Autologous haematopoietic stem-cell transplantation versus bortezomib-melphalan-prednisone, with or without bortezomib-lenalidomide-dexamethasone consolidation therapy, and lenalidomide maintenance for newly diagnosed multiple myeloma (EMN02/HO95): a multicentre, randomised, open-label, phase 3 study

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  • Michele Cavo, Bologna Univ, University of Bologna, AOU Policlinico S. Orsola-Malpighi, S Orsola Malpighi Hosp, Seragnoli Inst Hematol, Dept Expt Diagnost & Specialty Med,Sch Med
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  • Francesca Gay, Univ Torino, A.O.U. Citta della Salute e della Scienza di Torino, University of Turin, Azienda Osped Univ Citta Salute & Sci Torino, Myeloma Unit, Div Hematol
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  • Meral Beksac, Ankara Univ, Ankara University, Sch Med, Dept Hematol
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  • Lucia Pantani, Bologna Univ, University of Bologna, AOU Policlinico S. Orsola-Malpighi, S Orsola Malpighi Hosp, Seragnoli Inst Hematol, Dept Expt Diagnost & Specialty Med,Sch Med
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  • Maria Teresa Petrucci, Sapienza Univ Rome, Sapienza University Rome, University Hospital Sapienza Rome, Azienda Osped Policlin Umberto 1, Dept Translat & Precis Med, Hematol
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  • Meletios A. Dimopoulos, Natl & Kapodistrian Univ Athens, Athens Medical School, National & Kapodistrian University of Athens, Dept Clin Therapeut, Sch Med
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  • Luca Dozza, Bologna Univ, University of Bologna, AOU Policlinico S. Orsola-Malpighi, S Orsola Malpighi Hosp, Seragnoli Inst Hematol, Dept Expt Diagnost & Specialty Med,Sch Med
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  • Bronno van der Holt, Erasmus MC, Erasmus University Rotterdam, Erasmus MC, Inst Canc, Dept Trials & Stat, HOVON Data Ctr
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  • Sonja Zweegman, Vrije Univ Amsterdam, University of Amsterdam, Vrije Universiteit Amsterdam, Med Ctr, Canc Ctr Amsterdam, Dept Hematol
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  • Stefania Oliva, Univ Torino, A.O.U. Citta della Salute e della Scienza di Torino, University of Turin, Azienda Osped Univ Citta Salute & Sci Torino, Myeloma Unit, Div Hematol
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  • Vincent H. J. van der Velden, Erasmus MC, Erasmus University Rotterdam, Erasmus University Medical Center, Univ Med Ctr Rotterdam, Dept Immunol
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  • Elena Zamagni, Bologna Univ, University of Bologna, AOU Policlinico S. Orsola-Malpighi, S Orsola Malpighi Hosp, Seragnoli Inst Hematol, Dept Expt Diagnost & Specialty Med,Sch Med
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  • Giuseppe A. Palumbo, Univ Catania, University of Catania, Dipartimento Sci Med Chirurg & Tecnol Avanzate GF
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  • Francesca Patriarca, Univ Udine, Hospital Santa Maria della Misericordia, University of Udine, S Maria Misericordia Univ Hosp, Clin Hematol & Bone Marrow Transplant Ctr, DAME
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  • Vittorio Montefusco, Ist Nazl Tumori, Fondazione IRCCS Istituto Nazionale Tumori Milan, Fdn IRCCS, Dept Hematol
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  • Monica Galli, ASST Papa Giovanni XXIII, ASST Papa Giovanni XXIII, Hematol & Bone Marrow Transplant Unit
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  • Vladimir Maisnar, Charles Univ Prague, Charles University Prague, Fac Med 1, Anat
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  • Barbara Gamberi, Azienda USL IRCCS Reggio Emilia
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  • Markus Hansson, Skane Univ Hosp, Lund University, Skane University Hospital, Dept Pediat
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  • Angelo Belotti, AO Spedali Civili, Hospital Spedali Civili Brescia, SC Ematol & Dipartimento Oncol Clin
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  • Ludek Pour, Univ Hosp Brno, University Hospital Brno
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  • Paula Ypma, Haga Hosp, Haga Hospital, Dept Hematol
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  • Mariella Grasso, Azienda Osped S Croce Carle Cuneo, SC Ematol
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  • Alexsandra Croockewit, Radboud Univ Nijmegen, Radboud University Nijmegen, Dept Hematol, Med Ctr
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  • Stelvio Ballanti, Osped Santa Maria Misericordia, Hospital Santa Maria della Misericordia, Reparto Ematol TMO
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  • Massimo Offidani, AOU Osped Riuniti Ancona, Clin Ematol
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  • Iolanda D. Vincelli, Grande Osped Metropolitano Bianchi Melacrino More, Div Haematol
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  • Renato Zambello, Azienda Osped Padova, University of Padua, Azienda Ospedaliera - Universita di Padova, Hematol
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  • Anna Marina Liberati, Univ Perugia, University of Perugia, Fac Med
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  • Niels Frost Andersen
  • Annemiek Broijl, Erasmus MC, Erasmus University Rotterdam, Erasmus MC, Inst Canc, Dept Hematol
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  • Rossella Troia, Univ Torino, A.O.U. Citta della Salute e della Scienza di Torino, University of Turin, Azienda Osped Univ Citta Salute & Sci Torino, Myeloma Unit, Div Hematol
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  • Anna Pascarella, Osped Angelo, ULSS 3 Serenissima, Ospedale dell'Angelo Mestre, Hematol Unit
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  • Giulia Benevolo, Univ Torino, A.O.U. Citta della Salute e della Scienza di Torino, University of Turin, Azienda Osped Univ Citta Salute & Sci Torino, Myeloma Unit, Div Hematol
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  • Mark-David Levin, Albert Schweitzer Hosp, Albert Schweitzer Ziekenhuis, Dept Internal Med
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  • Gerard Bos, Maastricht Univ, Maastricht University, Dept Haematol, Med Ctr
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  • Heinz Ludwig, Wilhelminenspital Stadt Wien, Wilhelminenspital, Wilhelminen Canc Res Inst
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  • Sara Aquino, Osped Policlin San Martino, IRCCS, Ematol & Ctr Trapianti
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  • Anna Maria Morelli, Spirito Santo Civ Hosp, Dept Hematol Transfus Med & Biotechnol, Clin Hematol
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  • Ka Lung Wu, ZNA Stuivenberg, ZNA Stuivenberg, Dept Hematol
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  • Rinske Boersma, Amphia Hosp Breda, Amphia Hospital, Dept Internal Med
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  • Roman Hajek, Univ Ostrava, University of Ostrava
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  • Marc Durian, Charles Univ Prague, Charles University Prague, Fac Med 1, Anat
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  • Peter A. von dem Borne, Leiden Univ, Leiden University, Dept Hematol, Med Ctr
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  • Tommaso Caravita di Toritto, UOSD Ematol ASL Roma 1
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  • Thilo Zander, Kantonsspital, Kantonsspital Aarau AG (KSA), Lucerne Cantonal Hospital, Dept Oncol Hematol
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  • Giorgina Specchia, Univ Aldo Moro, Universita degli Studi di Bari Aldo Moro, Hematol
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  • Anders Waage, Norwegian Univ Sci & Technol NTNU, Norwegian University of Science & Technology (NTNU), Dept Phys, Biophys & Med Technol
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  • Peter Gimsing
  • Ulf-Henrik Mellqvist, South Elvsborg Hosp, Sect Hematol & Coagulat, Dept Med
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  • Marinus van Marwijk Kooy, Isala Kliniek, Isala Clinics
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  • Monique Minnema, Univ Utrecht, Utrecht University, Utrecht University Medical Center, UMC Utrecht, Dept Hematol
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  • Caroline Mandigers, Canisius Wilhelmina Hosp, Canisius-Wilhelmina Hospital, Dept Hematol
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  • Anna Maria Cafro, ASST Grande Osped Metropolitano, Dept Hematol
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  • Angelo Palmas, Osped San Francesco, Haematol
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  • Susanna Carvalho, IPOLFG, Inst Portugues Oncol Lisboa Francisco Gentil
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  • Andrew Spencer, Monash Univ, Florey Institute of Neuroscience & Mental Health, Monash University, Alfred Hosp, Dept Haematol
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  • Mario Boccadoro, Univ Torino, A.O.U. Citta della Salute e della Scienza di Torino, University of Turin, Azienda Osped Univ Citta Salute & Sci Torino, Myeloma Unit, Div Hematol
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  • Pieter Sonneveld, Erasmus MC, Erasmus University Rotterdam, Erasmus MC, Inst Canc, Dept Hematol

Background The emergence of highly active novel agents has led some to question the role of autologous haematopoietic stem-cell transplantation (HSCT) and subsequent consolidation therapy in newly diagnosed multiple myeloma. We therefore compared autologous HSCT with bortezomib-melphalan-prednisone (VMP) as intensification therapy, and bortezomib-lenalidomide-dexamethasone (VRD) consolidation therapy with no consolidation.

Methods In this randomised, open-label, phase 3 study we recruited previously untreated patients with multiple myeloma at 172 academic and community practice centres of the European Myeloma Network. Eligible patients were aged 18-65 years, had symptomatic multiple myeloma stage 1-3 according to the International Staging System (I S S), measurable disease (serum M protein >10 g/L or urine M protein >200 mg in 24 h or abnormal free light chain [FLC] ratio with involved FLC >100 mg/L, or proven plasmacytoma by biopsy), and WHO performance status grade 0-2 (grade 3 was allowed if secondary to myeloma). Patients were first randomly assigned (1:1) to receive either four 42-day cycles of bortezomib (1.3 mg/m 2 administered intravenously or subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32) combined with melphalan (9 mg/m(2) administered orally on days 1-4) and prednisone (60 mg/m(2) administered orally on days 1-4) or autologous HSCT after high-dose melphalan (200 mg/m(2)), stratified by site and ISS disease stage. In centres with a double HS CT policy, the first randomisation (1:1:1) was to VMP or single or double HSCT. Afterwards, a second randomisation assigned patients to receive two 28-day cycles of consolidation therapy with bortezomib (1.3 mg/m(2)either intravenously or subcutaneously on days 1, 4, 8, and 11), lenalidomide (25 mg orally on days 1-21), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12) or no consolidation; both groups received lenalidomide maintenance therapy (10 mg orally on days 1-21 of a 28-day cycle). The primary outcomes were progression-free survival from the first and second randomisations, analysed in the intention-to-treat population, which included all patients who underwent each randomisation. All patients who received at least one dose of study drugs were included in the safety analyses. This study is registered with the EU Clinical Trials Register (EudraCT 2009-017903-28) and ClinicalTrials.gov (NCT01208766), and has completed recruitment.

Findings Between Feb 25, 2011, and April 3, 2014, 1503 patients were enrolled. 1197 patients were eligible for the first randomisation, of whom 702 were assigned to autologous HSCT and 495 to VMP; 877 patients who were eligible for the first randomisation underwent the second randomisation to VRD consolidation (n=449) or no consolidation (n=428). The data cutoff date for the current analysis was Nov 26, 2018. At a median follow-up of 60.3 months (IQR 52. 2-67. 6), median progression-free survival was significantly improved with autologous HSCT compared with VMP (56.7 months [95% CI 49.3-64.5] vs 41.9 months [37.5-46.9]; hazard ratio [HR] 0.73, 0.62-0.85; p=0.0001). For the second randomisation, the number of events of progression or death at data cutoff was lower than that preplanned for the final analysis; therefore, the results from the second protocol-specified interim analysis, when 66% of events were reached, are reported (data cutoff Jan 18, 2018). At a median follow-up of 42.1 months (IQR 32.3-49.2), consolidation therapy with VRD significantly improved median progression-free survival compared with no consolidation (58.9 months [54.0-not estimable] vs 45.5 months [39.5-58.4]; HR 0.77, 0.63-0.95; p=0.014). The most common grade >= 3 adverse events in the autologous HSCT group compared to the VMP group included neutropenia (513 [79%] of 652 patients vs 137 [29%] of 472 patients), thrombocytopenia (541 [83%] vs 74 [16%]), gastrointestinal disorders (80 [12%] vs 25 [5%]), and infections (192 [30%] vs 18 [4%]). 239 (34%) of 702 patients in the autologous HSCT group and 135 (27%) of 495 in the VMP group had at least one serious adverse event. Infection was the most common serious adverse event in each of the treatment groups (206 [56%] of 368 and 70 [37%] of 189). 38 (12%) of 311 deaths from first randomisation were likely to be treatment related: 26 (68%) in the autologous HSCT group and 12 (32%) in the VMP group, most frequently due to infections (eight [21%]), cardiac events (six [16%]), and second primary malignancies (20 [53%]).

Interpretation This study supports the use of autologous HSCT as intensification therapy and the use of consolidation therapy in patients with newly diagnosed multiple myeloma, even in the era of novel agents. The role of high-dose chemotherapy needs to be reassessed in future studies, in particular in patients with undetectable minimal residual disease after four-drug induction regimens including a monoclonal antiboby combined with an immunomodulatory agent and a proteasome inhibitor plus dexamethasone. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

OriginalsprogEngelsk
TidsskriftThe Lancet Haematology
Vol/bind7
Nummer6
Sider (fra-til)E456-E468
Antal sider13
ISSN2352-3026
DOI
StatusUdgivet - 2020

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