Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis from a global, randomised, open-label, phase 3 trial

Background: In the primary (first interim) analysis of the DREAMM-7 trial (median follow-up 28·2 months), belantamab mafodotin, bortezomib, and dexamethasone (BVd) showed a statistically significant and clinically meaningful progression-free survival benefit versus daratumumab, bortezomib, and dexamethasone (DVd) in patients with relapsed or refractory multiple myeloma (RRMM) after at least one line of therapy. The aim of this study is to report overall survival from the second interim analysis, with extended follow-up. Methods: In the ongoing global, open-label, randomised, phase 3 DREAMM-7 trial done at 142 study centres (research facilities, hospitals, and institutions) in 20 countries across North America, South America, Europe, and the Asia-Pacific region, eligible patients were aged at least 18 years and had confirmed multiple myeloma (according to International Myeloma Working Group criteria), an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, and progression on or after at least one previous line of therapy. Patients were randomly assigned (1:1) by use of a central interactive response technology system to receive BVd, which comprised belantamab mafodotin 2·5 mg/kg intravenously every 3 weeks plus bortezomib 1·3 mg/m² subcutaneously (twice weekly in 21-day cycles, for up to eight cycles) plus dexamethasone 20 mg orally or intravenously (on the day of, and after, bortezomib; for up to eight cycles), or DVd, which comprised daratumumab 16 mg/kg intravenously (21-day cycles; once weekly in cycles 1–3, every 3 weeks in cycles 4–8, and every 4 weeks in cycle 9 and beyond) plus bortezomib and dexamethasone; bortezomib and dexamethasone doses and schedules were the same as those in the BVd group. Randomisation was stratified by number of previous lines of therapy, previous bortezomib, and Revised International Staging System stage. Treatment assignments were unmasked for study personnel and patients; however, they were masked to the independent review committee. Patients received treatment until progressive disease, death, unacceptable toxicity, withdrawal of consent, or loss to follow-up, whichever occurred first. The primary endpoint was progression-free survival; key secondary endpoints were overall survival, minimal residual disease negativity in patients with a complete response or better, duration of response to treatment, and safety. Analysis of efficacy endpoints was based on assessments in all patients who were randomly assigned (ie, the intention-to-treat population). The safety population included all randomly assigned patients who received one or more doses of study treatment. This trial is registered with ClinicalTrials.gov, NCT04246047, and is ongoing. Findings: From May 7, 2020, to June 28, 2021, of 623 patients assessed for eligibility, 494 were randomly assigned to receive BVd (n=243) or DVd (n=251); 272 (55%) were male, and 409 (83%) were White. The median age of the patients was 64·5 years (IQR 57·0–71·0). At the updated data cutoff (Oct 7, 2024) and median follow-up (39·4 months [IQR 14·6–42·9]), early, sustained, and significant overall survival benefit was observed with BVd versus DVd. Median overall survival was not reached (NR; 95% CI NR–NR) with BVd and NR (41·0 months–NR) with DVd (hazard ratio [HR] 0·58; 95% CI 0·43–0·79; p=0·0002). BVd versus DVd led to greater than double the minimal residual disease-negativity rates in patients with a complete response or better (25% [95% CI 19·8%–31·0%] vs 10% [6·9%–14·8%]) and median duration of response (40·8 months [95% CI 30·5 months–NR] vs 17·8 months [13·8–23·6]). Analysis of progression-free survival 2 showed that the treatment benefit favouring BVd versus DVd was maintained following subsequent antimyeloma therapy; median progression-free survival 2 was NR with BVd (95% CI 45·6–NR) versus 33·4 months (95% CI 26·7–44·9) with DVd (HR, 0·59; 95% CI, 0·45–0·77). The most common grade 3 or 4 adverse event was thrombocytopenia (135 [56%] of 242 with BVd vs 87 [35%] of 246 with DVd). Serious adverse events occurred in 129 (53%) of 242 patients receiving BVd and 94 (38%) of 246 patients receiving DVd; the most common events were pneumonia (29 [12%] vs 11 [4%]), pyrexia (12 [5%] vs 10 [4%]), and COVID-19 (11 [5%] vs 10 [4%]). Treatment-related serious adverse events that led to death occurred in seven (3%) of 242 patients receiving BVd (pneumonia [n=4], gastrointestinal haemorrhage [n=1], subdural haemorrhage [n=1], or mesenteric vessel thrombosis [n=1]) and two (1%) of 246 receiving DVd (COVID-19 [n=2]). Interpretation: DREAMM-7 showed significant and clinically meaningful overall survival, progression-free survival, minimal residual disease negativity, and duration of response benefits with BVd versus DVd. BVd could be a new standard of care for RRMM. Funding: GSK.