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. Issue 10192 (6th July 2019)

• Record Type: Journal Article
• Authors: Moreau, Philippe; Attal, Michel; Hulin, Cyrille; Arnulf, Bertrand; Belhadj, Karim; Benboubker, Lotfi; Béné, Marie C; Broijl, Annemiek; Caillon, Hélène; Caillot, Denis; Corre, Jill; Delforge, Michel; Dejoie, Thomas; Doyen, Chantal; Facon, Thierry; Sonntag, Cécile; Fontan, Jean; Garderet, Laurent; Jie, Kon-Siong; Karlin, Lionel; Kuhnowski, Frédérique; Lambert, Jérôme; Leleu, Xavier; Lenain, Pascal; Macro, Margaret; Mathiot, Claire; Orsini-Piocelle, Frédérique; Perrot, Aurore; Stoppa, Anne-Marie; van de Donk, Niels WCJ; Wuilleme, Soraya; Zweegman, Sonja; Kolb, Brigitte; Touzeau, Cyrille; Roussel, Murielle; Tiab, Mourad; Marolleau, Jean-Pierre; Meuleman, Nathalie; Vekemans, Marie-Christiane; Westerman, Matthijs; Klein, Saskia K; Levin, Mark-David; Fermand, Jean Paul; Escoffre-Barbe, Martine; Eveillard, Jean-Richard; Garidi, Reda; Ahmadi, Tahamtan; Zhuang, Sen; Chiu, Christopher; Pei, Lixia; de Boer, Carla; Smith, Elena; Deraedt, William; Kampfenkel, Tobias; Schecter, Jordan; Vermeulen, Jessica; Avet-Loiseau, Hervé; Sonneveld, Pieter;
• Is Part Of: Lancet. Volume 394:Issue 10192(2019)
• Page Start: 29
• Page End: 38
• Publication Date: 2019-07-06
• Subjects: Medicine -- Periodicals; Medicine -- Periodicals; Medicine; Medicine; Electronic journals; Periodicals; 610.5
• DOI: 10.1016/S0140-6736(19)31240-1
• Languages: English
• ISSNs: 0140-6736

Abstract

Summary: 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 withClinicalTrials.gov, numberNCT02541383 . 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. Funding: The Intergroupe Francophone du Myélome and Dutch-Belgian Cooperative Trial Group for Hematology Oncology.