The EMN02/HO95 trial is the largest multicenter, randomized, phase 3 study conducted in the novel agent era and aimed to prospectively compare (randomization 1, R1) autologous stem cell transplantation (ASCT) vs proteasome inhibitor-based intensification therapy, and (randomization 2) consolidation therapy vs no consolidation, followed by lenalidomide maintenance for newly diagnosed MM.
After 3 to 4 cycles of bortezomib-based induction therapy and subsequent PBSC collection, patients aged ≤65 years were randomized (R1, stratification by ISS stage) to receive high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT or standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for 4 additional 42-day cycles (each including 8 doses of bortezomib). Progression-free survival (PFS) from R1 was the primary study end point for R1. The preplanned second interim analysis of ASCT vs VMP was performed in July 2017 when at least 66% of required events had occurred, and results are herein reported.
A total of 1503 patients were registered and 1192 were eligible for R1. Based on the allocation ratio for R1 depending on the single (1:1) vs double (1:1:1) HDM policy of each center, 695 patients were randomly assigned to ASCT and 497 patients to VMP. Median age was 58 years in both groups; ISS stage III was 20% in ASCT arm and 21% in VMP arm. FISH analysis of CD138+ bone marrow plasma cells was available in approximately 75% of patients in both groups. According to IMWG criteria, a high-risk (HiR) cytogenetic profile defined by t(4;14) ± t(14;16) ± del(17p) positivity (HiR-cyto) was detected in 25% of patients in both groups. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population and for each of the two treatment groups. On an intention-to-treat basis, median PFS was not yet reached in the ASCT group and was 44 months in the VMP group; 3-year estimate of PFS was 64% vs 57%, respectively (HR=0.76; 95% CI=0.64-0.91; P=0.002), which represented a 24% reduced risk of progression or death in the ASCT group compared with the VMP group. Prespecified subgroup analyses of PFS confirmed that the benefit associated with ASCT was not influenced by revised ISS (R-ISS) disease stage (stage II: P=0.006; stage III: P<0.001), HiR-cyto (present: P=0.001; absent: P=0.048); LDH values (above and below the upper limits: P=0.030 and P=0.004, respectively); sex (males: P=0.017; females: P=0.038) and age (>55 years: P=0.027; ≤55 years: P=0.038). The probability of achieving ≥ best VGPR was 84% in the ASCT group and was 75% in the VMP group (odds ratio=1.79; CI=1.32-2.35; P<0.001). Minimal residual disease, as assessed by multiparameter flow cytometry (sensitivity: 10-5), was negative in 239 out of 316 evaluable patients who reached ≥VGPR and were treated with either ASCT (n=153, or 64%) or VMP (n=89, or 36%) (Oliva S. et al, 2017 ASCO Annual Meeting, Abstract 8011). In a multivariate Cox regression analysis, randomization to ASCT (HR=0.69; CI=0.56-0.86; P<0.001), best ≥VGPR (HR=0.40; CI=0.32-0.51; P<0.001), R-ISS stage I vs III (HR=0.48; CI=0.31-0.75; P=0.001), absence of HiR-cyto (HR=0.66; CI=0.51-0.85; P=0.001), R-ISS II vs III (HR=0.70; CI=0.51-0.98; P=0.037) and Hb ≥10.5 g/dL (HR=0.78; CI=0.62-0.99, P=0.037) were independent predictors of prolonged PFS. Overall survival (OS) rate (a secondary end point) at 3 years from R1 was 85% in both treatment arms. However, when the analysis was performed in predefined subgroups, a significantly longer OS associated with ASCT-2 vs ASCT-1 was observed for patients with R-ISS stage III (69% vs 47% at 3 years; HR=0.43; CI=0.23-0.81; P=0.009) and HiR-cyto (74 % vs 61%; HR=0.60; CI=0.38-0.94; P=0.027), including those with del(17p) positivity (75% vs 51%; HR=0.47; CI=0.24-0.92; P=0.028).
In comparison with VMP as standard-dose intensification therapy for newly diagnosed MM, HDM plus ASCT significantly increased the rate of high quality responses, ultimately leading to improved PFS. PFS benefit associated with ASCT was retained across predefined subgroups of patients at standard-risk and high-risk. Randomization to ASCT was an independent predictor for improved PFS and significantly prolonged OS in subgroups of patients with poor prognosis, including those with R-ISS stage III and who carried t(4;14) ± t(14;16) ± del(17p), a finding not observed in the first interim analysis.
Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Oliva: Celgene: Honoraria; Takeda: Honoraria. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Mellqvist: janssen: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: participation advisory board; Sandoz: Other: participation advisory board. Dimopoulos: Genesis Pharma: Research Funding; Novartis: Consultancy, Honoraria; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology. Zweegman: Takeda: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation; Celgene: Other: advisory board participation, Research Funding. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro: Mundipharma: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Sonneveld: Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.
Asterisk with author names denotes non-ASH members.
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