Highlights
– Updated DREAMM-7 results (median follow-up 39.4 months) report a statistically significant overall survival (OS) benefit for belantamab mafodotin plus bortezomib and dexamethasone (BVd) versus daratumumab plus bortezomib and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM) (HR 0.58; p=0.0002).
– BVd produced higher rates of minimal residual disease (MRD) negativity (25% vs 10% among patients achieving CR or better) and a markedly longer median duration of response (40.8 vs 17.8 months).
– Progression-free survival 2 (PFS2) favored BVd, indicating maintained benefit after subsequent therapies (HR 0.59).
– BVd was associated with more hematologic toxicity (notably grade 3–4 thrombocytopenia) and higher rates of serious adverse events, including infection-related events.
Background and Clinical Context
Relapsed and/or refractory multiple myeloma remains a significant therapeutic challenge despite advances in proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Patients progressing after first-line therapy face increasingly complex treatment decisions where depth and durability of response, impact on survival, and tolerability must be balanced. Targeting B-cell maturation antigen (BCMA) has emerged as a promising strategy; belantamab mafodotin is an antibody–drug conjugate that delivers a cytotoxic payload to BCMA-expressing plasma cells and has shown activity in heavily pretreated disease.
Study Design and Methods
DREAMM-7 is a global, randomized, open-label, phase 3 trial (NCT04246047) that compared belantamab mafodotin 2.5 mg/kg intravenously every 3 weeks plus bortezomib and dexamethasone (BVd) against daratumumab 16 mg/kg plus the same bortezomib and dexamethasone backbone (DVd) in patients with RRMM who had progressed after at least one prior line of therapy. Randomization was 1:1, stratified by number of prior lines, prior bortezomib exposure, and Revised International Staging System (R-ISS) stage. Primary endpoint was progression-free survival (PFS); key secondary endpoints included overall survival (OS), MRD-negativity rates in patients achieving complete response (CR) or better, duration of response (DoR), and safety. Efficacy analyses were intention-to-treat; safety included all patients who received at least one dose of study drug.
Between May 2020 and June 2021, 494 patients were randomized (243 to BVd, 251 to DVd). Median age was 64.5 years; 55% were male and 83% were White. At the updated analysis cutoff (Oct 7, 2024) median follow-up was 39.4 months.
Key Results
Overall Survival
The second interim analysis with extended follow-up demonstrated an early, sustained, and statistically significant OS benefit with BVd versus DVd. Median OS was not reached in the BVd arm (95% CI NR–NR) and was not reached versus 41.0 months (95% CI 41.0–NR) in the DVd arm; the hazard ratio for death was 0.58 (95% CI 0.43–0.79; p=0.0002). This HR translates to a 42% relative reduction in the risk of death with BVd over the period observed and indicates a clinically meaningful survival advantage.
Response Depth and Durability
BVd produced substantially deeper responses as measured by MRD negativity among patients achieving CR or better: 25% (95% CI 19.8%–31.0%) with BVd versus 10% (95% CI 6.9%–14.8%) with DVd, more than doubling the MRD-negative proportions. Median duration of response was markedly longer with BVd: 40.8 months (95% CI 30.5–NR) compared with 17.8 months (95% CI 13.8–23.6) with DVd. These findings indicate not only deeper responses but also prolonged disease control for responders treated with the belantamab-containing regimen.
Progression-Free Survival 2 (PFS2)
PFS2—time from randomization to progression on next-line therapy or death—favored BVd, suggesting the benefit of the initial BVd regimen persisted through subsequent lines of therapy. Median PFS2 was not reached 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). This metric supports that initial effective debulking and disease control may have downstream advantages beyond first progression.
Safety and Tolerability
Adverse event profiles differed between arms. The most common grade 3–4 adverse event in both groups was thrombocytopenia, but it was more frequent with BVd (56% of 242 patients) than DVd (35% of 246 patients). Serious adverse events (SAEs) occurred in 53% of patients receiving BVd versus 38% with DVd. The most common SAEs were pneumonia (12% vs 4%), pyrexia (5% vs 4%), and COVID-19 (5% vs 4%). Treatment-related SAEs resulting in death occurred in 3% of BVd-treated patients (including pneumonia in four patients) versus 1% in the DVd arm (both COVID-19).
Notably, the report highlights hematologic and infectious complications as the principal safety signals. Belantamab mafodotin is also known to be associated with ocular adverse events (corneal keratopathy) in other trials; although these specific rates are not the focal point of the updated survival analysis, clinicians should remain vigilant for ocular toxicity with BCMA-targeted antibody–drug conjugates and adhere to recommended ophthalmologic monitoring and dose modifications.
Interpretation and Clinical Implications
The DREAMM-7 update provides robust evidence that BVd yields substantial survival benefit and deeper, more durable responses than a daratumumab-containing triplet in patients with RRMM after at least one prior line of therapy. The OS advantage (HR 0.58) is statistically compelling and clinically meaningful in a disease where prolongation of survival remains a prime objective.
From a mechanistic standpoint, belantamab mafodotin targets BCMA, a near-universal antigen on malignant plasma cells, and delivers a cytotoxic payload directly to the tumour cell—offering a different mechanism from anti-CD38 monoclonal antibodies like daratumumab. The deeper MRD-negativity rates and prolonged DoR observed with BVd are consistent with potent tumoricidal activity and may explain the downstream survival benefit.
These results suggest that a BCMA-directed antibody–drug conjugate combined with proteasome inhibitor and steroid can offer an effective early salvage strategy and could shift the treatment paradigm for certain patients with RRMM. The PFS2 data indicate that choosing a regimen that achieves deeper initial remissions may positively influence outcomes through subsequent lines of therapy.
Strengths and Limitations
Strengths of DREAMM-7 include its global, randomized phase 3 design, reasonably mature follow-up (median 39.4 months), stratified randomization, and reporting of clinically relevant endpoints including OS and MRD. The statistically significant OS result is notable because overall survival endpoints are challenging to demonstrate in myeloma given multiple effective subsequent therapies.
Limitations include the open-label design, which may affect reporting or management of certain adverse events and subsequent treatment choices. The trial report does not provide extensive granularity on subsequent therapies post-progression, which can confound OS interpretation; however, the favorable PFS2 mitigates some concerns about bias from later-line treatments. The study population was predominately White (83%), which may limit generalizability. Differences in toxicity profiles require careful patient selection and monitoring: higher rates of thrombocytopenia and serious infections with BVd may influence regimen choice, particularly in frail patients or those with baseline cytopenias.
Practical Considerations for Clinicians
When considering BVd for patients with RRMM, clinicians should weigh the demonstrated survival and MRD advantages against the risks of hematologic toxicity and infection. Key practical steps include baseline and ongoing platelet monitoring, proactive infection surveillance and prophylaxis where appropriate, and routine ophthalmologic assessments given the known corneal toxicities associated with belantamab mafodotin in prior studies. Dose modifications and treatment holds should be applied according to established management guidance for belantamab-associated adverse events.
Future Directions and Research Gaps
Further work is needed to define optimal sequencing of BCMA-directed therapies with other modalities such as CAR T-cell therapy, bispecific antibodies, and newer antibody constructs. Comparative effectiveness in diverse patient subgroups (including those with high-risk cytogenetics, renal impairment, or frailty) requires more detailed subgroup analyses. Long-term ocular safety, strategies to mitigate corneal toxicity, and biomarkers predictive of response or toxicity will also be important to refine patient selection and supportive care.
Conclusion
The updated DREAMM-7 analysis demonstrates that belantamab mafodotin combined with bortezomib and dexamethasone provides statistically significant and clinically meaningful improvements in overall survival, MRD-negativity rates, and durability of response compared with a daratumumab-containing regimen in relapsed or refractory multiple myeloma. These data support BVd as a compelling therapeutic option in this setting, though clinicians must balance efficacy with the regimen’s hematologic and infectious toxicity profile and institute appropriate monitoring and management strategies.
Funding and Trial Registration
Funding: GlaxoSmithKline (GSK).
ClinicalTrials.gov identifier: NCT04246047.
References
Hungria V, Robak P, Hus M, Zherebtsova V, Ward C, Ho PJ, et al; DREAMM-7 study investigators. 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. Lancet Oncol. 2025 Aug;26(8):1067-1080. doi: 10.1016/S1470-2045(25)00330-4. Epub 2025 Jul 15. Erratum in: Lancet Oncol. 2025 Oct;26(10):e522. PMID: 40680754.
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