Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study

Blood - Tập 120 - Trang 1589-1596 - 2012
Laura Rosiñol1, Albert Oriol2, Ana Isabel Teruel3, Dolores Hernández4, Javier López-Jiménez5, Javier de la Rubia6, Miquel Granell7, Joan Besalduch8, Luis Palomera9, Yolanda González10, Mª Asunción Etxebeste11, Joaquín Díaz-Mediavilla12, Miguel T. Hernández13, Felipe de Arriba14, Norma C. Gutiérrez15, Mª Luisa Martín-Ramos16, Mª Teresa Cibeira1, Mª Victoria Mateos15, Joaquín Martínez16, Adrián Alegre17
1Hospital Clínic de Barcelona, Barcelona, Spain
2Hospital Germans Trias i Pujol, Badalona, Spain
3Hospital Clínico Universitario de Valencia, Valencia, Spain
4Hospital Universitário La Paz, Madrid, Spain
5Hospital Ramón y Cajal, Madrid, Spain
6Hospital La Fe, Valencia, Spain
7Hospital Sant Pau, Barcelona, Spain;
8Hospital Son Espases, Palma de Mallorca, Spain
9Hospital Clínico Univesitario Lozano Blesa, Zaragoza, Spain
10Hospital Universitari Dr Josep Trueta, Giorna, Spain
11Hospital de Donostia, Donostia, Spain
12Hospital Clínico San Carlos, Madrid, Spain
13Hospital Universitario de Canarias, La Laguna, Spain
14Hospital Morales Messeguer, Murcia, Spain
15Hospital Clínico Universitario de Salamanca, Salamanca, Spain
16Hospital Universitario Doce de Octubre, Madrid, Spain
17Hospital Universitario La Princesa, Madrid, Spain

Tóm tắt

Abstract

The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post–autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).


Tài liệu tham khảo

Cavo, 2011, International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation., Blood, 117, 6063, 10.1182/blood-2011-02-297325 Stewart, 2009, How I treat multiple myeloma in younger patients., Blood, 114, 5436, 10.1182/blood-2009-07-204651 Moreau, 2011, Current trends in autologous stem cell transplantation for myeloma in the era of novel therapies., J Clin Oncol, 29, 1898, 10.1200/JCO.2010.32.5878 Bladé, 2010, Hematopoietic stem cell transplantation for multiple myeloma beyond 2010., Blood, 115, 3655, 10.1182/blood-2009-08-238196 Lahuerta, 2008, Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival., J Clin Oncol, 26, 5775, 10.1200/JCO.2008.17.9721 Bladé, 2000, High-dose therapy autotransplantation/intensification vs continued standard chemotherapy in multiple myeloma in first remission: results of a non-randomized study from a single institution., Bone Marrow Transplant, 26, 845, 10.1038/sj.bmt.1702622 Alexanian, 2011, Impact of complete remission with intensive therapy in patients with multiple myeloma., Bone Marrow Transplant, 27, 1037, 10.1038/sj.bmt.1703035 Harousseau, 2009, The role of complete response in multiple myeloma., Blood, 114, 3139, 10.1182/blood-2009-03-201053 Dingli, 2007, Serm M-spike and transplant outcome in patients with multiple myeloma., Cancer Sci, 98, 1035, 10.1111/j.1349-7006.2007.00499.x Nadal, 2004, High-dose therapy/autologous stem cell transplantationin patients with chemosensitive myeloma: predictors of complete remission., Bone Marrow Transplant, 33, 61, 10.1038/sj.bmt.1704313 van de Velde, 2007, Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma., Haematologica, 92, 1399, 10.3324/haematol.11534 Moreau, 2011, Achievement of VGPR to induction therapy is an important prognostic factor for longer PFS in the IFM 2005-01 trial., Blood, 117, 3041, 10.1182/blood-2010-08-300863 Cavo, 2005, Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma., Blood, 106, 35, 10.1182/blood-2005-02-0522 Rajkumar, 2006, Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group., J Clin Oncol, 24, 431, 10.1200/JCO.2005.03.0221 Harousseau, 2010, Bortezomib-dexamethasone is superior to vincristine-doxorubicin-dexamethasone as induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase 3 trial., J Clin Oncol, 28, 4621, 10.1200/JCO.2009.27.9158 Lockhorst, 2010, A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and followed by thalidomide maintenance in patients with multiple myeloma., Blood, 115, 1113, 10.1182/blood-2009-05-222539 Morgan, 2012, Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destinated for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results., Haematologica, 97, 442, 10.3324/haematol.2011.043372 Neben, 2012, Administration of bortezomib before and after autologous stem-cell transplantation improves outcome in multiple myeloma patients with deletion 17p., Blood, 119, 940, 10.1182/blood-2011-09-379164 Oakervee, 2005, PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated multiple myeloma., Br J Haematol, 129, 755, 10.1111/j.1365-2141.2005.05519.x Wang, 2007, Bortezomib in combination with thalidomide-dexamethasone for previously untreated multiple myeloma., Hematology, 12, 235, 10.1080/10245330701214236 Bladé, 2005, 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 Coperative Croup PETHEMA., Blood, 106, 3755, 10.1182/blood-2005-03-1301 Delforge, 2010, Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues., Lancet Oncol, 11, 1086, 10.1016/S1470-2045(10)70068-1 Richardson, 2012, Management of treatment-emergent peripheral neuropathy in multiple myeloma., Leukemia, 26, 595, 10.1038/leu.2011.346 Bladé, 1998, 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, 102, 1115, 10.1046/j.1365-2141.1998.00930.x Durie, 2006, International uniform response criteria for multiple myeloma., Leukemia, 20, 1467, 10.1038/sj.leu.2404284 Gutiérrez, 2007, 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 a unique abnormality is not associated with adverse prognosis., Leukemia, 21, 143, 10.1038/sj.leu.2404413 Kaplan, 1958, Non-parametric estimation from incomplete observations., J Am Stat Assoc, 53, 457, 10.1080/01621459.1958.10501452 Peto, 1973, Conservation of the approximation sigma (O-E)2-E in the log-rank test for survival data or tumor incidence data., Biometrics, 29, 579, 10.2307/2529177 Cavo, 2010, 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 randomized phase 3 study., Lancet, 376, 2075, 10.1016/S0140-6736(10)61424-9 Moreau, 2011, Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma., Blood, 118, 5752, 10.1182/blood-2011-05-355081 Popat, 2008, Bortezomib, doxorubicin and dexamethasone (PAD) front-line treatment of multiple myeloma: updated results after long-term follow-up., Br J Haematol, 141, 512, 10.1111/j.1365-2141.2008.06997.x Moreau, 2011, Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study., Lancel Oncol, 12, 431, 10.1016/S1470-2045(11)70081-X Wang, 2011, The speed of response to single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma: an exploratory analysis of results from 2 multicenter phase 2 clinical trials [abstract]., Blood (ASH Annual Meeting Abstracts), 118 Fonseca, 2009, International Myeloma Working Group molecular classification of multiple myeloma: spotlight review., Leukemia, 23, 2210, 10.1038/leu.2009.174 Shaughnessy, 2009, TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3., Br J Haematol, 147, 347, 10.1111/j.1365-2141.2009.07864.x Avet-Loisseau, 2010, Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p)., J Clin Oncol, 28, 4630, 10.1200/JCO.2010.28.3945 Mateos, 2011, Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance., Blood, 118, 4547, 10.1182/blood-2011-04-345801 Rosiñol, 2011, A Phase III PETHEMA/GEM randomized trial of posttransplant (ASCT) maintenance in multiple myeloma: superiority of bortezomib/thalidomide compared with thalidomide and alfa-2b interferon., Blood (ASH Annual Meeting Abstracts), 118, 3962