An FDA advisory committee recommended approval of belantamab mafodotin, a first-in-class BCMA-targeted therapy, to treat patients with multiple myeloma refractory to several other drugs. Agency officials had raised concerns about the high incidence of corneal disease linked to the therapy, but clinical experts felt that the demonstrated benefits outweighed the risks of ocular toxicity.
An FDA advisory committee voted unanimously on July 14 in favor of approving belantamab mafodotin (Blenrep; GlaxoSmithKline), a first-in-class B-cell maturation antigen (BCMA)–targeted therapy, to treat patients with multiple myeloma refractory to several other drugs. Because BCMA is universally expressed on the surface of malignant plasma cells but not outside of the B-cell lineage, BCMA has emerged as a leading therapeutic target among myeloma drug developers.
FDA officials had raised concerns about the high incidence of corneal disease in clinical trials of the therapy, an antibody–drug conjugate (ADC) composed of a BCMA-directed monoclonal antibody bound to a microtubule-disrupting agent called monomethyl auristatin F. Yet, every member of the agency's 12-person advisory panel agreed that the drug's demonstrated benefits outweighed the ocular-toxicity risks for adults with relapsed/refractory multiple myeloma who have received at least four therapies including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.
“It's clear that this is an active agent and that the toxicity is not life-threatening,” said the committee chair, Philip Hoffman, MD, of the University of Chicago Medical Center in Illinois, before the vote. “In many instances, it is comfort-threatening, but I think patients are willing to take this risk.”
The FDA regularly taps outside experts—in this case, oncologists, hematologists, ophthalmologists, patient advocates, and a biostatistician—to help review marketing applications. Although the agency needn't follow committees' recommendations, it usually does so, especially when committee members overwhelmingly agree; a decision on belantamab mafodotin is anticipated in the next several weeks. The European Medicines Agency's Committee for Medicinal Products for Human Use also voted in the drug's favor in July, with approval expected in September.
In the phase II DREAMM-2 trial, 31 of 97 patients who received 2.5 mg/kg of belantamab mafodotin achieved an overall response: 18 patients had a very good partial response or better, including seven with complete or stringent complete responses, according to 13-month follow-up data presented at the American Society of Clinical Oncology annual meeting in May.
Cross-trial comparisons with the only other treatment approved for patients with triple-class refractory multiple myeloma, the XPO1 inhibitor selinexor (Xpovio; Karyopharm Therapeutics) plus low-dose dexamethasone, suggest that belantamab mafodotin yields more durable responses than the selinexor regimen—a median of 11 months versus 4.4 months. Median overall survival was also longer for belantamab mafodotin than selinexor: 13.7 months versus 8.6 months, respectively. Plus, hematologic side effects were less common in the belantamab mafodotin trial.
However, most patients who received the anti-BCMA therapy developed keratopathy, which causes epithelial changes in the cornea that can lead to blurred vision and dry eyes. This problem is common in experimental ADCs with auristatin payloads, but not one typical of other myeloma treatments, including selinexor. Although the mechanism of ocular toxicity is not completely understood, some research points to ADCs damaging stem cells in the corneal epithelium.
DREAMM-2 investigators tried prophylactic steroid eye drops in a subset of patients, but they had no impact on the frequency or severity of corneal damage. Only dose modifications in tandem with lubricating eye drops seemed to help, and with careful management most cases of visual impairment proved temporary.
“The toxicities are unusual,” notes Nina Shah, MD, of the University of California, San Francisco, who was not involved in reviewing or testing the therapy, “and, for us as a myeloma community, we just aren't used to it.”
But trial investigator Rakesh Popat, MBBS, PhD, of University College London, UK, points out that “there's this regular, predictable pattern that happens in the majority of the patients—and as long as you're being careful, you often don't see this severe eye toxicity because you're interrupting the dose, waiting for it to get better, and redosing the patients.” Plus, as clinicians explore various dosing levels and treatment schedules, the likelihood of debilitating vision problems should decrease, Popat says. –Elie Dolgin