The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 5 to 3 against the risk:benefit profile of the proposed dosage of belantamab mafodotin (Blenrep) in combination with bortezomib (Velcade) and dexamethasone (BVd) for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy; and 7 to 1 against the risk:benefit profile of the proposed dosage of belantamab mafodotin in combination with pomalidomide (Pomalyst) and dexamethasone (BPd) for patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy, including lenalidomide (Revlimid).1
In November 2024, the FDA accepted a biologics license application (BLA) seeking the approval of BVd and BPd in these indications in relapsed/refractory multiple myeloma based on data from the phase 3 DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials, respectively.2 In both studies, the belantamab mafodotin–based regimen significantly improved progression-free survival (PFS) vs standard-of-care triplets.
Notably, the dosage selected for belantamab mafodotin in the BVd combination was 2.5 mg/kg every 3 weeks; the dosage specified in the BPd combination was 2.5 mg/kg in cycle 1, followed by 1.9 mg/kg every 4 weeks.3
During the ODAC meeting, the FDA sought input from the committee on whether appropriate dosages of belantamab mafodotin were identified for the proposed relapsed/refractory patient population in the context of observed ocular toxicity, the regimen’s tolerability, and efficacy results.3,4
Although both DREAMM-7 and DREAMM-8 met their primary PFS end points—with DREAMM-7 showing a statistically significant improvement in OS—high rates of any-grade and grade 3 or higher adverse effects (AEs), frequent recurrences, and unresolved AEs led the FDA to express dosing concerns. Moreover, the FDA stated that there are not only limited data supporting dosage selection, but that available data showed poor tolerability with the proposed dose levels, suggesting that these doses may not be optimized. Other key areas of uncertainty included the relevance of the data from DREAMM-7/DREAMM-8 for patients in the United States (US), and the risk:benefit profile for patients who have received more than 1 prior line of therapy.
“This was a challenging decision because the efficacy data were strong, but the toxicity data were also very strong. I’d like to emphasize the [verbiage of the question stating], ‘at the proposed dosage.’ This was, for me, what swayed the decision. I think this was just a missed opportunity over the course of many years of development of this drug to explore these different dosages. We’ve heard impassioned testimonials from key opinion leaders and from many researchers in the myeloma community. All of the building blocks are here to explore this question in the future, from patients to researchers to physicians, but that was the rationale for why I voted no [for both questions], “ Neil Vasan, MD, PhD, of NYU Langone, stated in his explanation for voting no.
In August 2020, the FDA granted accelerated approval to belantamab mafodotin for the treatment of patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody based on results of the phase 2 DREAMM-2 trial (NCT03525678).5
However, belantamab mafodotin was voluntarily withdrawn from the US market for this indication in November 2022 following the FDA’s request due to failure of the confirmatory phase 3 DREAMM-3 trial (NCT04162210) to demonstrate a significant progression-free survival benefit compared to standard therapy.6
Although the reasons for the failure of DREAMM-3 to meet its primary end point are not clear, Andrea Baines, MD, a medical officer in the Division of Hematology Products at the FDA, argued on behalf of the regulatory agency. She noted that it is possible that poor tolerability of the 2.5 mg/kg once every 3 weeks dosage may have negatively impacted the efficacy of belantamab mafodotin monotherapy.
“This is probably one of the most difficult votes I’ve done as a member of this committee,” Grzegorz S. Nowakowski, MD, stated while explaining the rationale for voting yes to the first question. “On the one hand, from a regulatory perspective…the whole drug development program probably made all the possible mistakes which could have happened, including the lack of US representation in the pivotal studies, and also the lack of early dose optimization, which could have avoided a lot of the toxicity discussion we had. On the other hand, I’m also a practicing hematologist, and the drug is clearly active. [Toxicity] could be mitigated to some degree, although not without reservations in a setting of careful optometrical follow-up and dose reductions or interruptions.”
In contrast, John DeFlice, MD, of Cedars-Sinai Samuel Oschin Cancer Center, explained why he voted yes to both questions, stating that, “I think they are the wrong issues to be evaluated based on the clinical experience of the researchers and the testimonies that we’ve heard, this is an amazing drug for an incurable disease.”
DREAMM-7 Overview
The randomized, open-label DREAMM-7 trial enrolled patients at least 18 years of age with multiple myeloma who received at least 1 prior line of therapy and had documented disease progression during or after their most recent treatment.7 Prior treatment with a BCMA-directed therapy was not permitted or disease that was refractory to anti-CD38 therapy were not permitted.
Eligible patients were randomly assigned 1:1 to receive BVd or DVd. In the experimental arm, belantamab mafodotin was administered at 2.5mg/kg once every 3 weeks. The trial’s primary end point was PFS, with secondary end points including OS, duration of response, and minimal residual disease (MRD)–negativity rate.
Findings from the randomized, open-label trial published in the New England Journal of Medicine showed that at a median follow-up of 28.2 months (range, 0.1-40.0), patients treated with BVd (n = 243) achieved a median PFS of 36.6 months (95% CI, 28.4-not reached [NR]) compared with 13.4 months (95% CI, 11.1-17.5) in patients treated with daratumumab (Darzalex) plus DVd (DVd; n = 251; HR, 0.41; 95% CI, 0.31-0.53; P < .001).3
Regarding safety, all patients experienced at least 1 AE. Grade 3 or higher AEs were reported in 95% of the patients in the BVd group vs 78% in the DVd group. Serious AEs occurred in 50% and 37% of patients, respectively. Ocular AEs occurred in 79% of patients in the experimental arm vs 29% in the DVd arm. These AEs were managed with dose modifications, and the majority of worsened visual acuity events were resolved.
DREAMM-8 Overview
The randomized, open-label DREAMM-8 trial enrolled patients at least 18 years of age with multiple myeloma who were previously treated with at least 1 prior line of therapy, including a lenalidomide-containing regimen.8 Documented disease progression during or after their most recent therapy, an ECOG performance status of 0 to 2, measurable disease, and adequate organ function were all required.
Eligible patients were randomly assigned 1:1 to receive BPd or PVd. The trial’s primary end point was PFS, and secondary end points included OS, DOR, MRD-negativity rate, overall response rate, and safety.
Data from this study were also published in the New England Journal of Medicine. At a median follow-up of 21.8 months (range, <0.1-39.2), treatment with BPd yielded a 48% reduction in the risk of disease progression or death compared with PVd (HR, 0.52; 95% CI, 0.37-0.73; P < .001). The estimated 12-month PFS rates were 71% (95% CI, 63%-78%) for BPd (n = 155) vs 51% (95% CI, 42%-60%) with PVd (n = 147). Notably, OS did not reach statistical significance at the first interim analysis (HR, 0.77; 95% CI: 0.53, 1.14).3
In terms of safety, any-grade AEs occurred in 99% of patients in the BPd arm (n = 150) vs 96% of patients in the PVd arm (n = 145); 91% and 73% of these AEs, respectively, were grade 3/4.8 Serious AEs occurred in 63% of patients in the BPd arm and 45% of patients in the PVd arm.
Any-grade ocular AEs occurred in 89% of patients in the BPd arm vs 30% of patients in the control arm. In the BPd arm, ocular AEs were managed with dose holds (83%) and reduced doses (59%). Treatment discontinuation due to ocular AEs occurred in 9% of patients in the BPd arm and no patients in the PVd arm.
FDA’s Position
High Ocular Toxicity Rates
In their presentations during the ODAC meeting, the FDA highlighted keratopathy and visual acuity (KVA) events as a significant and unique safety concern associated with belantamab mafodotin that distinguishes it from other currently available therapies for multiple myeloma. High rates of ocular toxicity were observed in both the DREAMM-7 and DREAMM-8 trials, with similar incidence and severity across studies despite the lower dosing regimen utilized in DREAMM-8. Notably, dose modifications were frequently required due to ocular toxicity in both trials.
In DREAMM-7, 92% of patients experienced KVA events, 77% of which were grade 3 or 4 in severity. DREAMM-8 showed comparable findings, with 93% experiencing KVA events and 78% experiencing grade 3/4 events. A majority of grade 2 or higher KVA events occurred within 1 to 2 months of treatment initiation, and the median duration of KVA events was approximately 3 months. However, a substantial number of patients had unresolved events at the time of the data cutoff on October 7, 2024.
Dose modifications due to KVA events occurred in 76% of patients in DREAMM-7 and 78% in DREAMM-8. Additionally, patients experienced prolonged and recurrent treatment interruptions as a result of ocular toxicity. Clinically meaningful reductions in best corrected visual acuity to 20/50 or worse were reported in over 60% of patients in both trials. The median duration of these changes was approximately 3 weeks in DREAMM-7 and 4 weeks in DREAMM-8.
As of the data cutoff, over 70% of patients had ongoing ocular toxicity, and approximately two-thirds of these patients had discontinued study treatment. Given the median age at diagnosis for multiple myeloma is 69 years, this level of visual impairment could have a significant impact on daily functioning and quality of life, particularly in patients with pre-existing health conditions or functional limitations, Baines noted.
Uncertainty Regarding Proposed Dosages
The regulatory agency also questioned the appropriateness of the proposed dosage of belantamab mafodotin given high rates of ocular toxicity and poor tolerability combined with the limited dose exploration and additional data suggesting improved tolerability with lower doses and longer dosing intervals.
With respect to the safety and tolerability profile of belantamab mafodotin, data from DREAMM-7 and DREAMM-8 suggested that lower doses and/or extended dosing intervals may reduce the incidence and severity of ocular toxicity while preserving efficacy. Notably, patients who received the 1.9 mg/kg dose every 6 weeks in DREAMM-7 experienced fewer grade 2 or higher corneal AEs and fewer dose modifications than those receiving the same dose every 3 weeks. However, these findings are limited by the small number of patients in each dosing cohort. For example, in DREAMM-8, only 5 patients received the proposed dosing regimen of 2.5 mg/kg every 3 weeks. Despite the FDA’s recommendation to enroll more patients at the lower doses and in combination settings before finalizing the dose selection, the applicant proceeded with the 2.5 mg/kg every-3-weeks regimen, followed by 1.9 mg/kg every 4 weeks in DREAMM-8.
A greater proportion of patients receiving the 1.9 mg/kg dose remained on their intended dose longer than those at the 2.5 mg/kg dose level. Similarly, patients on extended dosing intervals (every 6 weeks vs every 3 weeks) tolerated treatment better with fewer interruptions and dose reductions.
Overall, the FDA noted that limited exploration of lower doses was conducted in a small patient population despite repeated FDA recommendation, and the selected regimens in DREAMM-7 and DREAMM-8 may not adequately reflect the optimal balance between efficacy and tolerability.
Relevance to a US-Based Population
Lastly, the FDA highlighted several concerns related to the applicability of the DREAMM-7 and DREAMM-8 trial results to the current US population of patients with relapsed/refractory multiple myeloma. One major limitation noted was the underrepresentation of North American patients, Black/African American patients, and adults 75 years of age or older in both trials, especially given the higher incidence of multiple myeloma among the African American population. Additionally, potential differences in disease biology, treatment access, and comorbidity management between US and non-US populations were cited as key concerns.
The FDA also emphasized uncertainty regarding the management of belantamab mafodotin–associated ophthalmologic toxicities in diverse real-world clinical settings across the US. The infrastructure and frequency of required ophthalmologic assessments may be more difficult to implement outside of controlled clinical trials, especially in community practice settings.
Another significant concern involved the relevance of the DREAMM-7 and DREAMM-8 trial control arms in the context of evolving US treatment practices. Increasing use of quadruplet frontline regimens incorporating CD38-targeting monoclonal antibodies and lenalidomide has altered the therapeutic landscape, raising questions about the generalizability of the observed treatment effects with belantamab. Additionally, the US market includes multiple therapies for relapsed/refractory with more robust safety profiles and demonstrated OS benefits, such as CAR T-cell therapies and bispecific T-cell engagers targeting BCMA.
References
- July 17, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed July 17, 2025. https://www.youtube.com/live/CLhBI3UXWyg
- Blenrep combinations accepted for review by the US FDA for the treatment of relapsed/refractory multiple myeloma. News release. GSK. November 25, 2024. Accessed July 17, 2025. https://www.gsk.com/en-gb/media/press-releases/blenrep-combinations-accepted-for-review-by-the-us-fda-for-the-treatment-of-relapsedrefractory-multiple-myeloma/
- Belantamab Mafodotin BLA 761440. FDA. July 17, 2025. Accessed July 17, 2025. https://www.fda.gov/media/187657/download
- Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Oncologic Drugs Advisory Committee (ODAC) agenda. FDA. July 17, 2025. Accessed July 17, 2025. https://www.fda.gov/media/187573/download
- FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. GSK. August 6, 2020. Accessed July 17, 2025. https://www.gsk.com/en-gb/media/press-releases/fda-approves-gsk-s-blenrep-belantamab-mafodotin-blmf-for-the-treatment-of-patients-with-relapsed-or-refractory-multiple-myeloma
- GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline. November 22, 2022. Accessed July 17, 2025. http://bit.ly/3gniPi1
- Hungria V, Robak P, Hus M, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(5):393-407. doi:10.1056/NEJMoa2405090
- Dimopoulos MA, Beksac M, Pour L, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma. N Engl J Med. 2024;391(5):408-421. doi:10.1056/NEJMoa2403407
