▪BackgroundThe role of single vs double autologous stem cell transplantation (ASCT) for newly diagnosed (ND) multiple myeloma (MM) continues to be debated in the novel agent era.MethodsThe phase III EMN02/HO95 study was designed to administer 3-4 cycles of bortezomib-cyclophosphamide-dexamethasone as induction therapy for NDMM and afterwards to randomize eligible patients to receive (randomization 1, R1) standard-dose intensification treatment with bortezomib-melphalan-prednisone (VMP) for four 42-day cycles or high-dose intensification treatment with melphalan at 200 mg/m2 (HDM) plus ASCT. A second randomization to receive or not receive consolidation therapy was planned after the intensification phase, followed by lenalidomide maintenance in both arms. In centers committed to a double ASCT policy, patients were randomized (1:1:1) to receive VMP or single ASCT (ASCT-1) or two sequential courses of HDM (administered 2 to 3 months apart) plus double ASCT (ASCT-2) in order to prospectively compare ASCT-1 vs ASCT-2, which was an additional study objective. For this purpose, and for consistency with the primary study end point, progression-free survival (PFS) from R1 was evaluated.ResultsA total of 1503 patients aged ≤65 years were registered and 1192 were eligible for R1. By study design, 618 patients who received the diagnosis of MM in centers with a double ASCT policy were randomly assigned to VMP (n=203) or ASCT-1 (n=208) or ASCT-2 (n=207). 415 of these patients who were randomized to receive ASCT-1 or ASCT-2 were included in the current pre-specified analysis. Median age was 58 years for patients in the ASCT-1 group and 57 years for those in the ASCT-2 group. The frequency of ISS stage III was 19% 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-3) was detected in 26% and 21% of patients who were evaluable in ASCT-1 (80%) and ASCT-2 (86%) groups. The presence of amp(1q) ± del(1p) ± 1 or more of t(4;14), t(14;16) and del(17p) identified a HiR cytogenetic profile (HiR-cyto-5) which was detected in 55% of patients in ASCT-1 arm and 50% of those in ASCT-2 arm. Median follow-up from R1 was 38 (IQR: 29-47) months for the overall patient population (36 and 39 months for patients randomized to ASCT-1 and ASCT-2, respectively). On an intention-to-treat basis, 3-year estimate of PFS was 73% (95% CI=66-79) for ASCT-2 group vs 64% (CI=57-71) for ASCT-1 group (HR=0.70; CI=0.50-0.98; P=0.040), which represented a 30% reduced risk of progression or death in the ASCT-2 group compared with the ASCT-1 group (Fig. 1a). PFS benefit associated with ASCT-2 was confirmed in subgroups of patients with HiR-cyto-3 (HR=0.42; CI=0.21-0.84; P=0.014), revised ISS (R-ISS) stage II+III (HR=0.64; CI=0.43-0.97; P=0.034), age >55 years (HR=0.64; CI=0.43-0.96; P=0.033); HiR-cyto-5 (HR=0.65; CI=0.42-1.01; P=0.059) and best ≥VGPR (HR=0.64; CI=0.44-0.94; P=0.023). Importantly, ASCT-2 overcame the adverse prognosis conferred by HiR-cyto-3 (3-year PFS: 76% vs 69% for patients with standard-risk cytogenetic profile; P=0.482) (Fig. 1b). In particular, 3-year PFS estimate for patients randomized to ASCT-2 and carrying or lacking del(17p) was 72% vs 73%, respectively (P=0.534). The corresponding PFS values in the ASCT-1 group were 43% vs 67%, respectively (P=0.014). In a multivariate Cox regression analysis, randomization to ASCT-2 (HR=0.65; CI=0.44-0.95; P=0.029), R-ISS I (HR=0.60; CI=037-0.98; P=0.042), absence of HiR-cyto-5 (HR=0.35; CI=0.22-0.55; P<0.001) and best ≥VGPR (HR=0.27; CI=0.17-0.44; P<0.001) were the leading independent predictors of PFS. Overall survival (OS) from R1 was significantly prolonged with ASCT-2 as compared with ASCT-1 (3-year rate: 89% vs 82%; HR=0.52; CI=0.31-0.86; P=0.011) (Fig. 1c), a benefit also seen in subgroups of patients with adverse prognosis, including those with R-ISS stage II+III (HR=0.48; CI=0.27-0.86; P=0.013) and HiR-cyto-5 (HR=0.52; CI=0.28-0.98; P=0.042).ConclusionsRandomization to ASCT-2 was superior over ASCT-1 in terms of prolonged PFS and OS for the overall patient population and for poor prognosis subgroups of patients with advanced R-ISS disease stage and HiR cytogenetic profile. Incorporation of bortezomib into ASCT-2 abrogated the increased risk of progression or death imparted by t(4;14) ± t(14;16) ± del(17p), and in particular by del(17p) positivity. [Display omitted] DisclosuresGay:Amgen: Honoraria; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria. Bringhen:Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Musto:janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Palumbo:Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Sonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding; Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy.