Salvage Autologous Transplant and Lenalidomide Maintenance Versus Continuous Lenalidomide/Dexamethasone for Relapsed Multiple Myeloma: Results of the Randomized GMMG Phase III Multicenter Trial Relapse

Introduction Salvage high dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is used in fit patients with relapsed multiple myeloma (RMM) in clinical practice. However, the role of this approach in the era of continuous novel agent based treatment has not been defined in randomized trials. The ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage HDCT/ASCT and lenalidomide (R) maintenance with standard continuous Rd in a randomized controlled multicenter 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/m²), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. In both arms stem cells were harvested after the 3^rd Rd cycle if no back-up transplant was available. Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS), response rates and toxicity. ISRCTN16345835, Eudra CT-No: 2009-013856-61.

Results Arm B and A were balanced regarding age (median 61.3 vs. 62.2 years), ISS (I/II/III in 62.6/24.4/13% vs. 59.7/31/9.3%) and WHO PS (0/1/2 in 69.1/30.9/0% vs. 76.1/23.2/0.7%). Almost all patients had only 1 prior therapy line (arm B: 94.2% vs. arm A: 93.5%) and had received front-line HDCT/ASCT (92.8% vs. 94.2%). More patients in arm B had high risk cytogenetic aberrations (HR-CA; 42.9% vs. 31.6%) based on a higher frequency of t(4;14) (20.2% vs. 10.1%).

The overall response rate (≥ partial response; ORR) for arm B and A was 77.9% and 74.6% (p=0.57) with 49.3% and 47.1% (p=0.81) achieving ≥ very good partial response as best response. Within a median follow up of 36.3 months, 183 PFS events and 76 deaths occurred. Median PFS in the ITT population was 20.7 months in arm B and 18.8 months in arm A without a statistically significant difference (HR 0.87; 95% CI 0.65-1.16; p=0.34). Median OS was not reached (NR) in arm B vs. 62.7 months in arm A (HR 0.81; 95% CI 0.52-1.28; p=0.37).

In arm B, 41 patients (29.5%) did not receive the planned HDCT/ASCT. Thus, exploratory landmark (LM) analyses from HDCT and the contemporaneous Rd cycle 5 in arm A were performed (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A]). They showed a trend towards superior PFS (23.3 vs. 20.1 months; HR 0.74; p=0.09) and significantly superior OS (NR vs. 57 months; HR 0.56; p=0.046) in arm B vs. A. Multivariate analyses revealed significant associations of treatment in arm B with superior LM PFS (HR 0.6; p=0.01) and LM OS (HR 0.39; p=0.006). Other factors in the LM multivariate models showing significant associations with survival were HR-CA (PFS, OS), number of prior therapy lines (PFS), and age (PFS). The ORR in arm B after HDCT/ASCT was significantly higher than in arm A after Rd cycle 5 (82.3% vs. 69.6%; p=0.04).

Grade ≥3 adverse events were reported in 83% (arm B) and 74.5% (arm A; p=0.11). Grade ≥3 leukopenia/neutropenia was reported in 61.5 vs. 24.8% (p<0.001), grade ≥3 thrombopenia in 45.2 vs. 11% (p<0.001) and grade ≥3 mucositis in 10.4% vs. 2.1% (p=0.005). No significant difference in grade ≥3 infections/infestations (33.3 vs. 27.6%; p=0.3) was observed. Eleven patients died on protocol treatment (B: 4 vs. A: 7). No deaths occurred in the HDCT/ASCT phase.

Conclusions This is the first RCT comparing salvage HDCT/ASCT with continuous novel agent based treatment. No significant PFS or OS difference was observed in the overall trial population. However, HR-CA were more frequent in the HDCT/ASCT arm and ~30% of patients did not receive the planned HDCT/ASCT. Landmark analyses from the time of HDCT indicate superior PFS and OS in patients actually undergoing salvage HDCT/ASCT. Salvage HDCT/ASCT was safe with an expected increase in hematological as wells as gastrointestinal toxicity but without treatment-related mortality in patients up to the age of 75 years in this multicenter trial. However, the number of patients not undergoing salvage HDCT/ASCT and the approval of more active Rd-based triplet regimens after the initiation of this trial prevents definite conclusions on the role of salvage HDCT/ASCT.