Introduction The randomized, controlled, multicenter, phase III GMMG ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage high dose chemotherapy, autologous stem cell transplantation (HDCT/ASCT) and lenalidomide (R) maintenance with standard continuous Rd. We have previously reported the absence of a significant survival benefit in the primary analysis. However, landmark analyses from salvage HDCT performed due to the fact that ~30% of patients in the HDCT arm did not receive salvage HDCT/ASCT suggested a survival benefit in patients undergoing salvage HDCT/ASCT. Here we report long term follow up results from the GMMG ReLApsE trial.
Methods Between 2010 and 2016, 282 patients were randomized of whom 277 constituted the intention-to-treat (ITT) population (arm B/A n=139/138). Arm B received 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, 22; 4 week cycles) re-induction, HDCT (melphalan 200 mg/m 2), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. Key inclusion criteria were 1-3 prior treatment lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. R-refractory disease was not permitted and only 30/277 patients (11%) were previously exposed to R. The primary endpoint was progression free survival (PFS). Protocol-specified long term follow up collection included overall survival (OS), further lines of treatment and further salvage HDCT/ASCT after trial participation. ISRCTN16345835, Eudra CT-No: 2009-013856-61.
Results Within the extended follow up period of 99 months, 238 PFS events (86%) and 174 deaths (63%) occurred. Median PFS in the ITT population was 20.5 months in arm B and 19.3 months in arm A without a statistically significant difference (HR 0.98; 95% CI 0.76-1.27; p=0.9). Median OS was 67.1 months in arm B vs. 62.7 months in arm A (HR 0.89; 95% CI 0.66-1.20; p=0.44). The absence of a significant PFS and OS benefit was consistent among key disease subgroups according to age, R-ISS, renal function, frontline single vs. tandem HDCT/ASCT, prior lines of treatment and prior maintenance treatment post HDCT/ASCT. Time to progression after frontline HDCT/ASCT was significantly associated with PFS in the total ITT population (p=0.001) as well as in both trial arms independently, but was not associated with a survival benefit from arm B vs. A (interaction test PFS p=1.0, OS p=0.7).
Multivariate analyses revealed significant associations of survival with age (PFS: HR 0.8, p=0.045), high risk cytogenetic aberrations (PFS: HR 2.1, p<0.001; OS: HR 2.5, p<0.001), ISS stage III vs. I (OS: HR 2.0, p=0.02), elevated LDH (PFS: HR 1.5, p=0.04; OS: HR 2.1, p<0.001), >1 prior lines of treatment (PFS: HR 2.3, p=0.003), and no prior HDCT/ASCT (PFS: HR 1.8, p=0.04; OS: HR 2.2, p=0.009), but not with treatment arm B vs. A (PFS: HR 0.9, p=0.4; OS: HR 0.9, p=0.37).
In landmark analyses from HDCT and the contemporaneous Rd cycle 5 in arm A (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A]) no significant differences in PFS (23.0 vs. 20.3 months; HR 0.91; 95% CI 0.68-1.22; p=0.52) or OS (76.3 vs. 66.0 months; HR 0.8; 95% CI 0.56-1.13; p=0.2) in arm B vs. A were observed.
Further lines of treatment after trial participation were reported in 88/139 (63%) and 96/138 (70%) patients in arm B and A (p=0.31). Significantly more salvage HDCT/ASCT were administered after trial participation in arm A vs. B (48/138 [35%] vs. 19/139 [14%], p<0.001). Immunomodulatory drug (lenalidomide, pomalidomide) based regimens were used comparably after both trial arms.
The rate of second primary malignancies was comparable in arm B and A (26/139 [19%] vs. 19/138 [14%], p=0.3).
Conclusions The GMMG ReLApsE trial is the only randomized, controlled trial comparing salvage HDCT/ASCT with continuous novel agent treatment. With extended follow up, no significant PFS or OS difference is observed in the overall trial population and the previously reported survival benefit in patients who actually received salvage HDCT/ASCT is not confirmed. Time to progression after frontline HDCT/ASCT which is frequently used to stratify for salvage HDCT/ASCT in clinical practice is a general prognostic parameter for PFS, but does not predict benefit from salvage HDCT/ASCT vs. continuous Rd treatment. The GMMG ReLApsE trial does not support salvage HDCT/ASCT for relapsed or refractory multiple myeloma.
Disclosures
Raab:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Heidelberg Pharma: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Heidelberg University Hospital: Current Employment. Merz:AMGEN, TAKEDA, BMS, JANSSEN, STEMLINE, ROCHE: Honoraria. Mai:BMS, Takeda, Sanofi, Janssen, GSK: Research Funding; BMS, GSK, Janssen, Stemline, Takeda: Other: Travel expenses; BMS, GSK, Jansen, Stemline, Takeda: Honoraria; BMS, GSK, Janssen, Stemline, Takeda: Consultancy. Klein:Amgen: Honoraria. Glass:Gilead, BMS, Novartis, Milteneyi, Roche, Jazz: Honoraria, Other: Advisory board. Graeven:Sanofi: Honoraria; Boehringer Ingelheim: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Honoraria; BioNTech: Current holder of stock options in a privately-held company; MSD: Consultancy, Honoraria; Fujifilm: Honoraria; Novartis: Honoraria; Celltrion: Honoraria; Ipsen: Research Funding; MacroGenics: Honoraria, Research Funding; GSK: Other: travel support. Fenk:Janssen, Amgen, GSK, Takeda, BMS: Honoraria. Hänel:Novartis, BMS/Celgene, Gilead, Pfizer, Incyte, Sanofi/Aventis, Roche, Amgen, SOBI, Janssen: Consultancy; Novartis, SOBI, Gilead, Falk Foundation: Honoraria. von Metzler:Takeda: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; BMS: Consultancy. Scheid:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nogai:Celgene, Takeda, Amgen, Alexion, Sanofi, Janssen, BMS: Honoraria; Celgene, Janssen, Takeda: Research Funding; Celgene, Takeda, Alexion: Other: Travel expenses. Salwender:Celgene, Janssen, Novartis, Takeda, Amgen, BMS,: Honoraria; Celgene, Janssen, Novartis, Amgen, BMS: Other: Travel support; Celgene, Janssen, Novartis, Amgen, BMS: Research Funding. Besemer:Janssen Cilag: Honoraria; GSK: Honoraria. Weisel:GlaxoSmithKline: Consultancy, Honoraria, Other: Research grant to institution; AstraZeneca: Honoraria; Karyopharm: Consultancy, Honoraria; Novartis: Honoraria; Stemline: Honoraria; Sanofi: Consultancy, Honoraria, Other: Research grant to institution; Roche Pharma: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Other: Research grant to institution; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Research grant; Janssen: Consultancy, Honoraria, Other: Research grant to institution; Adaptive Biotech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Research grant to institution; AbbVie: Consultancy, Honoraria, Other: Research grant to institution; Menarini: Consultancy, Honoraria. Goldschmidt:Johns Hopkins University: Research Funding; Dietmar-Hopp-Foundation: Research Funding; Chugai: Honoraria, Patents & Royalties, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Array Biopharma: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Glycomimetics: Research Funding; GSK: Honoraria, Other: Travel Support, Research Funding; Heidelberg Pharma: Research Funding; Hoffman- La Roche: Research Funding; KaryoPharm: Research Funding; Incyte: Research Funding; Millenium Pharmaceuticals: Research Funding; Molecular Partners: Research Funding; MSD: Research Funding; Morphosys AG: Research Funding; Pfizer: Honoraria, Patents & Royalties: Travel Support, Research Funding; Takeda: Research Funding; Novartis: Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees.