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Clinical Trial
. 2024 Aug;25(8):1003-1014.
doi: 10.1016/S1470-2045(24)00282-1. Epub 2024 Jun 15.

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  1 , Cyrille Hulin  2 , Aurore Perrot  3 , Bertrand Arnulf  4 , Karim Belhadj  5 , Lotfi Benboubker  6 , Sonja Zweegman  7 , Hélène Caillon  8 , Denis Caillot  9 , Hervé Avet-Loiseau  10 , Michel Delforge  11 , Thomas Dejoie  8 , Thierry Facon  12 , Cécile Sonntag  13 , Jean Fontan  14 , Mohamad Mohty  15 , Kon-Siong Jie  16 , Lionel Karlin  17 , Frédérique Kuhnowski  18 , Jérôme Lambert  19 , Xavier Leleu  20 , Margaret Macro  21 , Frédérique Orsini-Piocelle  22 , Murielle Roussel  23 , Jean Marc Schiano de Colella  24 , Niels Wcj van de Donk  7 , Soraya Wuillème  25 , Annemiek Broijl  26 , Cyrille Touzeau  27 , Mourad Tiab  28 , Jean-Pierre Marolleau  29 , Nathalie Meuleman  30 , Marie-Christiane Vekemans  31 , Matthijs Westerman  32 , Saskia K Klein  33 , Mark-David Levin  34 , Fritz Offner  35 , Martine Escoffre-Barbe  36 , Jean-Richard Eveillard  37 , Réda Garidi  38 , Winnie Hua  39 , Jianping Wang  40 , Alba Tuozzo  40 , Carla de Boer  41 , Melissa Rowe  42 , Veronique Vanquickelberghe  43 , Robin Carson  40 , Jessica Vermeulen  41 , Jill Corre  10 , Pieter Sonneveld  26 ; Intergroupe Francophone du Myélome, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the CASSIOPEIA Investigators
Affiliations
Clinical Trial

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 et al. Lancet Oncol. 2024 Aug.

Abstract

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.

Funding: Intergroupe Francophone du Myélome, Dutch-Belgian Cooperative Trial Group for Hematology Oncology, and Janssen Research & Development.

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Conflict of interest statement

Declaration of interests PM served on advisory boards for and received honoraria from Janssen, Bristol Myers Squibb, Amgen, Takeda, AbbVie, Sanofi, and Pfizer. CH received honoraria from Janssen, Bristol Myers Squibb, Amgen, AbbVie, and Pfizer. AP served in a consulting or advisory role for Bristol Myers Squibb, Janssen, and Pfizer; and received research funding from Bristol Myers Squibb, Sanofi, and Takeda. BA received research funding (paid to institution) from Bristol Myers Squibb; received honoraria from Janssen, Bristol Myers Squibb, Sanofi, and GSK; received travel funding from Janssen, Bristol Myers Squibb, and Sanofi; and served on an advisory board for Janssen, Bristol Myers Squibb, and Takeda. KB has a direct financial relationship with Janssen, Bristol Myers Squibb, Amgen, Sanofi, and Pfizer. SZ received research support from Janssen and Takeda; and served on advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen, and Takeda. MD received honoraria from and served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Janssen, Sanofi, and Stemline; and received research funding from Janssen. CS received consulting fees or honoraria from Takeda, Bristol Myers Squibb, Janssen, Amgen, Sanofi, and Pfizer. MMo received honoraria from Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, Janssen, Takeda, Novartis, and Sanofi; and received research funding from Celgene, Janssen, and Sanofi. LK received honoraria from, served on advisory boards for, or received travel funding from AbbVie, Amgen, Janssen, Celgene/Bristol Myers Squibb, Pfizer, Sanofi, and Takeda. MMa received honoraria from and served in a consulting or advisory role for Janssen, Bristol Myers Squibb/Celgene, Sanofi, and Takeda; received research funding from Janssen and Takeda; and received travel, accommodations, or expenses from Janssen and Sanofi. FO-P served on boards for Janssen, Sanofi, and Pfizer. MR served on an advisory board for Janssen and Pfizer; received research funding from Bristol Myers Squibb, Janssen, and Sanofi; gave lectures for Amgen, Bristol Myers Squibb, Janssen, and Takeda; and had travel, accommodations, or other expenses paid or reimbursed by Amgen, Bristol Myers Squibb, GSK, Janssen, Pfizer, Sanofi, and Takeda. JMSdC served on an advisory board and received honoraria from Janssen, Sanofi, GSK, and AbbVie; and received accommodations from Pfizer and Amgen. NWCJvdD received research support from Janssen, Amgen, Celgene, Novartis, Cellectis, and Bristol Myers Squibb; and serves on advisory boards for Janssen, Amgen, Celgene, Bristol Myers Squibb, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Merck, Pfizer, AbbVie, and Servier (all paid to institution). AB served on advisory boards for Janssen, Sanofi, Amgen, and Bristol Myers Squibb. CT served on an advisory board for and received honoraria from Janssen. NM served on an advisory board for Janssen. M-CV received travel support from Janssen and Sanofi. M-DL received travel expenses from Janssen. WH is an employee of Cytel and is a contractor for Johnson & Johnson. JW, CdB, MR, VV, RC, and JV are employees of Janssen and hold stock in Johnson & Johnson. AT is an employee of Janssen. JC served on advisory boards for Sanofi and Bristol Myers Squibb; served as a consultant for Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; received research support from Sanofi and Bristol Myers Squibb; and received travel support from Janssen, Sanofi, Bristol Myers Squibb, and Pfizer. PS served on an advisory board for Amgen, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, and Pfizer; and received research funding from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Karyopharm. All other authors declare no competing interests.

Figures

Figure 1:
Figure 1:. Study profile
Note: “Pre–progressive disease follow-up” includes any patient who was in follow-up without progressive disease by computerised algorithm. “Post–progressive disease follow-up” includes patients who were in follow-up and had progressive disease by computerised algorithm. *Patients may have multiple reasons for treatment discontinuation due to multiple treatments taken within each induction arm. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. VTd=bortezomib, thalidomide, and dexamethasone.
Figure 2:
Figure 2:. Progression-free survival and overall survival from first randomisation regardless of second randomisation
(A) The results of the Kaplan–Meier estimates of progression-free survival among patients in the intention-to-treat population. (B) The results of the Kaplan–Meier estimates of overall survival among patients in the intention-to-treat population. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. HR=hazard ratio. VTd=bortezomib, thalidomide, and dexamethasone.
Figure 2:
Figure 2:. Progression-free survival and overall survival from first randomisation regardless of second randomisation
(A) The results of the Kaplan–Meier estimates of progression-free survival among patients in the intention-to-treat population. (B) The results of the Kaplan–Meier estimates of overall survival among patients in the intention-to-treat population. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. HR=hazard ratio. VTd=bortezomib, thalidomide, and dexamethasone.
Figure 3:
Figure 3:. Progression-free survival from second randomisation
(A) The results of the Kaplan–Meier estimates of progression-free survival from second randomisation among patients in the maintenance-specific intention-to-treat population. (B) The results of the Kaplan–Meier estimates of progression-free survival from second randomisation by induction/consolidation and maintenance therapies in the maintenance-specific intention-to-treat population. Daratumumab and observation were the two randomly assigned (1:1) treatments at second randomisation; therefore, these are the comparisons with HRs, 95% CIs, and p values provided in the further breakdown of the data by induction/consolidation treatment (D-VTd or VTd). DARA=daratumumab. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. HR=hazard ratio. OBS=observation. VTd=bortezomib, thalidomide, and dexamethasone.
Figure 3:
Figure 3:. Progression-free survival from second randomisation
(A) The results of the Kaplan–Meier estimates of progression-free survival from second randomisation among patients in the maintenance-specific intention-to-treat population. (B) The results of the Kaplan–Meier estimates of progression-free survival from second randomisation by induction/consolidation and maintenance therapies in the maintenance-specific intention-to-treat population. Daratumumab and observation were the two randomly assigned (1:1) treatments at second randomisation; therefore, these are the comparisons with HRs, 95% CIs, and p values provided in the further breakdown of the data by induction/consolidation treatment (D-VTd or VTd). DARA=daratumumab. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. HR=hazard ratio. OBS=observation. VTd=bortezomib, thalidomide, and dexamethasone.
Figure 4:
Figure 4:. MRD-negativity rates at any time during maintenance and follow-up*
The proportion of patients who achieved complete response or better and MRD negativity in the maintenance-specific intention-to-treat population. MRD was assessed using bone marrow aspirates via next generation sequencing. Daratumumab and observation were the two randomly assigned (1:1) treatments at second randomisation; therefore, these are the comparisons with p values provided in the breakdown of the data by induction/consolidation treatment (D-VTd or VTd). DARA=daratumumab. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. MRD=minimal residual disease. OBS=observation. VTd=bortezomib, thalidomide, and dexamethasone. *Post-consolidation after the second randomisation.
Figure 5:
Figure 5:. Sustained MRD-negativity rates at any time during maintenance and follow-up*
Post hoc analysis of the proportion of patients who achieved complete response or better and sustained MRD negativity for ≥12 months and ≥24 months in the maintenance-specific intention-to-treat population. MRD was assessed using bone marrow aspirates via next generation sequencing. Daratumumab and observation were the two randomly assigned (1:1) treatments at second randomisation; therefore, these are the comparisons with p values provided in the breakdown of the data by induction/consolidation treatment (D-VTd or VTd). DARA=daratumumab. D-VTd=daratumumab, bortezomib, thalidomide, and dexamethasone. MRD=minimal residual disease. OBS=observation. VTd=bortezomib, thalidomide, and dexamethasone. *Post-induction after the second randomisation.
See this image and copyright information in PMC

References

    1. de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol 2011; 186(3): 1840–8. - PubMed
    1. Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood 2014; 124(21): 3474.
    1. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 2015; 7(2): 311–21. - PMC - PubMed
    1. Overdijk MB, Jansen JH, Nederend M, et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcgamma receptor-mediated cross-linking. J Immunol 2016; 197(3): 807–13. - PubMed
    1. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016; 128(3): 384–94. - PMC - PubMed

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