Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial

Abstract

A utologous transplantation is controversial for older patients with multiple myeloma. The role of age-adjusted high-dose melphalan and the impact of induction chemotherapy cycles is still unclear. A total of 434 patients aged 60-70 years were randomly assigned to 4 cycles of standard anthracycline-based induction chemotherapy or no induction. For all patients, double autologous transplantation after melphalan 140 mg/m 2 (MEL140) was planned. The primary end point was progression-free survival. Of 420 eligible patients, 85% received a first transplant and 69% completed double transplantation. Treatment duration was short with a median of 7.7 months with induction chemotherapy cycles and 4.6 months without induction. On an intention-to-treat basis, median progression-free survival with induction chemotherapy cycles (207 patients) was 21.4 months versus 20.0 months with no induction cycles (213 patients) (hazard ratio 1.04, 95% confidence interval 0.84-1.28; P=0.36). Per protocol, progression-free survival was 23.7 months versus 23.0 months (P=0.28). Patients aged 65 years or over (55%) did not have an inferior outcome. Patients with low-risk cytogenetics [absence of del17p13, t(4;14) and 1q21 gains] showed a favorable overall survival and included the patients with sustained first remission. MEL140 was associated with a low rate of severe mucositis (10%) and treatment-related deaths (1%). Based on hazard ratio, the short treatment arm consisting of mobilization chemotherapy and tandem MEL140 achieved 96% of the progression-free survival, demonstrating its value as an independent component of therapy in older patients with multiple myeloma who are considered fit for autologous transplantation. (clinicaltrials.gov identifier: 02288741)

Autotransplants in older multiple myeloma patients: hype or hope in the era of novel agents?

“…3 The randomized multicenter study by the German Multiple Myeloma Study Group (DSMM II) in 434 patients aged 60-70 years is therefore a long awaited trial endeavor, that, before the era of novel agents, tested non-induction with short-term dexamethasone alone vs. 4 cycles of conventional anthracycline dexamethasone induction (mostly VAD) with tandem MEL140 conditioning. 12 The treatment duration was short with a median of 7.7 months with induction and 4.6 months without it. The median PFS on the intention-to-treat basis with induction vs. without was 21.4 months vs. 20 months (HR 1.04; 95% CI 0.84-1.28; P=0.36), respectively.…”

“…12 Despite the fact that cross-comparison of other trials and representative historical data sets is problematic, median OS in the IFM 99-06 study with MP, MPT and MEL100 was 33.2, 51.6 and 38.3 months, respectively, 11 and in the Medical Research Council (MRC) study with MP, cyclophosphamide-thalidomide-dexamethasone (CTD) vs. ASCT in patients >64 years 30.6, 33.2 and 53 months, respectively, 13 thus the median OS in the DSMM II trial (median follow-up: 5.2 years) of 53.4 months with induction and 55.9 months without induction is encouraging, the more so since no modern induction or maintenance treatment were available and therefore not used in this trial. 12 The paper by Straka et al 12 encounters today's challenge, however, due to its enrollment from 2001 to 2006, the long follow-up until its publication and the unprecedented MM success, that non-induction or VAD induction is no longer employed, rather, highly effective induction, consolidation and maintenance approaches are employed as pre-and post-transplant strategies. 1,6,7,14,15 Thus, the MEL140 tandem ASCT back-bone of the DSMM II trial seems the most relevant today.…”

Is there still a role for stem cell transplantation in multiple myeloma?

“…15 In the DSSM II trial, in which patients underwent tandem ASCT conditioned with melphalan at 140 mg/m 2 , no difference in terms of TRM (1%) was reported between patients aged 60 to 65 years and those older than 65 years. 16 In another prospective trial Cancer August 1, 2019 comparing melphalan at 140 mg/m 2 with melphalan at 200 mg/m 2 in patients older than 65 years, the TRM rate at day +100 from transplantation was 0% in both arms, and this confirmed the feasibility of delivering high-dose melphalan to older patients. 17 Many studies have confirmed that chronological age is not itself a limitation for ASCT.…”

“…In a prospective study enrolling patients older than 65 years, ASCT, conditioned with melphalan at 100 mg/m 2 , was demonstrated to be feasible and effective (5‐year OS, 63%), especially among patients aged 66 to 70 years, whose treatment‐related mortality (TRM) was lower than that of patients older than 70 years (5% vs 19%) . In the DSSM II trial, in which patients underwent tandem ASCT conditioned with melphalan at 140 mg/m 2 , no difference in terms of TRM (1%) was reported between patients aged 60 to 65 years and those older than 65 years . In another prospective trial comparing melphalan at 140 mg/m 2 with melphalan at 200 mg/m 2 in patients older than 65 years, the TRM rate at day +100 from transplantation was 0% in both arms, and this confirmed the feasibility of delivering high‐dose melphalan to older patients …”

Real-life data on safety and efficacy of autologous stem cell transplantation in elderly patients with multiple myeloma

“…Most studies are retrospective analysis [9, 11, 30, 32]; some are even before the era of novel agents as proteasome inhibitors (PI) and immunomodulatory drugs (IMIDs) [31, 33, 34], and others use matched pair comparison [35]. Notwithstanding its limitations, these studies found similar toxicity, TRM, and non-inferiority in EFS, OS, or disease response to ASCT in elderly patients, even when considering a higher age threshold for older cohorts as 70 years [30, 32].…”