10.1158/1078-0432.CCR-11-0636.
  25. 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 III trial. Lancet Oncol. 2013;14(11):1055–66. doi: 10.1016/S1470-2045(13)70380-2.
  26. Dimopoulos MA, Weisel KC, Song KW, et al. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015;100(10):1327–33. doi: 10.3324/haematol.2014.117077.
  27. Dimopoulos MA, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia. 2014;28(8):1573–85. doi: 10.1038/leu.2014.60.
  28. ИМНОВИД® (IMNOVID®) инструкция по применению [электронный документ]. Доступно по: https://www.vidal.ru/drugs/imnovid__44356. Ссылка активна на 31.07.2017.[IMNOVID® instruction for medical use [Internet]. Available from: https://www.vidal.ru/drugs/imnovid__44356. (accessed 31.07.17) (In Russ)]
  29. Baz RC, Martin TG, Lin H-Y, et al. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016;127(21):2561–8. doi: 10.1182/blood-2015-11-682518.
  30. Lacy MQ, LaPlant BR, Laumann KM, et al. Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM). Blood. 2014;124(21):304.
  31. 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. 2013;62(12):1841–9. doi: 10.1007/s00262-013-1493-8.
  32. Veillette A, Guo H. CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. Crit Rev Oncol Hematol. 2013;88(1):168–77. doi: 10.1016/j.critrevonc.2013.04.003.
  33. Lonial S, Richardson P, Mateos M-V, et al. ELOQUENT-2 update: Phase III study of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM)—Identifying responders by subset analysis. 2016 ASCO Annual Meeting. Poster 8037. Available from: http://meetinglibrary.asco.org/record/126339/abstract (accessed 31.07.17).
  34. 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):482–8. doi: 10.1309/74r4-tb90-buwh-27jx.
  35. de Weers M, Tai YT, 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. 2011;186(3):1840–8. doi: 10.4049/jimmunol.1003032.
  36. Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124(21):3474.
  37. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. mAbs. 2015;7(2):311–21. doi: 10.1080/19420862.2015.1007813.
  38. Jansen JHM, Boross P, Overdijk MB, et al. Daratumumab, a human CD38 antibody induces apoptosis of myeloma tumor cells via Fc receptor-mediated crosslinking. Blood. 2012;120(21): Abstract 2974.
  39. Krejcik J, Casneuf T, Nijhof I, et al. Immunomodulatory effects and adaptive immune response to daratumumab in multiple myeloma. Blood. 2015:126(23): Abstract 3037.
  40. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373(13):1207–19. doi: 10.1056/NEJMoa1506348.
  41. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387(10027):1551–60. doi: 10.1016/S0140-6736(15)01120-4.
  42. Usmani SZ, Weiss BM, Plesner T, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37–44. doi: 10.1182/blood-2016-03-705210.
  43. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375:754–66. doi: 10.1056/NEJMoa1606038.