Multipl Myelomda Yeni Ajanlarla Güncel Tedavi Yaklaşımları

Year 2018, Volume: 9 Issue: 2, 103 - 112, 13.06.2018

Senem Maral

https://doi.org/10.5799/jcei.433823

Abstract

Multipl myelom kemik iliğinde anormal plazma hücre artışı ve immunglobulin veya hafif zincir

aşırı üretimi nedeniyle organ hasarı ile sonuçlanabilen malign bir hastalıktır. Hetereojen bir

hastalık olan myelomda kolay tolere edilen bir rejim ile mümkün olan en az toksisiteyle, hızlı ve

etkin şekilde hastalığı kontrol altına almak, hastalık ilişkili komplikasyonları düzeltmek ve

önlemek, erken ölüm riskini azaltmak hedeflenmektedir. Son yıllarda multipl myelom tedavisinde

çok sayıda yeni nesil ajanın hızla tedavi pratiğine eklenmesi ile hastaların sağ kalım süresi

dramatik şekilde uzamıştır. Mevcut tedaviler sağ kalım ve hastalıksız yaşam süresine olumlu

katkı sağlamakla birlikte, hastalık nüksünü engelleyememektedir. Halihazırda otolog kök hücre

nakli tedavideki yerini korumaktaysa da yeni nesil ajanlar ile gelecek için umut vaad etmektedir.

Keywords

Multipl myelom, proteozom inhibitörleri, monoklonal antikorlar, immun modulatörler, histondeasetilaz inhibitörler

References

• 1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:538-48.
• 2. Mateos MV, Lopez JM, Rodriguez-Otero P, et al. Curative Strategy for High-Risk Smoldering Myeloma (GEM-CESAR): Carfilzomib, Lenalidomide and Dexamethasone (KRd) As Induction Followed By HDT-ASCT, Consolidation with Krd and Maintenance with Rd. 2017 ASH Congress oral presentation
• 3. Kyle RA, Therneau TM, Rajkumar SV, et al. Incidence of multiple myeloma in Olmsted County, Minnesota: trend over 6 decades. Cancer. 2004; 101:2667-74.
• 4. 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;123:1826- 32.
• 5. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-14.
• 6. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma [published correction appears in N Engl J Med. 2000;342:64]. N Engl J Med. 1999;341:1565-71.
• 7. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015; 372: 142–52.
• 8. Dimopoulos MA, Moreau P, Palumbo A, et al. ENDEAVOR Investigators. 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. 2016; 17:27–38.
• 9. Kumar S, Berdeja JG, Niesvizky R, et al. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014;15:1503- 12.
• 10. Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci U S A. 2005; 102:8567– 8572.
• 11. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial [published correction appears in Lancet Oncol. 2015;16:e6]. Lancet Oncol. 2014; 15:1195– 206.
• 12. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatmentrefractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016; 387:1551–60.
• 13. Palumbo A, Chanan-Khan A, Weisel K, et al. CASTOR Investigators. Daratumumab, bortezomib and dexamethasone for multiple myeloma: CASTOR study. N Engl J Med. 2016; 375:754–66.
• 14. Dimopoulos MA, Oriol A, Nahi H, et al. POLLUX Investigators. Daratumumab, lenalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2016; 375:1319–31.
• 15. Mateos MV, Dimopoulos AM, Cavo M, et al Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma N Engl J Med 2018; 378:518-28.
• 16. Lonial S, Dimopoulos M, Palumbo A, et al. ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015; 373:621–31.
• 17. Richardson PG, Zimmerman TM, Hofmeister CC, et al. Phase 1 study of marizomib in relapsed or relapsed and refractory multiple myeloma: NPI-0052-101 Part 1. Blood. 2016; 127:2693– 700.
• 18. Vij R, Savona M, Siegel DS, et al. Clinical profile of single-agent oprazomib in patients (Pts) with multiple myeloma (MM): updated results from a multicenter, open-label, dose escalation phase 1b/2 study. Blood. 2014;124: 34.
• 19. Shah JJ, Kaufman JL, Zonder JA A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma.Cancer. 2017;123:4617-30.
• 20. Kumar SK, LaPlant B, Chng WJ, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood. 2015;125: 443–8.
• 21. Kumar SK, Vij R, Kaufman JL, et al. Safety and efficacy of Venetoclax (ABT-199/GDC-0199) monotherapy for relapsed/ refractory multiple myeloma: phase 1 preliminary results. Blood. 2015;126: 4219.
• 22. Raab MS, Ocio EM, Thomas SK, Günther A, Goh Y-T, Lebovic D, et al. Phase 1 study update of the novel pan-Pim kinase inhibitor LGH447 in patients with relapsed/ refractory multiple myeloma. Blood. 2014;122:3186–7. 23. Vogl DT, Dingli D, Cornell RF, et al. Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-CD38 Ab refractory multiple myeloma (MM): STORM study. Blood. 2016; 128: 491.
• 24. Martin TG , Baz R, Benson DM Jr, et al. A phase Ib dose escalation trial of SAR650984 (Anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. Blood. 2014; 65: 83 (NCT01749969) 25. Martin T, Richter J, Vij R, et al. A dose finding phase II trial of isatuximab (SAR650984, anti-CD38 mAb) as a single agent in relapsed/refractory multiple myeloma. Blood. 2015; 126: 509.
• 26. Siegel DSD, Donk N, Sonneveld P,et al. A phase 1b study of durvalumab (MEDI4736) alone or in combination with pomalidomide (POM) with or without low dose-dexamethasone (LoDEX) in patients (pts) with relapsed and refractory multiple myeloma (RRMM). J Clin Oncol 2016;34:15 (NCT02616640.)
• 27. Tolcher AW, Patnaik A, Papadopoulos KP, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015;75:183–9. 28. Yee AJ, Bensinger WI, Supko JG, et al. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016;17:1569-78.
• 29. Lin Y, Berdeja J, Raje N, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T cell therapy for relapsed/refractory multiple myeloma: updated results. Abstract presented at: 22nd Annual European Hematology Association Congress; June 22-25, 2017; Madrid, Spain. Abstract S142.
• 30. Rajan AM, Rajkumar SV. Interpretation of cytogenetic results in multiple myeloma for clinical practice. Blood. Cancer J. 2015;5:e365.
• 31. Rajkumar SV. Treatment of Multiple Myeloma. Nature Rev Clin Oncol. 2011; 8:479–491.
• 32. Sonneveld P, Goldschmidt H, Rosinol L, et al. Bortezomib-based versus nonbortezomib-based untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol. 2013;31:3279–87.
• 33. Sonneveld P, Schmidt IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30:2946–55. 34. Goldschmidt H, Lokhorts HM, Mai EK, et al. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia.2018;32:383-90.
• 35. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethsone compared with thalidomide plus dexametha- sone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomized phase 3 study. [published correction appears in Lancet. 2011 Nov 26;378:1846]. Lancet. 2010;376:2075–85.
• 36. Tacchetti P, Pantani L, De Stefano V, et al. Superior PFS2 with VTD vs TD for newly diagnosed, transplant eligible, multiple myeloma patients: update analysis of GIMEMA MMY-3006 study. Blood. 2014;124:abstract 196.
• 37. Moreau P, Hulin C, Macro M, et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016;127:2569–74.
• 38. Cavo M, Pantani L, Pezzi A, et al. Bortezomib-thalidomide-dexa-methasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma. Leukemia. 2015;29:2429–31.
• 39. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519–27.
• 40. Jakubowiak AJ, Chari A, Lonial S, et al. Daratumumab (DARA) in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) in patients with newly diagnosed multiple myeloma (MMY1001): an open-label, phase 1b study. J Clin Oncol. 2017;35(Suppl):abstract 8000.
• 41. Fayers PM, Palumbo A, Hulin C, et al. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patients in six randomized clinical trials. Blood. 2011;118:1239–47.
• 42. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. New Engl J Med. 2008;359:906–17.
• 43. Morabito F, Bringhen S, Larocca A, et al. Bortezomib, melphalan, prednisone (VMP) versus melphalan, prednisone, thalidomide (MPT) in elderly newly diagnosed multiple myeloma patients: a retrospective case-matched study. Am J Hematol. 2014;89:355–62.
• 44. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906–17.
• 45. Oostendorp M, Lammerts van Bueren JJ, Doshi P, et al. When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion. 2015; 55: 1555–62.
• 46. Bringhen S, Petrucci MT, Larocca A, et al. Carfilzomib, cyclophosphamide and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014;124:63–9.
• 47. Bringhen S, D’Agostino M, De Paoli L, et al. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2017 [Epub ahead of print]
• 48. Attal M, Harousseau JL, Stoppa AM, et al.Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-7.
• 49. Child JA, Morgan GJ, Davies FE, et al. Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stemcell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-83.
• 50. Gertz MA, Ansell SM, Dingli D, et al. Autologous stem cell transplantation in 716 patients with multiple myeloma: low treatment-related mortality, feasibility of outpatient transplant, and impact of a multidisciplinary quality initiative. Mayo Clin Proc. 2008;83:1131-8.
• 51. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma(IFM/DFCI 2009 trial.N Engl J Med.2017:376;1311-20.
• 52. Stadtmauer A, Pasquini C, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with Len maintenance, tandem Autohct with len maintenance and Autohct with Len maintenance for upfront treatment of patients with multiple myeloma: primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 - StaMINA Trial). Blood. 2016;128(22):LBA-1.
• 53. Sonneveld P, Beksac M, Van der Holt B, et al. Consolidation Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM Trial). Blood. 2016;128(22). Abstract 242.
• 54. Attal M, Lauwers-Cances V, Marit G, et al; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-91.
• 55. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770- 81.
• 56. Niesvizky R, Flinn IW, Rifkin RM, et al. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens J Clin Oncol 2015;33:3921-9. 57. Gertz MA, Lacy MQ, Inwards DJ, et al. Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma. Bone Marrow Transplant. 1999;23:221-6. 58. Dimopoulos M, Spencer A, Attal M, et al. Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma [published correction appears in N Engl J Med. 2009;361:544]. N Engl J Med. 2007; 357:2123–32.
• 59. Weber DM, Chen C, Niesvizky R, et al. Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007; 357:2133–42. 60. Berenson JR, Hilger JD, Yellin O, et al. Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy. Leukemia. 2014; 28: 1529–36.
• 61. Keats JJ, Chesi M, Egan JB, et al. Clonal competition with alternating dominance in multiple myeloma. Blood. 2012; 120:1067–76.
• 62. Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015; 126:2284–90.
• 63. Plesner T, Arkenau HT, Gimsing P, et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016; 128:1821–8.
• 64. Moreau P, Masszi T, Grzasko N, et al. TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016; 374:1621–34.
• 65. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130:974-81.
• 66. Mikhael JR, Reeder CB, Libby EN, et al. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015; 169:219–227.
• 67. Barlogie B, Kyle R, Anderson K, et al. Comparable survival in multiple myeloma (MM) with high dose therapy (HDT) employing MEL 140 mg/ m2 + TBI 12 Gy autotransplants versus standard dose therapy with VBMCP and no benefit from interferon (IFN) maintenance: results of Intergroup Trial S9321 [abstract A-135]. Blood. 2003;102:42a.