FDA’s ODAC Votes Belantamab Mafodotin at Proposed Dosing Unfavorable in Multiple Myeloma

The FDA’s Oncologic Drugs Advisory Committee (ODAC) has determined that the overall benefit-risk of belantamab mafodotin (Blenrep) in combination with bortezomib and dexamethasone (BVd) or pomalidomide and dexamethasone (BPd) is not favorable at the proposed dosage in patients with relapsed or refractory multiple myeloma (MM).

The Committee convened on July 17, 2025, at the Center for Drug Evaluation and Research (CDER) on the FDA White Oak Campus in Silver Spring, Maryland to discuss the Biologics License Application submitted in November 2024 by GlaxoSmithKline LLC (GSK) for the following regimens:

• Belantamab mafodotin in combination with BVd in adult patients who have received at least one prior line of therapy
• Belantamab mafodotin in combination with BPd in patients who have received at least one prior line of therapy, including lenalidomide

In introductory remarks, Deepti Telaraja, MD, of the FDA’s division of hematologic malignancies II, raised concerns about the high rates of ocular toxicity and uncertainty regarding the proposed dosages in the DREAMM-7 and DREAMM-8 trials.¹

Patients in DREAMM-7 received a dosage of 2.5 mg/kg every three weeks, and patients in DREAMM-8 received a starting dose of 2.5 mg/kg every three weeks on cycle 1, followed by 1.9 mg/kg every four weeks on cycle 2.¹

In DREAMM-7, the rates of ocular events were 79% with BVd versus 29% with daratumumab, bortezomib, and dexamethasone (DVd). In DREAMM-8, the rates were 89% with BPd versus 30% with pomalidomide, bortezomib, and dexamethasone (PVd). In both trials, ocular events were managed by dose modification of belantamab mafodotin.^3,4

“The toxicity is caused by damage to the corneal epithelium manifesting as corneal changes and visual acuity changes,” Dr. Telaraja explained.¹

Despite the high rate of ocular events, the drug met its primary end point of progression-free survival (PFS) in both trials.

In DREAMM-7, BVd showed superior PFS compared with DVd among patients with MM progression after one or more lines of therapy, having produced a median PFS of 36.6 months versus 13.4 months, respectively (P < 0.001).³

In DREAMM-8, the 12-month estimated PFS was 71% with BPd and 51% with PVd (P < 0.001) among lenalidomide-exposed patients with relapsed or refractory MM after one or more lines of therapy.⁴

“Ocular events are reversible with time and effectively managed with dose modifications, allowing patients to remain on treatment and derive benefit,” said Hesham A. Abdullah, MD, MSc, RAC, senior vice president and global head of oncology at GSK.¹ “The dose and schedule of Blenrep has been extensively studied in almost 400 patients. The proposed 2.5 mg/kg starting dose and use of dose reductions and delays to manage ocular events is the most optimal approach for dosing to gain maximal benefit-risk.”

Natalie Afshari, MD, chief of cornea and refractive surgery and professor of ophthalmology at Shiley Eye Center, University of California, San Diego, explained the pathophysiology behind belantamab mafodotin-related ocular events.

“Blenrep causes microcyst-like changes in the corneal epithelium…these may occur without symptoms but can affect vision depending on severity and location. They begin in the peripheral epithelium then move toward the center, where they may impact vision. As new cells grow from the periphery inwards, older cells are replaced, and vision recovers. It’s this pathophysiology that supports the resolution of ocular events associated with Blenrep,” Dr. Afshari explained.¹

Results from a patient questionnaire presented at the meeting showed that 50% of patients who experienced ocular adverse events while receiving belantamab mafodotin reported at least moderate symptoms, and 20% reported severe symptoms.¹

“More than 10% of patients in both trials experienced a very severe change in best corrected visual acuity to 20/200 or worse, which qualifies as legal blindness,” said Andrea Baines, MD, PhD, a clinical reviewer at the FDA’s division of hematologic malignancies II. “This degree of vision loss would be expected to greatly impair a patient’s independence and ability to perform everyday tasks.”

Regarding other safety findings from the two trials, grade 3 or higher adverse events (AEs) occurred more frequently with BVd than with DVd, at 95% versus 78%, respectively, and with BPd versus PVd, at 94% versus 76%, respectively.^3,4

Sagar Lonial, MD, chair and chief medical officer at the Winship Cancer Institute, Emory University School of Medicine, concurred that dose adjustments provide patients with a more tolerable safety profile with continued efficacy.

“The results were consistently improved across all end points, including overall response rate, duration of response, MRD [measurable residual disease] negativity, PFS, and overall survival,” he said.¹ “These results validate the dose modification scheme outlined in DREAMM-7 and DREAMM-8 and are among the longest PFS seen in any randomized phase 3 trials in early relapsed myeloma. This magnitude of benefit is not observed with most currently available treatment combinations.”

However, according to Ankit Shah, PhD, clinical pharmacology team leader at the FDA’s Division of Cancer Pharmacology, the dose modifications may not be adequately optimized. “The applicant conducted very limited dose exploration in a small number of patients to support selection of the belantamab mafodotin dosages in DREAMM-7 and DREAMM-8,” he said.¹ “The available data also suggest that lower exposure of belantamab mafodotin may result in fewer dose modifications and corneal adverse events without necessarily affecting the efficacy.”

Following a public hearing, three committee members voted “Yes” and five voted “No” to the question of whether the overall benefit-risk of belantamab mafodotin in combination with BVd is favorable at the proposed dosage in the proposed patient population.

Additionally, one Committee member voted “Yes” and seven voted “No” to the question of whether the overall benefit-risk of belantamab mafodotin in combination with BPd is favorable at the proposed dosage in the proposed dosage in the proposed patient population.

Lack of early dose optimization was identified as a large factor for those who voted “No.”

“This was a challenging decision because the efficacy data were strong, but the toxicity data were also very strong,” said Neil Vasan, MD, PhD, acting chairperson of ODAC, who voted “No” to both questions.¹ “I took a textualist interpretation to this question and I’d like to emphasize the words ‘at the proposed dosage.’ This was what swayed the decision. This was just a missed opportunity over the course of many years of development at the drug to explore these different dosages.”

“Based on the clinical experience of the researchers and the testimonies we heard, this is an amazing drug for an incurable disease,” said John DeFlice, MD, who voted “Yes” to both questions.¹

“The question asked do we have a safe and effective dose, and I think there needs to be more work done,” added Paul Beringer, PharmD, who voted “No” to both questions.¹

Despite the outcome of the meeting, many committee members expressed hope for the drug to become optimized and available in the US.

Belantamab mafodotin-blmf was FDA approved in 2020 for use in adults with relapsed or refractory MM who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.⁵ However, the drug was voluntarily withdrawn from the US market in February 2024 due to a failed confirmatory trial.¹

The recommendations that ODAC generates for the FDA are not legally binding. However, the FDA usually has adopted these ODAC-issued recommendations.