Maintenance with Daratumumab in Newly Diagnosed MM: CASSIOPEIA Trial

CASSIOPEIA part 1 showed that daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) were better than bortezomib, thalidomide, and dexamethasone (VTd) for induction and consolidation in patients with newly diagnosed multiple myeloma who were suitable for an autologous stem-cell transplant (ASCT). Part 2 examined the difference between keeping daratumumab and just watching it. CASSIOPEIA is a randomized, open-label, phase 3 trial with two parts. It is being done in 111 European academic and community practice centers with patients 18 to 65 years old who have just been diagnosed with multiple myeloma and have an Eastern Cooperative Oncology Group performance level of 0 to 2. In part 1, patients were given a 50/50 chance of getting D-VTd or VTd for induction and consolidation. Patients who were still in the study and had a partial response or better were randomly assigned (1:1) by an interactive web-response system to get daratumumab 16 mg/kg intravenously every eight weeks (less often than the usual long-term dosing of daratumumab) or just to be observed for up to 2 years. In part 1, the induction treatment and the level of reaction were used to divide the groups. The main goal of part 2 was to see how long people lived without getting worse after the second randomization. This planned preliminary analysis of progression-free survival was done after 281 events and will be considered the primary analysis of progression-free survival.

Sponsor employees and representatives who helped with the analysis were not told which treatment group they were in until the independent data monitoring committee said the planned preliminary analysis should be used as the primary progression-free survival analysis in part 2. If that happened, the treatment orders would be revealed. A split Cox regression model that had the interaction term between maintenance treatment and induction and consolidation treatment was used to test the interaction between induction, consolidation, and maintenance at a two-sided significance level of 0.05. The maintenance-specific intention-to-treat group, including all patients who underwent a second randomization, was used for the effectiveness analyses. All patients in the daratumumab group who got at least one dose were looked at for safety and all patients who were randomly given only monitoring. Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to either daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35.4 months (IQR 30·2-39·9) from the second randomization, the median progression-free survival (PFS) was not reached (95% CI not evaluable [NE]-NE) with daratumumab versus 46·7 months (40·0-NE) with observation only (hazard ratio 0·53, 95% CI 0·42-0·68, p<0·0001). The results of a pre-planned analysis of progression-free survival showed that maintenance treatment and induction and consolidation therapy interact significantly (p<0·0001). The most common side effects of grade 3 or 4 were lymphopenia (16 [4%] of 440 patients in the daratumumab group vs. eight [2%] of 444 patients in the observation-only group), hypertension (13 [3%] vs seven [2%]), and neutropenia (nine [2%] vs ten [2%]). 100 (23%) of the people in the daratumumab group and 84 (19%) in the observation-only group had severe side effects. The study concluded that daratumumab maintenance increases PFS in individuals with newly diagnosed multiple myeloma eligible for ASCT.

Source:https://pubmed.ncbi.nlm.nih.gov/34529931/

Clinical Trial:http://clinicaltrials.gov/show/NCT02541383

Moreau P, Hulin C, Perrot A, Arnulf B, Belhadj K, Benboubker L, Béné MC, Zweegman S, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Mohty M, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Macro M, Orsini-Piocelle F, Roussel M, Stoppa AM, van de Donk NWCJ, Wuillème S, Broijl A, Touzeau C, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Offner F, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Krevvata M, Zhang K, de Boer C, Vara S, Kampfenkel T, Vanquickelberghe V, Vermeulen J, Avet-Loiseau H, Sonneveld P. 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, randomized, phase 3 trial. Lancet Oncol. 2021 Oct;22(10):1378-1390. doi: 10.1016/S1470-2045(21)00428-9. Epub 2021 Sep 13. PMID: 34529931.