Impact of Autologous Transplantation Vs. Chemotherapy Plus Lenalidomide in Newly Diagnosed Myeloma According to Patient Prognosis: Results of a Pooled Analysis of 2 Phase III Trials

Background: Autologous stem cell transplantation (ASCT) improves outcome in comparison with chemotherapy (CC) innewly diagnosed multiple myeloma (NDMM) patients. The primary objective of our analysis was to compare progression-free survival (PFS) and overall survival (OS) of patients randomized to ASCT vs. chemotherapy (CC): we tested the hypothesis that benefit of ASCT could vary in different subsets of patients defined according to baseline prognostic features and response to induction.

Methods: Data of 2 phase III multicenter randomized trials (RV-MM-PI-209 and RV-MM-EMN-441) enrolling patients younger than 65 years were pooled together. In both trials, patients received lenalidomide-dexamethasone induction and stem cell mobilization. Patients were randomized to either consolidation with 2 courses of Melphalan 200 mg/mq followed by ASCT (Mel200-ASCT) or 6 cycles of CC plus lenalidomide (CC+R) (RV-MM-PI-209: melphalan-prednisone-lenalidomide; RV-MM-EMN-441: cyclophosphamide-dexamethasone-lenalidomide). We evaluated PFS and OS of Mel200-ASCT vs. CC+R patients in the following subgroups, defined according to baseline features (Karnofsky performance status (PS) [60-70%, 80-100%], International Staging System (ISS) stage [I, II, III], cytogenetic profile [presence of del17 or t(4;14) or t(14;16); absence of del17, t(4;14) and t(14;16)]) and response to induction (≥very good partial response [VGPR], <VGPR). Data cut-off was June, 2014.

Results: 791 patients were enrolled in the two trials; 529 were eligible for consolidation: 268 patients received Mel200-ASCT and 261 patients received CC+R. Median follow-up for survivors was 4 years. Mel200-ASCT significantly prolonged PFS (median: 42 vs. 24 months, HR 0.52, 95%CI 0.41-0.65, P<0.001) and OS (4-year: 83% vs. 68%, HR 0.59, 95%CI 0.40-0.90 P=0.012) in comparison with CC+R. Mel200-ASCT significantly improved PFS in all the subgroups of patients analyzed. (Table). The most significant OS benefit was noticed in patients with a Karnofsky PS 80-100% (4-year: 85% vs. 73%, HR 0.55, 95% CI 0.35-0.88, P=0.013), with ISS Stage I disease (4-year: OS 89% vs. 77%, HR 0.43, 95% CI 0.20-0.91, P=0.027), with absence of del17, t(4;14) and t(14;16) (4-year: 87% vs. 78%, HR 0.57, 0.33-0.98, P=0.040), and in patients achieving ≥VGPR after lenalidomide-dexamethasone induction (4-year: 84% vs. 65%, HR 0.46, 95% CI 0.22-0.96, P=0.039).

Conclusions: In NDMM patients, Mel200-ASCT significantly improved PFS and OS in comparison with CC+R. The most significant OS advantage was observed in patients with baseline Karnofsky PS 80-100%, ISS Stage I, with absence of del17, t(4;14) or t(14;16) and in patients achieving ≥VGPR after induction. These data suggest intensifying treatment in good-prognosis patients and in patients with a chemo-sensitive disease. More effective novel agents are needed for patients with a more aggressive disease.