After Setbacks, FDA Approves Belantamab Mafodotin Combo in Myeloma

The FDA has approved belantamabmafodotin (Blenrep) in combination with bortezomib (Velcade) and dexamethasone (BVd) for the treatment of patients with multiple myeloma who have received at least 2 prior lines of therapy.¹

This approval is supported by data from the phase 3 DREAMM-7 (NCT04246047) trial.

In the DREAMM-7 study, BVd was compared against daratumumab (Darzalex) in combination with bortezomib and dexamethasone (DVd) in patients who had received at least 1 prior therapy. The trial enrolled 494 participants. The updated analysis, with a median follow-up of 39.4 months, revealed a statistically significant overall survival benefit for the BVd arm (median OS not reached) compared to the DVd arm (median OS, 41.0 months), with a hazard ratio (HR) of 0.58 (95% CI, 0.43–0.79; P =.0002). Furthermore, BVd demonstrated greater than double the minimal residual disease (MRD) negativity rates in patients achieving a complete response or better (25% vs 10%) and a significantly longer median duration of response (40.8 months vs 17.8 months).

The journey to belantamab mafodotin’s approval has been long and marked with several setbacks. The agent was first granted accelerated approval by the FDA in August 2020 in patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.² This approval was supported by the DREAMM-2 study (NCT03525678).

In November 2022, the FDA requested that GSK, the sponsor, withdraw belantamabmafodotin from the market, as data from the confirmatory DREAMM-3 study (NCT04162210) did not meet requirements for accelerated approval.³

In November 2024, the FDA accepted the biologics license application (BLA) of BVd and BPd and set the Prescription Drug User Fee Act target action date as July 23, 2025.⁴ In July 2025, the FDA’s Oncologic Drugs Advisory Committee (ODAC) convened to discuss the BLA. They voted that the benefit-risk profile of belantamabmafodotin-based combinations was unfavorable for the treatment of early relapsed/refractory multiple myeloma at its proposed dosage.⁵

"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, during the meeting. "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."

The main concerns with belantamabmafodotin from the FDA’s standpoint were ocular toxicities and dosing. While ocular toxicities are a known risk with other antibody-drug conjugates (ADCs), this level of toxicity is not seen with other multiple myeloma treatments.

Regarding dosing, there was significant concern that the dosages of belantamab mafodotin evaluated in DREAMM-7 and DREAMM-8, assessing belantamab mafodotin with pomalidomide and dexamethasone (BPd), 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 belantamabmafodotin 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.

However, several unmet needs persist in the myeloma treatment landscape. While BCMA-directed CAR T-cell therapies are approved for early relapsed/refractory multiple myeloma and show high response rates 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.

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.

In July 2025, the European Union approved BPd and BVd in this patient population.⁶

REFERENCES:

1. Blenrep approved by US FDA for use in treatment of relapsed/refractory multiple myeloma. GSK. October 23, 2025. Accessed October 23, 2025. https://tinyurl.com/arpwwz7f

2. FDA granted accelerated approval to belantamabmafodotin-blmf for multiple myeloma. News release. US FDA. August 5, 2020. Accessed October 7, 2025. https://tinyurl.com/26x4j76f 

3. GSK provides an update on Blenrep (belantamabmafodotin-blmf) US marketing authorization. News release. GSK. November 22, 2022. Accessed October 7, 2025. https://tinyurl.com/2bjcenr3 

4. Blenrep combinations accepted for review by the US FDA for the treatment of relapsed/refractory multiple myeloma. News release. GSK plc. November 25, 2024. Accessed October 7, 2025. https://tinyurl.com/45hh2e38 

5. Meeting of the Oncologic Drug Advisory Committee. FDA. July 17, 2025. Accessed October 7, 2025. https://tinyurl.com/bdf6dfuk 

6. Blenrep (belantamabmafodotin) combinations approved in EU for treatment of relapsed/refractory multiple myeloma. News release. GSK. July 24, 2025. Accessed October 7, 2025. https://tinyurl.com/2tnym3w4