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来那度胺、硼替佐米和地塞米松联合移植治疗骨髓瘤的研究
Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma


Michel Attal ... 肿瘤 • 2017.04.06
相关阅读
• 伊沙佐米治疗复发性骨髓瘤 • 干细胞移植对双重打击淋巴瘤无效 • 达雷木单抗、来那度胺和地塞米松治疗多发性骨髓瘤的研究

摘要


背景

对于新近确诊的65岁以下多发性骨髓瘤成人患者,大剂量化疗联合自体干细胞移植一直是标准治疗方案。来那度胺、硼替佐米和地塞米松联合治疗方案(RVD)在该患者群体中获得了令人鼓舞的结果;然而,这些结果引出了关于移植所起的作用和时机的问题。

 

方法

我们将700例多发性骨髓瘤患者随机分组,所有患者均先接受3个周期RVD诱导治疗;之后,一组再接受5个周期RVD巩固治疗(350例),另一组接受大剂量美法仑联合干细胞移植,继之以2个周期的RVD治疗(350例)。2组患者均接受来那度胺维持治疗1年。主要终点是无进展生存期。

 

结果

与RVD单独治疗组的患者相比,移植组的中位无进展生存期显著延长(50个月对36个月;调整后的疾病进展或死亡的风险比为0.65;P<0.001)。我们在所有患者亚组均观察到该治疗获益,包括根据不同分期(依据国际分期系统[International Staging System]确定)和细胞遗传学危险度进行分层的患者。移植组中获得完全缓解的患者百分比高于RVD单独治疗组(59%对48%,P=0.03),微小残留病未检出的患者百分比也是如此(79%对65%,P<0.001)。在第4年时,移植组和RVD单独治疗组的总生存率没有显著差异(分别为81%和82%)。与RVD单独治疗组相比,移植组中下列不良事件的发生率显著高于RVD单独治疗组:3级或4级中性粒细胞减少(92%对47%),3级或4级胃肠道疾病(28%对7%)和感染(20%对9%)。对于下列事件的发生率,我们未观察到两组间有显著差异:治疗相关死亡、第二原发癌、血栓栓塞事件和周围神经病变。

 

结论

在多发性骨髓瘤成人患者中,与RVD单独治疗相比,RVD治疗联合移植可显著延长无进展生存期,但两种治疗方法的总生存期没有显著差异(由新基[Celgene]公司等资助;IFM 2009研究在ClinicalTrials.gov注册号为NCT01191060)。





作者信息

Michel Attal, M.D., Valerie Lauwers-Cances, M.D., Cyrille Hulin, M.D., Xavier Leleu, M.D., Denis Caillot, M.D., Martine Escoffre, M.D., Bertrand Arnulf, M.D., Margaret Macro, M.D., Karim Belhadj, M.D., Laurent Garderet, M.D., Murielle Roussel, M.D., Catherine Payen, M.D., Claire Mathiot, M.D., Jean P. Fermand, M.D., Nathalie Meuleman, M.D., Sandrine Rollet, M.S., Michelle E. Maglio, B.S., Andrea A. Zeytoonjian, B.S., Edie A. Weller, Ph.D., Nikhil Munshi, M.D., Kenneth C. Anderson, M.D., Paul G. Richardson, M.D., Thierry Facon, M.D., Hervé Avet-Loiseau, M.D., Jean-Luc Harousseau, M.D., and Philippe Moreau, M.D., for the IFM 2009 Study*
From the Institut Universitaire du Cancer de Toulouse-Oncopole (M.A., M.R., C.P., S.R., H.A.-L.) and Service d’Epidémiologie, Centre Hospitalier et Universitaire de Toulouse (V.L.-C.), Toulouse, Hôpital Haut-Lévêque, Bordeaux Pessac (C.H.), Centre Hospitalier et Universitaire la Miletrie, Poitiers (X.L.), Centre Hospitalier Le Bocage, Dijon (D.C.), Centre Hospitalier et Universitaire de Rennes, Rennes (M.E.), Hôpital St.-Louis (B.A., J.P.F.), Centre Hospitalier Universitaire, Hôpital St.-Antoine (L.G.), Institut Curie (C.M.), and Haute Autorité de Santé (J.-L.H.), Paris, Institut d’Hématologie de Basse Normandie, Centre Hospitalier et Universitaire de Caen, Caen (M.M.), Centre Hospitalier et Universitaire Henri Mondor, Creteil (K.B.), Hôpital Claude Huriez, Lille (T.F.), and Hôtel Dieu, Nantes (P.M.) — all in France; Institut Jules Bordet, Brussels (N. Meuleman); and Dana–Farber Cancer Institute, Boston (M.E.M., A.A.Z., E.A.W., N. Munshi, K.C.A., P.G.R.). Address reprint requests to Dr. Attal at the Institut Universitaire du Cancer de Toulouse-Oncopole, 1 Ave. Irène Joliot Curie, 31059 Toulouse, France, or at attal.michel@iuct-oncopole.fr. *A complete list of investigators in the Intergroupe Francophone du Myélome (IFM) 2009 Study is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Attal M, Harousseau J-L, Stoppa A-M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med 1996;335:91-97

2. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348:1875-1883

3. Moreau P, Avet-Loiseau H, Harousseau JL, Attal M. Current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies. J Clin Oncol 2011;29:1898-1906

4. Facon T, Mary JY, Hulin C, et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet 2007;370:1209-1218

5. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol 2009;27:3664-3670

6. Palumbo A, Bringhen S, Caravita T, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 2006;367:825-831

7. Waage A, Gimsing P, Fayers P, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010;116:1405-1412

8. Wijermans P, Schaafsma M, Termorshuizen F, et al. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol 2010;28:3160-3166

9. Beksac M, Haznedar R, Firatli-Tuglular T, et al. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol 2011;86:16-22

10. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009;23:2147-2152

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

12. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007;357:2123-2132

13. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010;11:29-37

14. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med 2014;371:906-917

15. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906-917

16. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol 2010;28:4621-4629

17. Sonneveld P, Schmidt-Wolf IG, 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;30:2946-2955

18. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 2010;28:5101-5109

19. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010;376:2075-2085

20. Roussel M, Lauwers-Cances V, Robillard N, et al. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol 2014;32:2712-2717

21. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010;116:679-686

22. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia 2006;20:1467-1473

23. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996;17:343-346

24. Laubach JP, Voorhees PM, Hassoun H, Jakubowiak A, Lonial S, Richardson PG. Current strategies for treatment of relapsed/refractory multiple myeloma. Expert Rev Hematol 2014;7:97-111

25. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014;371:895-905

26. Gay F, Oliva S, Petrucci MT, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol 2015;16:1617-1629

27. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 2012;366:1759-1769

28. Paiva B, Vidriales MB, Cerveró J, et al. Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008;112:4017-4023

29. Rawstron AC, Child JA, de Tute RM, et al. Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. J Clin Oncol 2013;31:2540-2547

30. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e328-e346

31. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1782-1791

32. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012;366:1770-1781

33. Dong C, Hemminki K. Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958-1996: a search for common mechanisms. Br J Cancer 2001;85:997-1005

34. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142-152

35. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 2016;374:1621-1634

36. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015;373:1207-1219

37. 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;387:1551-1560

38. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med 2015;373:621-631

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