Subgroup Analyses of the Randomized GMMG Phase III Multicenter Trial Relapse Suggest Survival Benefit of Salvage Autologous Transplant Primarily in Low Risk Multiple Myeloma

Abstract

Introduction The ReLApsE trial compared lenalidomide (LEN)/dexamethasone (DEX; Rd) re-induction, salvage high dose chemotherapy (HDCT), autologous stem cell transplantation (ASCT) and LEN maintenance with continuous Rd in relapsed multiple myeloma. Landmark (LM) analyses from salvage HDCT were performed due to the fact that ~30% of patients in the HDCT arm did not receive salvage HDCT/ASCT. These analyses showed a survival benefit in patients actually undergoing salvage HDCT/ASCT. Median PFS and OS from LM were 23.3 vs. 20.1 months (HR 0.74; p=0.09) and not reached vs. 57 months (HR 0.56; p=0.046) favoring the salvage HDCT/ASCT arm. Multivariate LM analyses showed significant associations of the salvage HDCT/ASCT arm with superior PFS (HR 0.6; p=0.01) and OS (HR 0.39; p=0.006). The present analysis aims to dissect treatment efficacy in relevant subgroups and provide clues for treatment stratification. Methods The ReLApsE trial (ISRCTN16345835) compared 3 Rd (LEN 25 mg, d1-21; DEX 40 mg, d1,8,15,22; 4 week cycles) re-induction cycles, HDCT (melphalan 200 mg/m2), ASCT and LEN maintenance (10 mg/d) until PD (arm B, n=139) with Rd until PD (arm A, n=138). Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75, time to PD in case of front-line HDCT/ASCT (TTP1) ≥ 12 months and WHO PS ≤ 2. Exploratory subgroup analyses were performed in the ITT population for PFS/OS using an LM at HDCT (B; n=103) and the contemporaneous Rd cycle 5 (A; n=114). The median interval from randomization to LM was 117/122 days in arm B/A. Heterogeneity of treatment effect was assessed by cox regression with interaction term between treatment and subgroup factor. Results No significant differences in the PFS/OS benefit between arms were observed in subgroups according to baseline ISS (I/II/III; interaction p[i-p]=0.5/0.66), age (</≥65 yrs; i-p=0.13/0.89), renal function (MDRD </≥ 60 ml/min; i-p=0.68/0.34), response to re-induction (</≥ PR; i-p=0.92/0.48), prior therapy lines (1/>1; i-p=0.37/0.22), single vs. tandem front-line HDCT/ASCT (i-p=0.34/0.56), and TTP1 (12-24 vs. 24-48 vs. >48 months; i-p=0.91/0.21). The subgroups according to front-line HDCT/ASCT (yes/no) differed significantly with regard to PFS/OS benefit in arm B (i-p=0.006/0.001). A significant benefit was observed in patients with front-line HDCT/ASCT treated in arm B regarding PFS (HR 0.68, p=0.03; n=107[A]/98[B]) and OS (HR 0.43, p=0.009). Patients without front-line HDCT/ASCT constituted a very small subgroup with imbalances in baseline parameters adversely affecting arm B and had expectably inferior survival in arm B (PFS: HR 4.35, p=0.08; OS: HR 19.83, p=0.0078; n=7[A]/5[B]). The subgroup with baseline LDH </> upper limit of normal (ULN) differed significantly in PFS benefit in arm B (i-p=0.03) but not in OS benefit (i-p=0.46). Patients with LDH<ULN had significantly better PFS (HR 0.61, p=0.01; n=98[A]/85[B]) in arm B whereas no significant difference between trial arms was observed in patients with LDH>ULN (PFS: HR 1.54, p=0.31; n=16[A]/18[B]). The subgroups according to baseline cytogenetic risk and R-ISS showed a trend towards a differential benefit in arm B regarding OS (i-p=0.05 and 0.09) but not PFS (i-p=0.5 and 0.88). Patients with low risk cytogenetics (i.e. absence of t(4;14), del17p, +1q>3 copies and t(14;16)) had significantly superior OS in arm B (HR 0.21; p=0.01; n=57[A]/35[B]), whereas patients with high risk cytogenetics had no significant difference in OS according to trial arm (HR 0.82, p=0.67; n=25[A]/28[B]). Patients with R-ISS I had significantly superior OS in arm B (HR 0.08; p=0.02; n=33[A]/25[B]), whereas no significant difference in OS according to trial arm was seen in patients with R-ISS II (HR 0.72, p=0.42; n=52[A]/43[B]) and R-ISS III (HR 0.65, p=0.6; n=3[A]/5[B]). Conclusions The ReLApsE trial is the first RCT of salvage HDCT/ASCT vs. continuous novel agent treatment. In the absence of a significant survival benefit for the primary endpoint, LM analyses indicated a significant PFS/OS benefit in patients actually undergoing HDCT/ASCT. No heterogeneity of treatment effect was observed according to ISS, age, renal function, response to re-induction, prior therapy lines, single vs. tandem front-line HDCT/ASCT, and TTP1. Subgroup effects regarding PFS and/or OS benefit from HDCT/ASCT were seen favoring patients with front-line HDCT/ASCT and patients with low risk according to LDH, cytogenetics and R-ISS. Disclosures Baertsch: Takeda: Consultancy; Novartis: Consultancy, Research Funding. Raab:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hillengass:Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; amgen: Consultancy, Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Sanofi: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Fenk:Bristol-Meyers Squibb: Honoraria, Other: travel grant; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Travel grant, Research Funding. Haenel:Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Honoraria. Scheid:Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Salwender:Janssen: Honoraria, Other: travel support, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Carfilzomib, Lenalidomide, and Dexamethasone Followed by Salvage Autologous Stem Cell Transplant with or without Maintenance for Relapsed or Refractory Multiple Myeloma

“…Unfortunately, outside of clinical trials these parameters are not routinely collected at relapse, which precluded inclusion in our multivariate model. However, this may be partially compensated for by inclusion of TTP1, which can be viewed as an integrated marker of risk as it represents the behavior of the disease under prior treatment [26,30].…”

Multiple myeloma: Role of autologous transplantation

“…The landmark analysis suggested a survival benefit among patients undergoing salvage ASCT [39]. Low-risk patients derived the largest benefit [40]. Retrospective studies have also confirmed the efficacy and safety of salvage ASCT [41].…”

Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

“…However, 1 of 3 patients randomized to the ASCT arm did not receive the assigned therapy. A landmark analysis at the 5th Rd cycle in arm A and at ASCT in arm B showed a trend for improved PFS with ASCT as well as improved OS [38,43,44].…”