Abstract
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.
Subgroup analysis of PFS and OS in Mel200-ASCT vs CC+R patients
| . | PFS . | OS . | ||||
|---|---|---|---|---|---|---|
| . | HR . | 95% CI . | P-value . | HR . | 95% CI . | P-value . |
| ISS | ||||||
| Stage I Stage II Stage III | 0.43 0.61 0.60 | 0.30-0.63 0.42-0.90 0.36-0.98 | <0.001 0.012 0.042 | 0.43 0.69 0.75 | 0.20-0.91 0.33-1.42 0.38-1.47 | 0.027 0.315 0.397 |
| Cytogenetic profile | ||||||
| No del17, t(4;14), t(14;16) Del17 or t(4;14) or t(14;16) | 0.61 0.44 | 0.44-0.86 0.27-0.70 | 0.004 <0.001 | 0.57 0.60 | 0.33-0.98 0.31-1.15 | 0.040 0.120 |
| Karnofsky PS | ||||||
| 60-70% 80-100% | 0.46 0.52 | 0.26-0.81 0.40-0.68 | 0.008 <0.001 | 0.72 0.55 | 0.29-1.73 0.35-0.88 | 0.450 0.013 |
| Response to induction | ||||||
| ≥VGPR <VGPR | 0.48 0.53 | 0.30-0.80 0.40-0.70 | <0.001 <0.001 | 0.46 0.71 | 0.22-0.96 0.43-1.18 | 0.039 0.193 |
| . | PFS . | OS . | ||||
|---|---|---|---|---|---|---|
| . | HR . | 95% CI . | P-value . | HR . | 95% CI . | P-value . |
| ISS | ||||||
| Stage I Stage II Stage III | 0.43 0.61 0.60 | 0.30-0.63 0.42-0.90 0.36-0.98 | <0.001 0.012 0.042 | 0.43 0.69 0.75 | 0.20-0.91 0.33-1.42 0.38-1.47 | 0.027 0.315 0.397 |
| Cytogenetic profile | ||||||
| No del17, t(4;14), t(14;16) Del17 or t(4;14) or t(14;16) | 0.61 0.44 | 0.44-0.86 0.27-0.70 | 0.004 <0.001 | 0.57 0.60 | 0.33-0.98 0.31-1.15 | 0.040 0.120 |
| Karnofsky PS | ||||||
| 60-70% 80-100% | 0.46 0.52 | 0.26-0.81 0.40-0.68 | 0.008 <0.001 | 0.72 0.55 | 0.29-1.73 0.35-0.88 | 0.450 0.013 |
| Response to induction | ||||||
| ≥VGPR <VGPR | 0.48 0.53 | 0.30-0.80 0.40-0.70 | <0.001 <0.001 | 0.46 0.71 | 0.22-0.96 0.43-1.18 | 0.039 0.193 |
Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Off-label use of Lenalidomide.. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Di Raimondo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Caravita:Celgene: Honoraria. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Offidani:Janssen-Cilag: Honoraria; Mundipharma: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Ria:Janssen-Cilag: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy. Cavallo:Onyx: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Spencer:Celgene: Honoraria. Palumbo:Sanofi Aventis: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Array BioPharma: Honoraria; Genmab A/S: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.
Author notes
Asterisk with author names denotes non-ASH members.
