Chronic lymphocytic leukemia

Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial

Abstract

The phase III trial GEM05MENOS65 randomized 390 patients 65 years old or younger with newly diagnosed symptomatic multiple myeloma (MM) to receive induction with thalidomide/dexamethasone, bortezomib/thalidomide/dexamethasone and Vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone bortezomib (VBMCP/VBAD/B) followed by autologous stem cell transplantation (ASCT) with MEL-200. After ASCT, a second randomization was performed to compare thalidomide/bortezomib (TV), thalidomide (T) and alfa-2b interferon (alfa2-IFN). Maintenance treatment consisted of TV (thalidomide 100 mg daily plus one cycle of intravenous bortezomib at 1.3 mg/m2 on days 1, 4, 8 and 11 every 3 months) versus T (100 mg daily) versus alfa2-IFN (3 MU three times per week) for up to 3 years. A total of 271 patients were randomized (TV: 91; T: 88; alfa2-IFN: 92). The complete response (CR) rate with maintenance was improved by 21% with TV, 11% with T and 17% with alfa2-IFN (P, not significant). After a median follow-up of 58.6 months, the progression-free survival (PFS) was significantly longer with TV compared with T and alfa2-IFN (50.6 vs 40.3 vs 32.5 months, P=0.03). Overall survival was not significantly different among the three arms. Grade 2–3 peripheral neuropathy was observed in 48.8%, 34.4% and 1% of patients treated with TV, T and alfa2-IFN, respectively. In conclusion, bortezomib and thalidomide maintenance resulted in a significantly longer PFS when compared with thalidomide or alfa2-IFN. (no. EUDRA 2005-001110-41).

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References

  1. 1

    Bladé J, Rosiñol L, Cibeira MT, Rovira M, Carreras E . Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. Blood 2010; 115: 3655–3663.

    Article  Google Scholar 

  2. 2

    Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM et al. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood 2002; 99: 3163–3168.

    CAS  Article  Google Scholar 

  3. 3

    Shustik C, Belch A, Robinson S, Rubin SH, Dolan SP, Kovacs M et al. A randomized comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol 2007; 136: 203–211.

    CAS  Article  Google Scholar 

  4. 4

    Fritz E, Ludwig H . Interferon-α treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol 2000; 11: 1427–1436.

    CAS  Article  Google Scholar 

  5. 5

    Myeloma Trialists Collaborative Group. Interferon as therapy for multiple myeloma: an individual patient data overview of 24 randomized trials and 4012 patients. Br J Haematol 2001; 113: 1020–1034.

    Article  Google Scholar 

  6. 6

    Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood 2006; 108: 3289–3294.

    CAS  Article  Google Scholar 

  7. 7

    Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.

    CAS  Article  Google Scholar 

  8. 8

    Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol 2009; 27: 1788–1793.

    CAS  Article  Google Scholar 

  9. 9

    Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood 2010; 115: 1113–1120.

    CAS  Article  Google Scholar 

  10. 10

    Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM et al. The role of maintenance thalidomide therapy in multiple myeloma: MRC myeloma IX results and meta-analysis. Blood 2012; 119: 7–15.

    CAS  Article  Google Scholar 

  11. 11

    Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A et al. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinical Trials Group Myeloma 10 Trial. Blood 2013; 121: 1517–1523.

    CAS  Article  Google Scholar 

  12. 12

    Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K et al. Thalidomide arm of total therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood 2008; 112: 3115–3121.

    CAS  Article  Google Scholar 

  13. 13

    Sonneveld P, Schmidt-Wolf IGH, van der Holt B, El Jarari L, Bertsch U, Salwender H 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; 24: 2946–2955.

    Article  Google Scholar 

  14. 14

    Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1782–1791.

    CAS  Article  Google Scholar 

  15. 15

    McCarthy P, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson P et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 2012; 366: 1770–1781.

    CAS  Article  Google Scholar 

  16. 16

    Palumbo A, Cavallo F, Gay F, Di Raimondo F, Yehuda DB, Petrucci MT et al. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med 2014; 371: 895–905.

    Article  Google Scholar 

  17. 17

    Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J et al. Superiority of bortezomib, thalidomide and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 2012; 120: 1581–1596.

    Article  Google Scholar 

  18. 18

    Bladé J, Rosiñol L, Sureda A, Ribera J, Díaz-Mediavilla J, García-Laraña J et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish Cooperative Group PETHEMA. Blood 2005; 106: 3755–3759.

    Article  Google Scholar 

  19. 19

    Bladé J, Samson D, Reece D, Apperley J, Björkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated with high-dose therapy and haematopoietic stem-cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplantation. Br J Haematol 1998; 102: 1115–1123.

    Article  Google Scholar 

  20. 20

    Durie BGM, Harousseau JL, San Miguel J, Bladé J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.

    CAS  Article  Google Scholar 

  21. 21

    Gutiérrez NC, Castellanos MV, Martín ML, Mateos MV, Hernández M, Fernández M et al. Prognostic and biological implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas Rb deletion as unique abnormality is not associated with adverse prognosis. Leukemia 2007; 21: 143–150.

    Article  Google Scholar 

  22. 22

    Kaplan EL, Meier P . Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  23. 23

    Peto R, Pike MC . Conservation of the approximation sigma (O-E)2-E in the log-rank test for survival data or tumor incidence data. Biometrics 1973; 29: 579–584.

    CAS  Article  Google Scholar 

  24. 24

    Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 2012; 120: 2582–2588.

    Article  Google Scholar 

  25. 25

    Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L 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.

    CAS  Article  Google Scholar 

  26. 26

    Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessments in multiple myeloma. Lancet Oncol 2016; 17: e328–e348.

    Article  Google Scholar 

  27. 27

    Gonsalves WI, Gertz MA, Dispenzieri A, Lacy MQ, Lin Y, Singh PP et al. Implications of continued response after autologous stem cell transplantation for multiple myeloma. Blood 2013; 122: 1746–1749.

    CAS  Article  Google Scholar 

  28. 28

    Fernández de Larrea C, Dávila J, Isola I, Ocio EM, Rosiñol L, García-Sanz R et al. Absence of spontaneous response improvement beyond day +100 after autologous stem cell transplantation in multiple myeloma. Bone Marrow Transplant 2016; e-pub ahead of print 21 november 2016; doi:10.1038/bmt.2016.299.

  29. 29

    Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A et al. Carfilzomib, lenalidomide and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015; 372: 142–152.

    Article  Google Scholar 

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Acknowledgements

This work has been supported in part by grants RD12/0036/0046 and PI12/1093 from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER), and 2014SGR-552 from AGAUR (Generalitat de Catalunya).

Author contributions

JB, LR, JJL and JSM designed the trial; all authors performed the research; AO performed the statistical analysis; LR and JB analyzed and interpreted the data; LR wrote the initial draft of the manuscript; JB, AO, MVM, JJL and JSM reviewed the draft manuscript; and all authors approved the final version for submission.

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Correspondence to J Bladé.

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LR received honoraria from Janssen and Celgene, AO has served as member of advisory boards for Janssen and Celgene, MVM has served as member of advisory boards for Celgene, Janssen and Millenium, JJL received honoraria from Janssen and Celgene, JSM discloses consultation fees from Celgene, Janssen and Millenium, and JB received grant support from Janssen and received honoraria from Janssen and Celgene. The remaining authors declare no conflict of interest.

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Rosiñol, L., Oriol, A., Teruel, A. et al. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia 31, 1922–1927 (2017). https://doi.org/10.1038/leu.2017.35

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