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

Abstract

IntroductionTreatment of patients with multiple myeloma (MM) is disappointing. In this regard, the Southwest Oncology Group (SWOG) experience on standard dose therapy in 7 consecutive, large phase 3 studies has shown median survival times of less than 3 years, irrespective of the treatment given. 1 In addition, the Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA) group found that increased doses of conventional chemotherapy did not result in significant prolongation of survival. 2 Finally, meta-analysis of 6633 patients from 27 randomized trials failed to show any superiority of combination chemotherapy over melphalan/ prednisone in terms of duration of response and survival. 3 Furthermore, the Nordic Myeloma Study Group reported no survival improvement in conventionally treated younger patients with myeloma in the past 2 decades. 4 These limitations led to the current tendency to offer high-dose therapy (HDT)/stem cell support to MM patients as part of the frontline treatment. 5 Two randomized trials conducted by the Intergroup Français du Myeloma (IFM) and the Medical Research Council (MRC) showed that HDT significantly increased complete remission (CR), event-free survival (EFS), and overall survival (OS) compared with conventional chemotherapy. 5,6 However, 2 other randomized trials, reported in abstract form, failed to show any superiority of autologous J.B. and J.S.M. created the initial concept/design of the trial, analyzed and interpreted the data, wrote the manuscript, modified subsequent drafts, and finalized the manuscript; L.R. and A. Sureda contributed to analysis and interpretation of the data and to drafting the manuscript; J.B., J.S.M., L.R., and A. Sureda brought a significant number of patients to the study; M.F. participated in the analysis of the data and in the updating process throughout the study period; and J.M.R., J.D.-M., J.G.-L., M.V.M., L.P., J.F.-C, J.M.M., P.G., F.C., M.C., J.T., S.G., M.J.M., A.B., A. Soler, and L.F. participated in the conception/design of the study, included patients, provided the PETHEMA database with the patient data and periodic updating, and actively discussed the progress of the trial at the annual PETHEMA meetings. All the authors are members of PETHEMA and reviewed and approval the final version of the manuscript.An Inside Blood analysis of this article appears in the front of this issue.Reprints: Joan Bladé , Hematology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: jblade@clinic.ub.es.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on March 22, 2019. by guest www.bloodjournal.org From transplantation. 7,8 The objective of the present study was to investigate, in a prospective randomized trial, the efficacy of HDT intensification therapy compared with continuation with conventional chemotherapy in patients wit...

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

“…However, three randomized trials show that OS is similar whether ASCT is done early (immediately following four cycles of induction therapy) or delayed (at the time of relapse as salvage therapy) [89][90][91]. Further, in a Spanish randomized trial, patients responding to induction therapy failed to benefit from ASCT trial, suggesting that the greatest benefit from early ASCT may be mainly among the small proportion of patients with disease refractory to induction therapy [92]. Two randomized trials have found benefit with tandem (double) versus single ASCT, with the benefit primarily seen in patients failing to achive CR or VGPR with the first ASCT [93,94].…”

Impact of early relapse after auto-SCT for multiple myeloma

“…[5][6][7] However, not all trials have been able to demonstrate a survival advantage for auto-SCT in myeloma, and it is not clear if all or only a selected set of patients derive survival benefit from auto-SCT. [8][9][10] Nevertheless, auto-SCT performed early in the disease course, typically after four cycles of initial therapy, remains the most common approach in patients who are considered eligible to undergo the procedure. More recently, clinical trials incorporating novel therapies such as thalidomide and its analogs and the proteasome inhibitor bortezomib continue to redefine the role of auto-SCT in this new era.…”

A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy

“…28 Several prospective randomized trials confirmed a benefit with HDC when compared with conventional chemotherapy, [29][30][31][32] and this procedure has been part of the standard of care for over two decades. 33 In the 2000s, an improvement of clinical outcomes was observed with the advent of immunomodulatory drugs and proteasome inhibitors.…”

“…3,14 HDM at a dose of 200 mg/m 2 is considered to be the standard conditioning regimen. 14,17,18,30 However, a variety of strategies has been explored with the aim of improving the results of HDM 200 mg/m 2 , including dose escalation, 22 addition of other agents such as busulfan, thiotepa or TBI 14,15,[17][18][19][20][21][22] or, conversely, dose reduction as part of a tandem auto-SCT procedure, 20 with overall mixed results. Further evidence is however necessary on the best conditioning regimen.…”