SUMMARY: The FDA on October 23, 2025, approved Belantamab mafodotin-blmf (BLENREP®), a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor conjugate, with Bortezomib and Dexamethasone for adults with Relapsed or Refractory Multiple Myeloma (RRMM) who have received at least two prior lines of therapy, including a Proteasome Inhibitor and an immunomodulatory agent.
Context and Rationale
Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.
Patients with newly diagnosed multiple myeloma often receive triplet and quadruplet regimens that incorporate Proteasome Inhibitors, immunomodulators, and anti-CD38 antibodies as first line therapy, as these regimens are associated with prolonged Progression Free Survival (PFS) and Overall Survival (OS). However, most patients relapse and frontline use of Lenalidomide therapy has increased the number of patients with Lenalidomide-refractory disease at the time of the first relapse. New novel combinations are needed for patients who have relapsed or refractory myeloma, after disease progression during frontline therapy.
B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and multiple myeloma. B-Cell Maturation Antigen is therefore an established target in myeloma.
Belantamab Mafodotin: A Multimodal Antibody-Drug Conjugate
Belantamab mafodotin is a BCMA-targeting antibody-drug conjugate comprising a humanised B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a non-cleavable linker. Auristatin F induces cytotoxicity, Antibody-Dependent Cellular Cytotoxicity and phagocytosis, and induction of immunogenic cell death. Early-phase data demonstrated sustained, deep responses in heavily pretreated populations, suggesting potential benefit when used earlier in the disease course in combination with established backbones.
Study Design: DREAMM-7
The Phase III DREAMM-7 trial (DRiving Excellence in Approaches to Multiple Myeloma) was an open-label, multicenter, randomized study comparing Belantamab mafodotin plus Bortezomib and Dexamethasone (BVd) versus Daratumumab plus Bortezomib and Dexamethasone (DVd) in patients with RRMM who had received at least one prior line of therapy. A total of 494 patients were randomized 1:1 to BVd (N=243) or DVd (N=251). Baseline characteristics were well balanced between arms: approximately half of participants (51%) had received one prior line of therapy, 52% had prior Lenalidomide exposure, 34% were Lenalidomide-refractory, and 28% harbored high-risk cytogenetic abnormalities. The Primary endpoint was PFS as assessed by an Independent Review Committee. Key Secondary endpoints included OS, Duration of Response (DOR), Minimal Residual Disease (MRD) negativity by Next-Generation Sequencing, Overall Response Rate (ORR), and safety.
Primary Analysis: Robust Progression-Free Survival Benefit
At a median follow-up of 28.2 months, the trial met its Primary endpoint. The median PFS was 36.6 months (95% CI, 28.4–not reached) in the BVd arm versus 13.4 months (95% CI, 11.1–17.5) in the DVd arm, corresponding to a 59% reduction in risk of progression or death (HR=0.41; 95% CI, 0.31–0.53; P<0.00001).
BVd achieved higher rates of Complete Response or better with MRD negativity (25% vs 10%) and a more favorable DOR distribution (P<0.001). Median DOR was 35.6 months with BVd compared to 17.8 months with DVd. Treatment benefits with BVd were preserved even after subsequent therapy (PFS2 HR= 0.56; 95% CI, 0.41–0.76). Although median OS was not reached at this time point, a strong trend favored BVd (HR=0.57; 95% CI, 0.40–0.80).
Second Interim Analysis: Statistically Significant OS Advantage
At the second interim analysis, conducted at a median follow-up of 39.4 months, BVd demonstrated a 42% reduction in the risk of death versus DVd (HR=0.58; 95% CI, 0.43–0.79; P=0.00023). Median OS was not reached in either arm, but projected estimates were striking, 84 months for BVd compared with 51 months for DVd. The 3-year OS rate was 74% with BVd versus 60% with DVd, with survival separation evident as early as 4 months and sustained over time.
Subgroup Analysis and FDA Approval
In the subset of patients who had received two or more prior lines of therapy (the population used for regulatory evaluation, N=108 in the BVd and N=109 in the DVd groups), BVd maintained substantial efficacy. Median PFS was 31.3 months (95% CI, 23.5–NR) compared with 10.4 months (95% CI, 7.0–13.4) with DVd (HR, 0.31; 95% CI, 0.21–0.47). Median OS was not reached with BVd and 35.7 months with DVd (HR, 0.49; 95% CI, 0.32–0.76), representing a 51% reduction in risk of death.
Depth of Response and MRD Negativity
The BVd regimen achieved statistically significant improvements in MRD negativity, with rates more than 2.5 times higher than those observed with DVd (P<0.00001). Superior depth and durability of response were reflected in all major efficacy endpoints, including DOR and PFS2, underscoring the potential for more sustained disease control with the Belantamab-containing triplet.
Safety Profile and Ocular Events
Adverse events were consistent with prior experience for the individual agents. Grade ≥3 thrombocytopenia occurred in 56% of patients receiving BVd versus 35% with DVd; grade ≥3 anemia and neutropenia were comparable between groups. Ocular events, a known risk associated with Belantamab mafodotin, were manageable with dose modifications and rarely led to discontinuation. Only 10% of patients in the BVd arm discontinued therapy due to ocular toxicity.
Clinical Implications
The DREAMM-7 results represent the first head-to-head Phase III evidence of a statistically significant OS advantage for a BCMA-targeting therapy in RRMM compared with a Daratumumab-based regimen. The combination of Belantamab mafodotin with Bortezomib and Dexamethasone delivered a tripling of median PFS, a clinically meaningful OS benefit, and deeper MRD-negative responses, establishing a compelling new benchmark for patients experiencing their first relapse or later. These data reinforcing the OS benefit and may solidify BVd as a new standard of care for relapsed or refractory multiple myeloma.
Belantamab Mafodotin, Bortezomib, and Dexamethasone Vs Daratumumab, Bortezomib, and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Overall Survival Analysis and Updated Efficacy Outcomes of the Phase 3 Dreamm-7 Trial. Hungria V, Robak P, Hus M, et al. Blood (2024) 144 (Supplement 1): 772. https://doi.org/10.1182/blood-2024-200336
