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. van De 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 De 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
2 Département d'Hématologie Clinique [CHU Nantes]
3 SIRIC-ILIAD - Site de Recherche Intégrée sur le Cancer - Imaging and Longitudinal Investigations to Ameliorate Decision-making
4 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
5 Hôpital Haut-Lévêque [CHU Bordeaux]
6 Service d'hématologie biologique
7 IMRB - Institut Mondor de Recherche Biomédicale
8 Service d'hématologie [Tours]
9 CHU Nantes - Centre Hospitalier Universitaire de Nantes
10 Service d'Hématologie Clinique (CHU de Dijon)
11 Universitaire Ziekenhuizen Leuven
12 Laboratoire de Biochimie [Nantes]
13 CIC CHU ( Lille)/inserm
14 Hôpital JeanMinjoz
15 CHU Saint-Antoine [AP-HP]
16 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
17 Service d'Hématologie [Institut Curie]
18 Service de biostatistiques et information médicale [Saint-Louis]
19 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
20 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
21 Hôpital Universitaire de Caen
22 IFM - Intergroupe francophone du myélome
23 Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois]
24 Service d'Hématologie [CHRU Nancy]
25 Service d’Hématologie [Institut Paoli Calmettes, Marseille]
26 Département d'hématologie et de biologie [CHU Nantes]
27 Amsterdam UMC - Amsterdam University Medical Center
28 Service d'Hématologie
29 CRCINA-ÉQUIPE 10 - Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma
30 Service de Médecine Onco-hématologie [La Roche sur Yon]
31 Service clinique des Maladies du Sang
32 Institut Jules Bordet [Bruxelles]
33 Service d'hématologie adulte [Hôpital de Saint Louis]
34 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
35 CHU-Brest-Hemato - CHRU Brest - Service d'Hématologie
36 Hôpital Saint-Quentin
37 CRCT - Centre de Recherches en Cancérologie de Toulouse
38 Erasmus MC - Erasmus University Medical Center [Rotterdam]

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.

Domaines: Sciences du Vivant [q-bio]

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. The Lancet, 2019, 394 (10192), pp.29-38. ⟨10.1016/S0140-6736(19)31240-1⟩. ⟨hal-03605015⟩