FDA ODAC Votes Belantamab Mafodotin Risks Outweigh Benefits in Myeloma

The FDA's Oncologic Drugs Advisory Committee (ODAC) voted that the benefit-risk profile of belantamab mafodotin (Blenrep)-based combinations was unfavorable for the treatment of early relapsed/refractory mutiple myeloma.¹

The ODAC convened to discuss the biologics license application of belantamab mafodotin in combination with bortezomib (Velcade) and dexamethasone (BVd) as well as with pomalidomide and dexamethasone (BPd).

The votes were 5 nos and 3 yeses to the first voting question and 7 nos and 1 yes to the second voting question of whether the overall benefit-risk profiles of belantamab mafodotin in combination with BVd and BPD, respectively, were favorable at the proposed dosages.

"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 the ODAC and director of Breast Cancer Translational Research at Perlmutter Cancer Center, NYU Langone Health. "I took a textualist interpretation to this question, and I'd like to emphasize the words, 'at the proposed dosage.' This was, for me, what swayed the decision."

About Belantamab Mafodotin, DREAMM-7, and DREAMM-8

Belantamab mafodotin is an antibody-drug conjugate (ADC) that has had a notable and somewhat complex regulatory journey in the US, characterized by an initial accelerated approval, subsequent withdrawal, and a current reevaluation based on new combination therapy data.

The FDA granted belantamab mafodotin breakthrough therapy designation in 2017, signaling its potential to offer substantial improvement over available therapies for heavily pretreated relapsed/refractory multiple myeloma.

Based on data from the DREAMM-2 trial (NCT03525678), which showed a clinically meaningful overall response rate (ORR) of 31%, the FDA granted accelerated approval to belantamab mafodotin in August 2020 as a monotherapy.² The indication was for adult patients with relapsed/refractory multiple myeloma who had received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. This approval was contingent upon verification of clinical benefit in confirmatory trial(s). A Risk Evaluation and Mitigation Strategy (REMS) with Elements to Ensure Safe Use (ETASU) was implemented due to the observed ocular toxicity.

The regulatory path took a turn when the confirmatory phase 3 DREAMM-3 trial (NCT04162210) did not meet its primary end point of demonstrating superior progression-free survival (PFS) compared with a standard of care regimen of pomalidomide plus dexamethasone.¹ Although belantamab mafodotin showed a good ORR of 41% and durable responses in DREAMM-3, it did not demonstrate superiority in PFS, with a median PFS of 11.2 months vs 7.0 months for the comparator.¹

Consequently, at the request of the FDA, GSK initiated the process for withdrawal of the US marketing authorization for belantamab mafodotin as a monotherapy in November 2022.³

More recently, based on positive results from two other phase 3 head-to-head trials, DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623), which evaluated belantamab mafodotin in combination therapies, the FDA has accepted a biologics license application for belantamab mafodotin.¹ These trials showed statistically significant and clinically meaningful improvements in PFS with BVd in DREAMM-7 or BPd in DREAMM-8. This reevaluation aims to bring belantamab mafodotin back to the US market for use in combination regimens for patients with relapsed/refractory multiple myeloma who have received at least 1 prior line of therapy.

FDA’s Standpoint

Ocular Toxicities

Belantamab mafodotin is associated with a significant and unique safety concern: ocular toxicity, specifically keratopathy, visual acuity changes, and other eye-related symptoms like blurred vision and dry eye. While other ADCs can cause eye issues, this level of toxicity is not seen with other multiple myeloma treatments.

Key observations from the DREAMM-7 and DREAMM-8 trials highlight the severity of this issue. Most patients (over 90% in both trials) experienced keratopathy and visual acuity (KVA) events, with 77% to 78% being high-grade. Patients experienced severe ocular toxicities, including corneal ulcers and significant vision loss. Around 70% of patients had recurrent ocular toxicity events, with a median of 3 grade 2 or higher KVA events. Over half of the patients had ongoing grade 2 or higher KVA events at the data cut-off.

Patient-reported outcome results “showed that at each assessed time point, a group of patients reported severe visual side effects related to belantamab mafodotin,” said Andrea Baines, MD, PhD, clinical reviewer in the Department of Hematologic Malignancies II at the FDA. “There was progressive worsening and symptoms from baseline which peaked around weeks 13 to 17, and approximately 5% to 15% of respondents reported severe visual symptoms at most assessed time points.” At weeks 9 and 13, 34% of patients reported limitations in driving capabilities.

Resulting from these events, over 75% of patients required dose modifications (interruptions or reductions) due to KVA events. While dose modifications are the only effective mitigation strategy identified for reducing ocular toxicities, patients in the trials still experienced severe, recurrent toxicities and clinically significant vision changes despite strict protocol-defined guidelines. According to the FDA, replicating this stringent monitoring and management in a real-world setting may be challenging. Additionally, the reversibility of these ocular findings is not fully understood, and not all patients demonstrated reversal even after stopping treatment.

Dosing Concerns

There is significant concern that the dosages of belantamab mafodotin evaluated in DREAMM-7 and DREAMM-8 were not adequately optimized. Despite different dosing regimens in DREAMM-7 (2.5 mg/kg every 3 weeks) and DREAMM-8 (2.5 mg/kg cycle 1, then 1.9 mg/kg every 4 weeks), both trials showed poor tolerability of the intended doses, characterized by high rates of dose modifications. Fewer than 50% of patients in each trial received their full intended dose by cycle 3.

Limited dose-finding studies prior to DREAMM-7 and DREAMM-8 suggested that lower doses and longer dosing intervals of belantamab mafodotin might maintain efficacy while reducing ocular toxicity. Furthermore, data from a post marketing study, DREAMM-14 (NCT05064358), and pharmacokinetic/pharmacodynamic modeling also indicate that efficacy could be maintained with improved tolerability at lower doses.

Unclear Risk-Benefit Profile

The FDA's evaluation of belantamab mafodotin for relapsed or refractory multiple myeloma involves a critical benefit-risk assessment, considering several key factors. Given the widespread ocular toxicity, the need for frequent dose modifications, and the evidence suggesting that lower doses might be effective and better tolerated, there is uncertainty regarding whether the optimal dosages for belantamab mafodotin have been identified for its proposed indications. This assessment is especially critical given the availability of multiple approved therapies for relapsed/refractory multiple myeloma, including combination regimens, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapies.

Both the DREAMM-7 and DREAMM-8 trials met their primary end point of PFS. DREAMM-7 showed a statistically significant improvement in overall survival (OS), but DREAMM-8 did not. It was likely underpowered for this end point, in the FDA’s assessment.

Additionally, both trials had limited enrollment of US patients, particularly Black patients and those aged 75 and older. This raises concerns about the generalizability of the results to the broader US population.

Sponsor’s Standpoint

Unmet Needs and Limitations of Current Treatments

The sponsor, GSK, highlighted several unmet needs in the multiple myeloma treatment landscape. While BCMA-directed CAR T-cell therapies are approved for early relapsed/refractory multiple myeloma and show high ORRs of 85% to 94%, they are not suitable or accessible for all patients. These therapies require specialized treatment centers, and patients must be able to tolerate bridging therapy and the CAR T treatment itself.

“CAR T therapy…requires patients who are fit enough to tolerate lymphodepleting chemotherapy, and this leaves our older and frailer patients in search for other viable options,” said Paul Richardson, MD, clinical program leader and director of clinical research at Dana-Farber Cancer Center, during the sponsor’s presentation.

Additionally, significant safety concerns with CAR T therapies include cytokine release syndrome, neurotoxicity, prolonged or recurrent cytopenia, severe or life-threatening infections, and hypogammaglobulinemia.

Due to these limitations, there is a significant unmet need for effective, accessible therapies with new mechanisms of action that can provide deep, lasting responses, long-term remission, and improved survival.

Belantamab mafodotin, when given in combination with Vd or Pd, offers a new, highly effective, off-the-shelf anti-BCMA option. A key advantage is its accessibility, as it can be administered in an outpatient setting without requiring hospitalization or specialized care, addressing a critical gap in current treatment options.

Efficacy of Belantamab Mafodotin-Containing Triplets in Multiple Myeloma

Across the DREAMM-7 and DREAMM-8 studies, belantamab mafodotin in combination with other agents demonstrated consistent, statistically significant, and clinically meaningful benefits compared with control regimens. Notably, in the DREAMM-7 study, the belantamab mafodotin-containing triplet of BVd significantly outperformed a triplet including daratumumab (Darzalex), a key early-line treatment for relapsed/refractory multiple myeloma.

Both DREAMM-7 and DREAMM-8 met their primary PFS end points, showing significant improvements for the belantamab mafodotin arms arm. DREAMM-7 demonstrated a 59% reduction in the risk of progression or death (HR, 0.41), with an approximately 2-year improvement in median PFS (36.6 months for BVd vs 13.4 months for DVd. DREAMM-8 showed a 48% reduction in the risk of progression or death (HR, 0.52). While median PFS was not reached at the primary analysis, an updated analysis showed 32.6 months for the belantamab mafodotin arm vs 12.5 months for the comparator arm. Further, a strong PFS benefit favoring belantamab mafodotin was observed across all subgroups, including those with poor prognoses, including those who were lenalidomide-refractory and with high-risk cytogenetics or extramedullary disease.

Regarding OS, DREAMM-7 demonstrated a robust improvement in OS with a statistically significant 42% reduction in the risk of death (HR, 0.58). The sponsor maintained that DREAMM-8 showed a positive trend in OS, with follow-up ongoing.

Both studies showed that belantamab mafodotin triplet therapy led to deeper responses, with at least a doubling of complete response (CR)/stringent CR rates. There were also 2-fold increases in the median durations of response in the belantamab mafodotin arms. Additionally, DREAMM-7 and DREAMM-8 demonstrated a 2.5 to 5 times improvement in measurable residual disease negativity rates for the belantamab mafodotin arms compared with the comparator arms.

Patient-Reported Outcomes

Despite the occurrence of ocular adverse events in patients receiving belantamab mafodotin, their overall quality of life, as measured by the EORTC-QLQ-C30, remained stable over time in both the DREAMM-7 and DREAMM-8 studies. There were no significant differences in quality of life between the belantamab mafodotin treatment groups and the comparator groups.

Regarding vision-related functioning, assessed by the Ocular Surface Disease Index, patients who experienced a "minimally important deterioration" (a noticeable worsening in vision-related function) typically saw improvement or resolution within 6 to 8 weeks in both the BVd and BPd treatment arms. This indicates that symptomatic worsening of visual function was reversible for most patients. The median time for visual function to improve after a minimally important deterioration was approximately 1.5 to 2 months.

Risk-Benefit Management

According to the sponsor, belantamab mafodotin’s overall benefit-risk profile is considered favorable, supported by the 2 independent phase 3 studies. A robust REMS, including ETASU, prescribing information, and an enhanced pharmacovigilance plan, is in place to manage its known risks, particularly ocular events.

“We have developed a comprehensive risk management strategy to ensure safe use of [belantamab mafodotin]. This is based on our vast experience in more than 7500 patients across multiple clinical trials and the earlier postmarketing setting,” said Zeshaan Rasheed, MD, PhD, senior vice president and head of oncology clinical development at GSK. “All of these data have allowed us to better understand the AE profile to best inform patients and health care professionals on the benefits and risks of [belantamab mafodotin] as they navigate the treatment of relapsed/refractory multiple myeloma.”

The sponsor noted that while nearly all patients will experience ocular events, these are generally transient and manageable through dose modifications. Additionally, the sponsor highlighted that ocular events are not a new risk for ADCs, and oncologists are accustomed to collaborating with eye care professionals for such products.

ODAC's Discussion

During the discussion section of the meeting, members of the ODAC expressed concern regarding the dosing strategies and trial design.

“I just think this was a real missed opportunity…. There could have been more dose exploration in those early phase trials, or there could have even been a third arm added to this to one of these trials looking at lower dosages. Certainly, that approach we have seen in many clinical trials across all cancer types where AEs are an issue,” said Vasan.

“This is a very high rate of dose modifications that we have seen with this particular application,” said Bindu Kanapuru, MD, supervisory associate director for therapeutic review in the Division of Hematologic Malignanices II at the FDA, echoing Vasan’s comments.

“I would argue, probably across oncology, we have suboptimal dosing understanding and strategies for a lot of our treatments. I think it's really the unique toxicity here that add some gravity to this question. But I think it's easy to criticize the dosing strategy, but I actually think it's not that different than a lot of other dosing we have across oncology,” said Ravi Madan, MD, ODAC member and senior clinician at the National Cancer Institute.

ODAC members Grzegorz S. Nowakowski, MD, FASCO, professor of medicine and oncology at Mayo Clinic and Daniel Spratt, MD, associate chief scientific officer at University Hospitals Cleveland Medical Center, expressed dissatisfaction at the low US enrollment, expressing skepticism that the results could be applicable for an approval in the US.

REFERENCES:

1. Meeting of the Oncologic Drug Advisory Committee. FDA. July 17, 2025. Accessed July 17, 2025. https://tinyurl.com/bdf6dfuk

2. FDA approves GSK’s BLENREP (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. GlaxoSmithKline plc. August 5, 2020. Accessed July 17, 2025. https://bit.ly/31uAclA

3. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GlaxoSmithKline plc. November 22, 2022. Accessed July 17, 2025. https://tinyurl.com/2uv6hcfd