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Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies

Michele Cavo, Hartmut Goldschmidt, Laura Rosinol, Lucia Pantani, Sonja Zweegman, Hans Jürgen Salwender, Juan Jose Lahuerta, Henk M. Lokhorst, Maria Teresa Petrucci, Igor Blau, Albert Oriol, Nicoletta Testoni, Katja Weisel, Rafael Rios, Francesca Patriarca, Jesús Blanchard, Luca Dozza, Maria-Victoria Mateos, Monica Galli, Jesus F San-Miguel, Mario Boccadoro, Joan Blade and Pieter Sonneveld

Abstract

Introduction: Conflicting results from two recently reported randomized studies comparing double vs single autotransplantation (ASCT) for newly diagnosed multiple myeloma (MM) patients (pts) [(Cavo M et al, Blood 2017;130(1); Stadtmauer EA et al, Blood 2016;128(22)] are likely to reflect differences in the design of the trials. To address this controversial issue, we performed a long-term follow-up analysis of pt-level data from three phase 3 trials of bortezomib-thalidomide-dexamethasone (VTD) (Cavo M et al, Lancet 376; 2075-85, 2010; Rosinol L et al, Blood 120; 1589-96, 2012) or bortezomib-doxorubicin-dexamethasone (PAD) (Sonneveld P et al, J Clin Oncol 30; 2946-55, 2012) as induction therapy before ASCT, followed by post-ASCT bortezomib-based consolidation and/or maintenance treatment. According to study design, patients were assigned to receive either a single or double ASCT (ASCT-1 or ASCT-2), thus allowing a comparison between these treatments.

Methods: The intent-to-treat population included 909 pts who were randomized to either VTD or PAD arms of the studies and for whom ASCT-1 (n=501) or ASCT-2 (n=408) were planned at study entry. Median age was 58 yrs in both groups; the rate of ISS stage III was 20% and 17%, respectively, while 18% and 23% of pts in ASCT-1 and ASCT-2 groups were positive for t(4;14) and/or del(17p) (cut-off levels ≥10% and ≥20%, respectively) by FISH analysis.

Results: With a median follow up of 117 mos (IQR 91-126), assignment to ASCT-2 resulted in superior PFS (median: 47 vs 38 mos; HR 0.76, 95%CI=0.65-0.89, p=0.0008) and OS (estimated 10-yr probability: 58% vs 47%; HR 0.69, CI 0.56-0.84, p=0.0002) in comparison with ASCT-1 (Figure 1). PFS benefit with ASCT-2 was retained across prespecified subgroups, including pts with both standard-risk (median: 53 vs 43 mos; HR 0.74, CI 0.61-0.91, p=0.005) and high-risk cytogenetics (cyto) (median: 36 vs 20 mos; HR 0.67, CI 0.46-0.97, p=0.032). The 10-yr OS rates were 72% with ASCT-2 vs 60% with ASCT-1 (HR 0.68, CI 0.52-0.88, p=0.004) for pts with standard-risk and 51% vs 34% (HR 0.54, CI 0.36-0.83, p=0.004) for those with high-risk cyto. In a multivariate Cox regression analysis, independent predictors for prolonged PFS included ASCT-2 (HR 0.81, CI 0.66-0.99, p=0.048), platelet (PLT) count >150.000/mmc (HR 0.74, CI 0.54-0.99, p=0.049), ISS stage I+II (HR 0.62, CI 0.48-0.80, p<0.001), absence of t(4;14) and/or del(17p) (HR 0.57, CI 0.45-0.73, p<0.001), and complete response (CR) recorded at any time throughout treatment (best CR) (HR 0.53, CI 0.43-0.64, p<0.001). These variables were also significantly related to longer OS (ASCT-2: HR 0.75, CI 0.57-0.98, p=0.036; PLTs: HR 0.55, CI 0.38-0.78, p=0.001; ISS stage: HR 0.66, CI 0.48-0.91, p=0.010; cyto: HR 0.55, CI 0.41-0.73, p<0.001; best CR: HR 0.55, CI 0.43-0.72, p<0.001).

HR estimates of the leading, not including therapy, predictors of outcomes (ISS stage II+III, high-risk cyto and failure to achieve best CR) were used to build a score index that stratified patients into 3 subgroups at low-risk (20%, none of the 3 adverse variables), intermediate-risk (42%, 1 adverse variable) and high-risk (38%, 2 or 3 adverse variables). Median PFS for these subgroups was 87, 53 and 27 mos (p<0.001), while the corresponding 10-yr OS rates were 78%, 53% and 32% (p<0.001) (Figure 2). There was a trend to improved PFS, but not OS, with ASCT-2 vs ASCT-1 in the low-risk subgroup (53% vs 28% at 10 yrs; HR 0.66, CI 0.66-0.41, p=0.093). Conversely, in the high-risk subgroup assignment to ASCT-2 significantly prolonged both PFS (median: 32 vs 20 mos, HR 0.71, CI 0.54-0.93, p=0.012) and OS (43% vs 20% at 10 yrs; HR 0.58, CI 0.42-0.80; p=0.001) in comparison with ASCT-1. Notably, the greatest benefit from ASCT-2 was observed in the ultra high-risk subset of pts with 3 adverse variables who enjoyed a two-fold increased PFS (median: 35 vs 14 mos; HR 0.45, CI 0.21-0.79; p=0.008) and 56% reduction in the risk of death (26% vs 6% estimated 10-yr OS probability; HR 0.44, CI 0.21-0.90; p=0.025) compared with ASCT-1.

Conclusions: Results of this pooled analysis of phase 3 studies incorporating bortezomib-based triplets into ASCT confirmed the superiority of ASCT-2 over ASCT-1 in terms of extended PFS and OS. The subgroup of pts at high-risk mostly benefited from ASCT-2, in particular those who had advanced ISS stage, adverse cyto and failed to achieve CR.

Disclosures Cavo: GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, 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; Adaptive Biotechnologies: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Goldschmidt: Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Chugai: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Zweegman: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Salwender: Novartis: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Janssen: Honoraria, Other: travel support, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding. Lahuerta: 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; 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. Petrucci: Bristol-Myers Squibb: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board. Oriol: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weisel: Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rios: Amgen, Celgene, Janssen, and Takeda: Consultancy. Patriarca: Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; MSD Italy: Other: Advisory Role. Mateos: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Galli: Sigma-Tau: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria. San-Miguel: Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria; BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Blade: Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Sonneveld: Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

  • * Asterisk with author names denotes non-ASH members.