What was the committee asked to consider?
On July 17, 2025, the U.S. Food and Drug Administration (FDA) convened the Oncologic Drugs Advisory Committee (ODAC) to vote on whether the overall benefit-risk profile of two new combination regimens (belantamab mafodotin + bortezomib + dexamethasone [BVd] and belantamab mafodotin + pomalidomide + dexamethasone [BPd]) for treatment of multiple myeloma is favorable, and to discuss whether the proposed dosages were appropriate for the proposed patient population.
Why does this matter for patients and drug development?
Recent advances, such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies, have significantly extended survival for patients with multiple myeloma, but remain costly, complex, and often inaccessible outside specialized centers. In the clinical trials supporting BVd and BPd (DREAMM-7 and DREAMM-8), BVd and BPd improved progression‑free survival (PFS) with a median PFS of 37 months vs. 13 months in DREAMM‑7 (HR 0.41) and not reached vs. 13 months in DREAMM‑8 (HR 0.52). DREAMM‑7 also showed a statistically significant overall survival (OS) benefit (HR 0.58). These results confirm the regimens are active; however, they were accompanied by high rates of ocular toxicity and frequent dose modifications, framing the committee’s discussion around whether the proposed doses appropriately balanced efficacy with tolerability. Patient testimonials during the open public hearing emphasized the importance of having more accessible and convenient treatment options, noting that belantamab mafodotin can be administered in community settings with toxicities managed closer to where patients live.
What was discussed?
Meeting discussions and presentations focused on two key issues:
- Appropriateness of Proposed Dosages
Presentations described high rates of grade 3-4 ocular toxicities – primarily keratopathy and visual acuity changes – that often led to prolonged, recurrent treatment interruptions and dose modifications. Patient experience data indicated toxicities interfered at least somewhat in daily activities for 50% of patients, with more than 20% of patients reporting the toxicities interfered quite a bit in regular daily activities. However, during the open comment period, patients shared that these toxicities were temporary and manageable with follow-up care.
The committee also heard presentations on the results of early dose exploration studies, dose selection for DREAMM-7 and DREAMM-8, and justification of the proposed dosages. In early dosage studies, patients experienced fewer toxicities at lower dose levels with extended intervals. Despite these findings, a higher dose level at a more frequent interval was selected for use in follow-up trials including DREAMM-7 and DREAMM-8. The committee expressed disappointment over the missed opportunity to explore alternative dosages, which contributed to a lack of data to justify the proposed doses. While patients described the toxicities as temporary and manageable given the improved outcomes, FDA and committee members agreed that the high toxicity rates and limited data at lower doses raised concerns about the appropriateness of the proposed dosing regimen.
2. Applicability to U.S. Patients and Clinical Practice
Finally, the committee considered issues regarding the trials’ applicability to the U.S. patient population. Fewer than 5% of participants in DREAMM-7 and DREAMM-8 were from the U.S. Patients in these trials were also younger than the typical U.S. multiple myeloma population; while 33% of U.S. patients are over the age of 75, only 15% in DREAMM-7 and 12% in DREAMM-8 were in this age group. Black and African American patients, who are disproportionately affected by multiple myeloma in the U.S., were also underrepresented: only 5% of patients in DREAMM-7 and no patients in the DREAMM-8 trial were Black or African American. In addition to underrepresentation of U.S. patients demographically and geographically, the control arm used in DREAMM-8 is not commonly used in U.S. clinical practice.
What are the outcomes and implications of the meeting?
The committee voted that the overall benefit-risk profiles for both the BVd and BPd combination regimens are not favorable at the proposed dosages in the proposed patient populations. Voting members acknowledged the significance of patient testimonies and the importance of approving new, effective, and more accessible treatment options. However, members pointed to the lack of data justifying the proposed dosages and concerns that the trials did not adequately represent the U.S. population and U.S. clinical practice. Members expressed disappointment that further dose optimization was not pursued, particularly given FDA’s earlier encouragement to explore alternative dosages. Early studies had suggested that lower doses or extended intervals might have been more tolerable while maintaining efficacy. Their discussion underscored the importance of conducting prospectively designed dose exploration studies that prioritize patient-centered assessments of tolerability and rigorously evaluate multiple dosages to optimize both efficacy and tolerability.
The committee’s vote also underscored the importance of conducting trials that adequately represent U.S. patients and clinical practice. Committee members echoed FDA’s concerns regarding the limited representation of U.S. patients across both trials and the use of a control arm in DREAMM-8 that is not commonly used in U.S. clinical practice. These factors contributed to concerns about the applicability of trial results and whether available data could accurately inform a benefit-risk assessment for U.S. patients. To close the meeting, Dr. Richard Pazdur, Director of the Oncology Center of Excellence (OCE), emphasized FDA’s commitment to ensuring global trials remain applicable to U.S. patients, highlighting appropriate control arm selection as a critical factor.
This topic will be further explored at Friends’ 2025 Annual Meeting on November 4th, which will feature a panel discussion and accompanying white paper on selecting appropriate control arms in multi-regional clinical trials (MRCT).