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Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study

Philippe Moreau 1, 2, 3 Michel Attal 4 Cyrille Hulin 5 Bertrand Arnulf 6 Karim Belhadj 7 Lotfi Benboubker 8 Marie C. Bene 9 Annemiek Broijl Helene Caillon 9 Denis Caillot 10 Jill Corre 4 Michel Delforge 11 Thomas Dejoie 12 Chantal Doyen Thierry Facon 13 Cecile Sonntag Jean Fontan 14 Laurent Garderet 15 Kon-Siong Jie Lionel Karlin 16 Frederique Kuhnowski 17 Jerome Lambert 18 Xavier Leleu 19 Pascal Lenain 20 Margaret Macro 21 Claire Mathiot 22 Frederique Orsini-Piocelle 23 Aurore Perrot 24 Anne-Marie Stoppa 25 Niels W. C. J. Donk Soraya Wuilleme 26 Sonja Zweegman 27 Brigitte Kolb 28 Cyrille Touzeau 29, 2, 3 Murielle Roussel 4 Mourad Tiab 30 Jean-Pierre Marolleau 31 Nathalie Meuleman 32 Marie-Christiane Vekemans Matthijs Westerman Saskia K. Klein Mark-David Levin Jean Paul Fermand 33 Martine Escoffre-Barbe 34 Jean-Richard Eveillard 35 Reda Garidi 36 Tahamtan Ahmadi Sen Zhuang Christopher Chiu Lixia Pei Carla Boer Elena Smith William Deraedt Tobias Kampfenkel Jordan Schecter Jessica Vermeulen Herve Avet-Loiseau 37 Pieter Sonneveld 38
1 CRCINA-ÉQUIPE 11 - Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
29 CRCINA-ÉQUIPE 10 - Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
Abstract : Background Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. Methods In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. Findings Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1.60, 95% CI 1.21-2.12, p=0.0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10(-5) sensitivity threshold, assessed by multiparametric flow cytometry; both p<0.0001). Median progression-free survival from first randomisation was not reached in either group (hazard ratio 0.47, 95% CI 0 . 33-0.67, p<0.0001). 46 deaths on study were observed (14 vs 32, 0.43, 95% CI 0.23-0.80). The most common grade 3 or 4 adverse events were neutropenia (28% vs 15%), lymphopenia (17% vs 10%), and stomatitis (13% vs 16%). Interpretation D-VTd before and after autologous stem-cell transplantation improved depth of response and progression-free survival with acceptable safety. CASSIOPEIA is the first study showing the clinical benefit of daratumumab plus standard of care in transplant-eligible patients with newly diagnosed multiple myeloma. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
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Soumis le : jeudi 10 mars 2022 - 17:28:36
Dernière modification le : mercredi 27 avril 2022 - 04:04:43

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Philippe Moreau, Michel Attal, Cyrille Hulin, Bertrand Arnulf, Karim Belhadj, et al.. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. LANCET, 2019, 394 (10192), pp.29-38. ⟨10.1016/S0140-6736(19)31240-1⟩. ⟨hal-03605015⟩

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