The first-in-class drug belantamab mafodotin (Blenrep) has been granted an accelerated approval by the US Food and Drug Administration (FDA) for use in the treatment of relapsed and refractory multiple myeloma in patients who have already tried other therapies.
This follows a recommendation for approval on July 15 by an FDA advisory committee, which voted 12-0 in favor of the drug's benefits outweighing risks in this patient population.
The product has a novel mechanism of action: it targets B-cell maturation antigen (BCMA), a protein that is present on the surface of virtually all multiple myeloma cells but is absent from normal B cells.
The drug had already received an FDA breakthrough therapy designation, which facilitates the development of drugs that have shown clinical promise for conditions in which there is significant unmet need.
Belantamab mafodotin was recommended for conditional marketing approval in the European Union on July 24 and was accepted into the European Medicines Agency (EMA) PRIME scheme for medicines that have potential to address unmet medical needs.
The new drug is indicated for patients with refractory or relapsed multiple myeloma who have already tried treatment with one of the three major classes of drugs, namely, an immunomolatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
For patients who no longer respond to these drugs, the outlook is bleak, the EMA comments. There is an unmet medical need for new treatments that improve survival of these patients beyond the currently observed 3 months or less.
"While treatable, refractory multiple myeloma is a significant clinical challenge with poor outcomes for patients whose disease has become resistant to the current standard of care," commented Sagar Lonial, MD, chief medical officer of the Winship Cancer Institute of Emory University in Atlanta, Georgia, chair of the Department of Hematology and Medical Oncology at Emory, and a principal investigator for the clinical trial that led to the approval.
"Due to the limited options currently available, these patients are often re-treated with drugs from the same classes after they relapse, which is why the approval of belantamab mafodotin, the first anti-BCMA therapy, is significant for both patients and physicians alike,” he said.
The product is an antibody-drug conjugate that combines a monoclonal antibody that targets BCMA with the cytotoxic agent maleimidocaproyl monomethyl auristatin F (mcMMAF). It homes in on BCMA on myeloma cell surfaces. Once inside the myeloma cell, the cytotoxic agent is released, leading to apoptosis, the programmed death of the cancerous plasma cells.
Approval Based on Response Rates
The accelerated approval from the FDA and the recommendation for conditional approval from the EMA are based on results for overall response rate and duration of response from a phase 2, open-label, randomized, two-arm study known as DREAMM-2. Both agencies said that they are waiting for further data on clinical benefit from ongoing trials.
The DREAMM-2 study investigated the efficacy and safety of two doses of belantamab mafodotin in multiple myeloma patients whose disease was still active after three or more lines of therapy and who no longer responded to treatment with immunomodulatory drugs, proteasome inhibitors, and an anti-CD38 monoclonal antibody.
Six-month results from this study were published in The Lancet Oncology in December. The overall response rate was 31% in the cohort given a 2.5-mg/kg dose of the drug; 30 of 97 patients had outcomes that met the study's positive threshold.
Another 99 patients in DREAMM-2 received a dose of 3.4 mg/kg, which was judged to have a less favorable safety profile.
The median duration of response (DoR) had not been reached at the 6-month analysis, but for 73% of responders, DoR was ≥6 months.
The most commonly reported adverse events (≥20%) were keratopathy (changes in the cornea), decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue, the manufacturer notes.
One of the most common adverse events with this product affects the eyes.
Ocular adverse reactions occurred in 77% of the 218 patients in the pooled safety population and included keratopathy (76%), changes in visual acuity (55%), blurred vision (27%), and dry eye (19%).
Corneal adverse events were monitored with eye exams prior to each dose, allowing dose reductions or interruptions as appropriate, the manufacturer noted. Patients also used preservative-free eyedrops. Keratopathy leading to treatment discontinuation affected 2.1% of patients in the 2.5-mg/kg cohort.
Because of this ocular toxicity, the company has set up a risk evaluation and mitigation strategy (REMS) for the product. This requires education for all physicians who prescribe the product as well as their patients regarding the ocular risks associated with treatment. It also requires monitoring that includes regular ophthalmic examinations. Information about the scheme can be found at www.blenreprems.com.
At the FDA advisory committee meeting last month, one of the panelists, Gita Thanarajasingam, MD, an assistant professor of medicine at the Mayo Clinic, in Rochester, Minnesota, said belantamab appeared to be well tolerated but for ocular toxicity. Physicians need to acknowledge how severe this risk may be for patients while keeping in mind that belantamab still may be more tolerable for some people than current treatments, she said.
"It's reasonable to leave open the option for decision making. Patients can express their values and preferences," Thanarajasingam said. "There's adequate, albeit not complete, information to guide this risk-benefit discussion in a REMS program."
Another panelist, Heidi D. Klepin, MD, a professor at Wake Forest University Health Sciences, Winston Salem, North Carolina, agreed that the informed consent process should allow patients "to choose whether the trade-off is worth it to them" with belantamab.
The article was originally published on Medscape.com.