Upfront Autologous Hematopoietic Stem-Cell Transplantation Improves Overall Survival in Comparison with Bortezomib-Based Intensification Therapy in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the Randomized Phase 3 EMN02/HO95 Study
Authors: Cavo Michele , Gay Francesca , Beksac Meral , Dimopoulos Meletios A , Pantani Lucia , Petrucci Maria Teresa , Dozza Luca , Van Der Holt Bronno , Zweegman Sonja , Zamagni Elena , Palumbo Giuseppe A. , Patriarca Francesca , Galli Monica , Maisnar Vladimir , Hansson Markus , Belotti Angelo , Pour Ludek , Ypma Paula F , Grasso Mariella , Croockewit Sandra , Offidani Massimo , Zambello Renato , Liberati Anna Marina , Andersen Niels Frost , Broyl Annemiek , Troia Rossella , Musto Pellegrino , Ludwig Heinz , Morelli Anna Maria , Hajek Roman , Driessen Christoph , Waage Anders , Gimsing Peter , Mellqvist Ulf-Henrik , Zander Thilo , Boccadoro Mario , Sonneveld Pieter 
Published: November 2020

Introduction: The multicentre, randomized, open-label, phase 3 EMN02/HO95 study for patients with newly diagnosed multiple myeloma (NDMM) included two randomization stages (1:1) to (R1) intensification therapy with either upfront ASCT or bortezomib-melphalan-prednisone (VMP), and thereafter to (R2) consolidation therapy or no consolidation, followed by lenalidomide maintenance in both arms. Results of the final analysis from R1 (M. Cavo et al. Lancet Haematol. 2020, 7, e456-68) showed that at a median follow-up of 60.5 months progression-free survival (PFS), the primary study endpoint, was significantly improved with ASCT compared with VMP (median, 57 versus 42 months; HR 0.73, 95% CI 0.62-0.85, adjusted p=0.0001). However, no difference between these groups was found in terms of overall survival (OS), a secondary endpoint (HR 0·90, 0·71-1·13, adjusted p=0·35).
Methods: We performed an updated analysis of the study with longer-term follow-up. Efficacy endpoints included OS, PFS on next-line therapy (PFS2), and time to next treatment (TTnT). Analyses were restricted to patients randomized to either ASCT (n=702) or VMP (n=495). Clinical outcomes of patients randomized to upfront ASCT or receiving ASCT at the time of progression after primary randomization to VMP (delayed ASCT) were also explored.
Results: At an extended median follow-up of 75 months (IQR 67-84), patients randomized to ASCT had a significantly longer OS than those randomized to VMP (Figure). Median OS was not reached in both arms, and the 75-month survival estimate was 69% (95% CI 65-73) in the ASCT group versus 63% (95% CI 59-68) in the VMP group (HR 0.81, 95% CI 0.66-0-98, adjusted p=0.034). Patients who benefited the most from randomization to ASCT were those with unfavourable prognostic characteristics at baseline, including ISS disease stage 2-3 (HR 0.78, 95% CI 0.61-0.99, p=0.047), R-ISS stage 2-3 (HR 0.79, 95% CI 0.62-0.99, p=0.042), and the presence of at least one of the following cytogenetic abnormalities on FISH analysis: t(4;14) and/or t(14;16) in ≥10% CD138-positive plasma cells, and/or del(17p) in ≥20% enriched plasma cells. Overall, the 75-month OS estimate for patients with a high-risk cytogenetic profile was 54% with ASCT versus 39% with VMP (HR 0.61, 95% CI 0.42-0.89, p=0.010). The magnitude of OS benefit with ASCT, as measured by the HR value, was the highest for patients with del(17p) positivity (HR 0.49, 95% CI 0.28-0.86, p=0.013). PFS2 from R1 was significantly longer for patients in the ASCT arm than for those in the VMP arm. The 75-month PFS2 estimate was 57% in the ASCT group and it was 49% in the VMP group (HR 0.76, 95% CI 0.64-0.90, adjusted p=0.002) (Figure). Patients randomized to ASCT had a significantly longer TTnT in comparison with those who were randomly assigned to VMP. Median TTnT values for these groups were 66 versus 47 months, respectively (HR 0.71, 95% CI 0.60-0.82, adjusted p &lt;0.001) (Figure). Demographic and clinical characteristics at baseline of patients in the delayed ASCT group were comparable with those of patients who were randomized to upfront ASCT. PFS2 and TTnT in the upfront ASCT group were significantly longer than in the delayed ASCT group. Median PFS2 values were 85 versus 51 months, respectively (HR 0.52, 95% CI 0.40-0.66, p &lt;0.001). Median TTnT values were 59 versus 29 months, respectively (HR 0.32, 95% CI 0.26-0.40, adjusted p &lt;0.001). At the time that this analysis was performed, the rate of events of death was 30% in the upfront ASCT group versus 46% in the delayed ASCT group. In both the ASCT and VMP arms of the study, lenalidomide maintenance at the dose of 10 mg orally on day 1-21 of 28-day cycles was planned until progressive disease or undue toxicity. The median duration of lenalidomide treatment was 34 (IQR 13-63) months; 28% of patients were still on treatment at 60 months after start of lenalidomide and 31% discontinued due to treatment-related adverse events (27%) or second primary malignancies (4%). At a median follow-up of 70 (IQR 60-77) months from start of maintenance therapy, median PFS with lenalidomide was 56 months in the ASCT arm and 42 months in the VMP arm (HR 0.77, 95% CI 0.65-0.91, adjusted p=0.002). OS curves started to diverge at 5 years, and the 70-month estimate was 74% in the ASCT arm versus 69% in the VMP arm, suggesting that longer-term follow-up analysis is required.
Conclusions: Upfront ASCT significantly prolonged OS, PFS2 and TTnT in comparison with VMP in NDMM patients.
Figure

Disclosures
Cavo: Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: 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, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Petrucci:GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zamagni:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Maisnar:Janssen, Takeda, Amgen, BMS/Celgene, The Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Belotti:Celgene: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Offidani:Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Liberati:Verastem: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Research Funding; Morphosys: Research Funding; Novartis: Research Funding; GSK: Research Funding; Incyte: Honoraria; Oncopeptides: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; Onconova: Research Funding; Pfizer: Research Funding; Karyopharm: Research Funding. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Musto:Amgen: Honoraria; Celgene: Honoraria. Ludwig:Seattle Genetics: Other: Advisory Boards; Takeda: Research Funding; Sanofi: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Celgene: Speakers Bureau. Hajek:Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Mellqvist:Janssen. Celgene, Amgen: Honoraria. Boccadoro:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Mundipharma: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Skyline Dx: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.