BLENREP: BALANCING BENEFIT-RISK

July 18, 2025.

Yesterday the FDA Oncology Drug Advisory Committee (ODAC) voted NO on the benefit-risk favorability of belantamab mafodotin (BLENREP) in combination with bortezomib-dexamethasone (DREAMM-7 study) or pomalidomide-dexamethasone (DREAMM-8 study) for relapsed myeloma patients.

The Agency began the meeting by reminding the committee of the evidentiary standard required for approval, emphasizing the need for a careful benefit-risk assessment. FDA representatives also clarified that a Risk Evaluation and Mitigation Strategy (REMS)—a drug safety program reserved for medications with significant safety concerns—cannot substitute for an unfavorable benefit-risk profile. Following these remarks, the committee engaged in four hours of rigorous discussion. The main points are summarized below:

This is clearly an active agent

Both studies successfully met their primary endpoint of Progression-Free Survival (PFS):

· DREAMM-7: HR = 0.41 (95% CI 0.31, 0.53); p < 0.0001

· DREAMM-8: HR = 0.52 (95% CI 0.37, 0.73); p = 0.0001

Source: July 17 BLENREP ODAC Meeting

Moreover, Overall Survival (OS) reached statistical significance in DREAMM-7 (HR = 0.58, 95% CI 0.43, 0.79; p = 0.0005), though OS did not reach significance for DREAMM-8, which was not powered for that endpoint.

Source: July 17 BLENREP ODAC Meeting

Additionally, deeper treatment responses were seen in the belantamab mafodotin arms compared to controls, with an absolute increase of ≥ Very Good Partial Response (VGPR) by 20% for BVd vs. DVd (DREAMM-7) and by 25% for BPd vs. PVd (DREAMM-8). Minimal residual disease (MRD) negativity rates were two- to four-fold higher in the belantamab mafodotin groups.

Source: July 17 BLENREP ODAC Meeting

Deeper responses have been associated with improved outcomes, particularly MRD negativity which has been recently recognized as an early endpoint in myeloma clinical trials to support accelerated approvals of new treatments.

Ocular Toxicity remains a concern

A notable proportion of patients experienced significant changes in visual acuity during the trials.

Source: July 17 BLENREP ODAC Meeting

It is important to note:

· 20/50 vision is often the minimum standard for unrestricted driving in many US states.

· 20/200 vision is considered legally blind.

Source: July 17 BLENREP ODAC Meeting

The sponsor highlighted that these visual changes were generally transient, returning to baseline with sufficient follow-up, and that no cases of permanent, bilateral vision loss have been documented. Multiple measures have been put in place such as an easy-to-use and sensitive KVA tool to gain timely intervention and dose modification guidance. ODAC panel members raised concerns regarding potential barriers to accessing ophthalmology specialists, particularly within community healthcare settings.

Ongoing concerns about dosing

The Agency repeatedly raised dosing concerns during the development of belantamab mafodotin and reminded the ODAC yesterday that dosage selection for DREAMM-7 and DREAMM-8 was based on limited data.

Source: July 17 BLENREP ODAC Meeting

The FDA has long questioned the 2.5 mg/kg dose, encouraging exploration of the lower 1.9 mg/kg dose and/or alternate dosing intervals, which, based on preliminary data, seem to offer similar efficacy with improved tolerability.

Source: July 17 BLENREP ODAC Meeting

The sponsor has indicated that dose optimization is being investigated. In the ongoing DREAMM-10 trial, belantamab mafodotin is administered at 1.9 mg/kg every 8 weeks for 24 weeks, then every 12 weeks thereafter. DREAMM-14 also evaluates lower doses.

The FDA stressed that establishing a safe and effective dose is crucial prior to approval, citing concerns that post-marketing dose adjustments may expose many patients to poorly tolerated doses and present logistical challenges for trial design and benefit-risk assessment.

Relevance to current US patients is uncertain

The Agency underscored that the clinical relevance of DREAMM-7 and DREAMM-8 to today’s US myeloma patients may be limited:

· US participants comprised less than 5% of subjects in each study.

· The studies included virtually no Black participants.

· Almost no participants were over 75 years old.

This enrollment situation was described as “missed opportunity” multiple times during the meeting.

Additionally, the comparators used may not accurately reflect current standard regimens in the US. In DREAMM-7, the DVd regimen may not be appropriate for second-line and beyond, especially since most US patients now receive four-drug regimens containing an anti-CD38 antibody in first-line. In DREAMM-8, the PVd comparator is not approved and its used limited in the US. These factors likely contributed in part to the low enrollment of US patients. Increasing US representation in global randomized trials is now a priority for the FDA and was a major factor in the negative ODAC vote for STARGLO earlier this year.

Conclusion

The July 17 ODAC’s decision may delay US access to a new agent that offers substantial survival benefits for myeloma patients, several of whom shared powerful testimonies at the meeting. There remains a crucial need for off-the-shelf therapies like belantamab mafodotin, especially in rural and underserved communities. While the FDA could still approve the drug — and we will know more at the PDUFA scheduled for July 23 — this ODAC meeting sent a clear message: more robust dose exploration and enrollment more representative of US patients are essential for regulatory approval of novel agents going forward.