Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial - Université de Picardie Jules Verne Accéder directement au contenu
Article Dans Une Revue Lancet Oncology Année : 2024

Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial

Philippe Moreau
  • Fonction : Auteur
Cyrille Hulin
  • Fonction : Auteur
Cécile Sonntag
  • Fonction : Auteur
Kon-Siong Jie
  • Fonction : Auteur
Xavier Leleu
  • Fonction : Auteur
Margaret Macro
  • Fonction : Auteur
Frédérique Orsini-Piocelle
  • Fonction : Auteur
Murielle Roussel
  • Fonction : Auteur
Jean Marc Schiano de Colella
  • Fonction : Auteur
Niels Wcj van de Donk
  • Fonction : Auteur
Soraya Wuillème
  • Fonction : Auteur
Annemiek Broijl
  • Fonction : Auteur
Cyrille Touzeau
  • Fonction : Auteur
Mourad Tiab
  • Fonction : Auteur
Nathalie Meuleman
  • Fonction : Auteur
Marie-Christiane Vekemans
  • Fonction : Auteur
Matthijs Westerman
  • Fonction : Auteur
Saskia Klein
  • Fonction : Auteur
Mark-David Levin
  • Fonction : Auteur
Fritz Offner
  • Fonction : Auteur
Martine Escoffre-Barbe
  • Fonction : Auteur
Jean-Richard Eveillard
  • Fonction : Auteur
Réda Garidi
  • Fonction : Auteur
Winnie Hua
  • Fonction : Auteur
Jianping Wang
  • Fonction : Auteur
Alba Tuozzo
  • Fonction : Auteur
Carla de Boer
  • Fonction : Auteur
Melissa Rowe
  • Fonction : Auteur
Veronique Vanquickelberghe
  • Fonction : Auteur
Robin Carson
  • Fonction : Auteur
Jessica Vermeulen
  • Fonction : Auteur
Jill Corre
  • Fonction : Auteur
Pieter Sonneveld
  • Fonction : Auteur

Résumé

Background CASSIOPEIA part 1 demonstrated superior depth of response and prolonged progression-free survival with daratumumab in combination with bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone as an induction and consolidation regimen in transplant-eligible patients newly diagnosed with myeloma. In CASSIOPEIA part 2, daratumumab maintenance significantly improved progression-free survival and increased minimal residual disease (MRD)-negativity rates versus observation. Here, we report long-term study outcomes of CASSIOPEIA. Methods CASSIOPEIA was a two-part, open-label, phase 3 trial of patients done at 111 European academic and community-based centres. Eligible patients were aged 18–65 years with transplant-eligible newly diagnosed myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. In part 1, patients were randomly assigned (1:1) to pre-transplant induction and post-transplant consolidation with D-VTd or VTd. Patients who completed consolidation and had a partial response or better were re-randomised (1:1) to intravenous daratumumab maintenance (16 mg/kg every 8 weeks) or observation for 2 years or less. An interactive web-based system was used for both randomisations, and randomisation was balanced using permuted blocks of four. Stratification factors for the first randomisation (induction and consolidation phase) were site affiliation, International Staging System disease stage, and cytogenetic risk status. Stratification factors for the second randomisation (maintenance phase) were induction treatment and depth of response in the induction and consolidation phase. The primary endpoint for the induction and consolidation phase was the proportion of patients who achieved a stringent complete response after consolidation; results for this endpoint remain unchanged from those reported previously. The primary endpoint for the maintenance phase was progression-free survival from second randomisation. Efficacy evaluations in the induction and consolidation phase were done on the intention-to-treat population, which included all patients who underwent first randomisation, and efficacy analyses in the maintenance phase were done in the maintenance-specific intention-to-treat population, which included all patients who were randomly assigned at the second randomisation. This analysis represents the final data cutoff at the end of the study. The trial is registered with ClinicalTrials.gov , NCT02541383 . Findings Between Sept 22, 2015 and Aug 1, 2017, 1085 patients were randomly assigned to D-VTd (n=543) or VTd (n=542); between May 30, 2016 and June 18, 2018, 886 were re-randomised to daratumumab maintenance (n=442) or observation (n=444). At the clinical cutoff date, Sept 1, 2023, median follow-up was 80·1 months (IQR 75·7–85·6) from first randomisation and 70·6 months (66·4–76·1) from second randomisation. Progression-free survival from second randomisation was significantly longer in the daratumumab maintenance group than the observation-alone group (median not reached [95% CI 79·9–not estimable (NE)] vs 45·8 months [41·8–49·6]; HR 0·49 [95% CI 0·40–0·59]; p<0·0001); benefit was observed with D-VTd with daratumumab maintenance versus D-VTd with observation (median not reached [74·6–NE] vs 72·1 months [52·8–NE]; 0·76 [0·58–1·00]; p=0·048) and VTd with daratumumab maintenance versus VTd with observation (median not reached [66·9–NE] vs 32·7 months [27·2–38·7]; 0·34 [0·26–0·44]; p<0·0001). Interpretation The long-term follow-up results of CASSIOPEIA show that including daratumumab in both the induction and consolidation phase and the maintenance phase led to superior progression-free survival outcomes. Our results confirm D-VTd induction and consolidation as a standard of care, and support the option of subsequent daratumumab monotherapy maintenance, for transplant-eligible patients with newly diagnosed multiple myeloma.

Domaines

Hématologie Cancer
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Dates et versions

hal-04618329 , version 1 (20-06-2024)

Identifiants

Citer

Philippe Moreau, Cyrille Hulin, Aurore Perrot, Bertrand Arnulf, Karim Belhadj, et al.. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncology, 2024, ⟨10.1016/S1470-2045(24)00282-1⟩. ⟨hal-04618329⟩
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