Double Vs Single Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma: Long-Term Follow-up (10-Years) Analysis of Randomized Phase 3 Studies
Author:
Cavo Michele1, Goldschmidt Hartmut2, Rosinol Laura3, Pantani Lucia4, Zweegman Sonja5, Salwender Hans Jürgen6, Lahuerta Juan Jose7, Lokhorst Henk M.8, Petrucci Maria Teresa9, Blau Igor10, Oriol Albert11, Testoni Nicoletta4, Weisel Katja12, Rios Rafael13, Patriarca Francesca14, Blanchard Jesús15, Dozza Luca4, Mateos Maria-Victoria16, Galli Monica17, San-Miguel Jesus F18, Boccadoro Mario19, Blade Joan20, Sonneveld Pieter21
Affiliation:
1. Seràgnoli Institute of Hematology and Medical Oncology, Bologna University School of Medicine, Bologna, Italy 2. Heidelberg University, Heidelberg, Germany 3. Hematopoietic Stem Cell Transplantation Unit, Hematology Department, Institute of Hematology and Oncology, IDIBAPS, Josep Carreras Research Institute, Hospital Clinic i Provincial, Barcelona, Spain 4. Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy 5. Department of Hematology, Cancer Cancer Amsterdam, Amsterdam University Medical Center, Amsterdam, Netherlands 6. Department of Hematology and Oncology, Asklepios Hospital Hamburg Altona, Hamburg, Germany 7. Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain 8. Department of Hematology, VU University Medical Center, Amsterdam, Netherlands 9. Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy 10. Department of Hematology, Oncology and Tumorimmunology, Charite University Berlin, Berlin, Germany 11. Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain 12. Universitatsklinikum Tubingen, Tübingen, Germany 13. Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain 14. Hematology and Bone Marrow Transplant Unit, University of Udine, Italy, Udine, Italy 15. Hospital Universitario Ramón y Cajal, Madrid, Spain 16. Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), Salamanca, Spain 17. Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy 18. Centro Investigación Medica Aplicada (CIMA), Clinica Universidad de Navarra, Pamplona, Spain 19. Department of Molecular Biotechnologies and Health Sciences, Hematology Division, University of Torino, Torino, Italy 20. Hematology Department, IDIBAPS, Hospital Clínica de Barcelona- Servicio de Onco-Hematología, Barcelona, Spain 21. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
Abstract
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.
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
Cited by
39 articles.
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