Summary
Belantamab mafodotin is an immunoconjugate targeting B-cell maturation antigen, a pathway shown to be important for the growth and survival of myeloma cells. The drug is currently under investigation for the treatment of multiple myeloma, the second most common blood cancer. It was granted Breakthrough Therapy designation from the FDA in 2017 for this indication, and then priority review in January 2020.
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Original Article
Encouraging Findings for Belantamab Mafodotin in Treating Multiple Myeloma
Oncology Times
By Sarah DiGiulio
Belantamab mafodotin is an immunoconjugate targeting B-cell maturation antigen, a pathway shown to be important for the growth and survival of myeloma cells. The drug is currently under investigation for the treatment of multiple myeloma, the second most common blood cancer. It was granted Breakthrough Therapy designation from the FDA in 2017 for this indication, and then priority review in January 2020.
While several treatments for multiple myeloma exist, some patients become refractory to these therapies after using them. However, recent clinical trial results that show efficacy and an acceptable safety profile for belantamab mafodotin for patients with multiple myeloma are promising, said Ajay K. Nooka, MD, MPH, FACP, Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and part of the hematology care team at Winship Cancer Institute.
“In all likelihood, belamaf [belantamab mafodotin] may be the first B-cell maturation antigen-targeting agent in myeloma to be approved,” he noted.
The drug works by binding to B-cell maturation antigen on plasma cells and delivering the microtubule-disrupting agent monomethyl auristatin F moiety, which induces apoptosis, enhances antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, and releases markers of immunogenic cell death, Nooka explained.
The research group recently presented two abstracts at the 2020 ASCO Annual Meeting for the drug as both a single-agent therapy and combination therapy.
Additional data from phase 2 trial for single-agent belantamab mafadotin promising
One abstract reports longer follow-up data for the ongoing open-label, two-arm, phase II DREAMM-2 study (Abstract 8536). Initial data from that trial were published online in The Lancet late last year (2019; doi.org/10.1016/S1470-2045(19)30788-0).
The trial included patients with relapsed or refractory multiple myeloma who had been treated with at least three prior lines of therapy and were refractory to either an immunomodulatory agent or a proteasome inhibitor—or refractory and/or intolerant to an anti-CD38 monoclonal antibody. This analysis included 97 patients receiving the drug at a dose of 2.5 mg/kg and 99 patients receiving the drug at a dose of 3.4 mg/kg.
The data showed that the overall response rates were 32 percent for the group receiving the 2.5 mg/kg dose and 35 percent for the group receiving the 3.4 mg/kg dose. Median duration of response was 11 and 6.2 months, respectively. Overall survival was 14.9 months for the lower-dose group and 14 months for the higher-dose group at a median follow up of 13 months.
“The toxicities are worth a mention,” Nooka said. The patients had received a median of six lines of prior therapy, but grade 3 or 4 hematological toxicities related to thrombocytopenia and anemia were seen in 20 percent of the patients. Also corneal events were seen in close to 40 percent of patients, but no patients lost vision because of these effects. And overall, 10 percent of patients had permanent discontinuation of belantamab mafodotin due to adverse events.
“The data show all toxicities are manageable, especially the corneal toxicities which improve upon withholding or discontinuation of treatment,” Nooka said. “Most impressively, we have seen activity of the drug even upon withholding the drug.”
Despite the learning curve for understanding and managing corneal toxicities being steep, he added: “We have prevailed before and delivered myeloma drugs with known toxicities safely and don’t see a reason why we cannot deliver belamaf safely.”
Data for belantamab mafadotin used as combination therapy also promising, but larger trials are needed
The other abstract reported data from the phase I/II ongoing, two-part, two-arm randomized DREAMM-6 study, which is evaluating the safety, tolerability, and clinical activity of belantamab mafodotin in combination with either bortezomib and dexamethasone or lenalidomide and dexamethasone in patients previously treated with at least one prior therapy (Abstract 8502). Interim data for 18 patients in the first group (those receiving belantamab mafodotin in combination with bortezomib and dexamethasone) was reported in this abstract.
At the time of analysis, the patients had been receiving the treatment for 18.2 weeks. Overall response rate was 78 percent—with half the patients showing a very good partial response. All patients reported corneal events (grade 2 or 3); grade 3 or higher keratopathy was reported in 10 patients. Thrombocytopenia was also a noteworthy adverse event occurring at grade 3 or higher in 11 patients.
The trial needs longer follow up to better understand the efficacy and safety profile of this drug combination, Nooka stated (median duration of response had not been met at the time of the reported analysis)—but these preliminary results are promising and showed no new signals for toxicity.
A phase III trial that will compare the belantamab mafodotin, bortezomib, and dexamethasone treatment with just bortezomib and dexamethasone is currently recruiting patients.
A drug with a new mechanism of action against multiple myeloma is exciting
The multiple myeloma treatment landscape has changed over the last couple of decades with many more drug options approved and available to treat patients with relapsed or refractory multiple myeloma and patients living much longer after being diagnosed, said C. Ola Landgren, MD, PhD, a hematologic oncologist and Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, who was not involved in the research or development of belantamab mafodotin. But because many of those drugs are used in combination treatments and because none are curative, “many patients still run out of options. There is a huge unmet need,” he noted.
The results from these two abstracts, as well as previously published data suggest that this drug does have efficacy against multiple myeloma with overall response rates in line with other drugs approved in this space. That data is exciting because belantamab mafodotin has a new mechanism of action—it’s the first one to target BCMA, Landgren noted. “So I think this drug will be important to move forward from a regulatory perspective.”
But like for any new drug, efficacy and safety need to be balanced. These two trials continue to show that patients experience high rates of keratopathy and blurry vision, which might make this drug more attractive as a later-line therapy option and less attractive for earlier use, he said.
It’s also encouraging that the DREAMM-6 data showed higher efficacy when the drug was used as a combination therapy (though that should be expected since it was used with drugs already approved for this indication), according to Landgren, but that trial only included 18 patients and more data is needed to better understand true efficacy rates.
“This [drug] could be a game changer for daratumamab-refractory patients,” added Nitya Nathwani, MD, Assistant Clinical Professor of Department of Hematology & Hematopoietic Cell Transplantation at City of Hope. (Nathwani is not involved in the development of the drug.) The toxicities are noteworthy, but manageable, he noted. “Fortunately, there were no grade 4 events; permanent loss of vision was not reported.”
Sarah DiGiulio is a contributing writer.