Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial

• Published in: The lancet oncology 2021-10, Vol.22 (10), p.1378-1390
• Main Authors: Moreau, Philippe, Hulin, Cyrille, Perrot, Aurore, Arnulf, Bertrand, Belhadj, Karim, Benboubker, Lotfi, Béné, Marie C, Zweegman, Sonja, Caillon, Hélène, Caillot, Denis, Corre, Jill, Delforge, Michel, Dejoie, Thomas, Doyen, Chantal, Facon, Thierry, Sonntag, Cécile, Fontan, Jean, Mohty, Mohamad, Jie, Kon-Siong, Karlin, Lionel, Kuhnowski, Frédérique, Lambert, Jérôme, Leleu, Xavier, Macro, Margaret, Orsini-Piocelle, Frédérique, Roussel, Murielle, Stoppa, Anne-Marie, van de Donk, Niels W C J, Wuillème, Soraya, Broijl, Annemiek, Touzeau, Cyrille, Tiab, Mourad, Marolleau, Jean-Pierre, Meuleman, Nathalie, Vekemans, Marie-Christiane, Westerman, Matthijs, Klein, Saskia K, Levin, Mark-David, Offner, Fritz, Escoffre-Barbe, Martine, Eveillard, Jean-Richard, Garidi, Réda, Ahmadi, Tahamtan, Krevvata, Maria, Zhang, Ke, de Boer, Carla, Vara, Sanjay, Kampfenkel, Tobias, Vanquickelberghe, Veronique, Vermeulen, Jessica, Avet-Loiseau, Hervé, Sonneveld, Pieter
• Format: Article
• Language: English
• Subjects: Adverse events; Autografts; Bone marrow; Bortezomib; Clinical medicine; Dexamethasone; Dosage; FDA approval; Hematology; Immunotherapy; Inhibitor drugs; Laboratories; Life Sciences; Lymphoma; Lymphopenia; Monoclonal antibodies; Multiple myeloma; Natural killer cells; Neutropenia; Oncology; Patients; Risk assessment; Septic shock; Stem cell transplantation; Steroids; Targeted cancer therapy; Thalidomide
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(21)00428-9

CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18–65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0–2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543