Despite evidence of durability, belantamab mafodotin misses endpoint for multiple myeloma
Key takeaways:
- Belantamab mafodotin did not significantly improve PFS compared with a combination of pomalidomide and dexamethasone.
- Median duration of response had not yet been reached for belantamab group as of data cutoff.
CHICAGO — Belantamab mafodotin monotherapy did not significantly extend PFS compared with the combination of pomalidomide and dexamethasone among adults with relapsed or refractory multiple myeloma, phase 3 study results showed.
However, data from the randomized trial presented at ASCO Annual Meeting suggest that single-agent treatment with belantamab mafodotin (Blenrep, GSK) may have greater durability than the pomalidomide-dexamethasone regimen, investigators noted.
“While this study did not meet its primary objective or demonstrating PFS superiority, single-agent [belantamab mafodotin] appears to show similar levels of clinical activity to a doublet regimen in relapsed or refractory multiple myeloma,” Katja Weisel, MD, deputy director and professor of hematology/oncology in the department of oncology, hematology and bone marrow transplantation at University Medical Center Hamburg-Eppendorf in Germany, said during a presentation.
Background
Belantamab mafodotin-blmf is an antibody-drug conjugate comprising a humanized B-cell maturation antigen monoclonal antibody conjugated to the cytotoxic agent auristatin F via a noncleavable linker.
The FDA granted accelerated approval for the agent in 2020 for adults with multiple myeloma who received at least four prior therapies, including an immunomodulatory agent, proteasome inhibitor and anti-CD38 antibody. The regulator made full approval for the indication contingent on demonstrating confirmed clinical benefit in the randomized phase 3 DREAMM-3 trial.
The latest results from the DREAMM3 confirmed a previous topline data announcement by the manufacturer showing that belantamab mafodotin failed to confer significant improvement in PFS when compared with pomalidomide (Pomalyst, Bristol Myers Squibb) plus dexamethasone. This prompted a subsequent announcement from GSK acknowledging that it would begin the process of withdrawing belantamab mafodotin from the U.S. market for the accelerated approval indication.
Methodology
The multicenter DREAMM-3 trial evaluated the efficacy and safety of single agent belantamab mafodotin compared with the combination of pomalidomide and dexamethasone as third line or later therapy in adults with relapsed or refractory multiple myeloma.
The study included 325 adults randomly assigned in a 2:1 ratio to receive either belantamab mafodotin (n = 218) 2.5 mg/kg every 3 weeks or pomalidomide (n = 107) 4 mg daily on days 1 to 21 of each 28-day cycle with once-weekly dexamethasone.
PFS served as the study’s primary endpoint. Secondary endpoints included overall response rate, OS, duration of response and safety.
Median follow-up was 11.5 months (range, 0.6-24.2) for the belantamab group and 10.8 months (range, 0-26.4) for the pomalidomide-dexamethasone group.
Key findings
The study did not meet its primary endpoint, with investigators noting that belantamab mafodotin failed to significantly improve PFS compared with the combination of pomalidomide and dexamethasone (HR = 1.03; 95% CI, 0.72-1.47).
However, researchers reported longer median PFS in the belantamab group (11.2 [95% CI, 6.4-14.5] months vs. 7 [95% CI, 4.6-10.6] months).
Investigators reported a 41% overall response rate in the belantamab group vs. 36% among those who received pomalidomide plus dexamethasone.
Median duration of response had not been reached for the belantamab group (95% CI, 17.9 to not yet reached) as of the study’s data cutoff date compared with 8.5 months (95% CI, 7.6 to not yet reached) in the pomalidomide-dexamethasone group.
Researchers noted a 77% (95% CI, 0.64-0.85) probability of maintaining a response to therapy with belantamab mafodotin at 1 year compared with 50% (95% CI, 0.25-0.67) among those who received pomalidomide plus dexamethasone.
Despite lacking overall maturity, investigators reported median OS of 21.2 months (95% CI, 18.7 to not yet reached) for the belantamab group vs. 21.1 months (95% CI, 15.1 to not yet reached) for the pomalidomide-dexamethasone group (HR = 1.14; 95% CI, 0.77-1.68).
Ninety-seven percent of patients in the belantamab group experienced treatment-related adverse events during the study, compared with 93% in the pomalidomide-dexamethasone group.
Eleven patients (11%) in the pomalidomide-dexamethasone group experienced fatal adverse events compared with 16 patients (7%) in the belantamab group.
Treatment discontinuation due to adverse events occurred in 15% of patients who received belantamab vs. 17% in the pomalidomide-dexamethasone group.
Clinical implications
Although it failed to provide significant PFS in the confirmatory DREAMM-3 trial, belantamab mafodotin continues to be investigated in combination with established and novel agents, according to Weisel.
“Patient-related outcomes data indicate that single agent [belantamab mafodotin] is a well-tolerated treatment option with a positive impact on important health outcomes for patients with third-line or greater relapsed or refractory multiple myeloma,” she said.
Perspective
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At face value, this study shows a hazard ratio greater than 1 when you look at the PFS between the two groups. However, the median PFS was longer and the responses were deeper with belantamab mafodotin vs. pomalidomide-dexamethasone.
In the United States, we use pomalidomide-dexamethasone much earlier in the treatment scheme and tend to give it in combinations. The average patient for whom we use belantamab mafodotin in the U.S. is pomalidomide-refractory and would not have been eligible for this study.
At the end of the day, belantamab mafodotin is a good drug. It has a very specific adverse event profile, which makes it complex because we need to work hand-in-hand with our ophthalmologists.
As we look at BCMA assets in myeloma right now, the leading entities are T-cell redirection therapies that require inpatient hospitalization, have very complex toxicity profiles and are primarily relegated to academic centers. Belantamab mafodotin is a drug that can more easily be administered in the community cancer setting. So, I think that although this trial has set back the use of belantamab mafodotin in the U.S., I hope the future of this drug will be better elucidated in some of the ongoing phase 3 studies.
I’m hoping we can get this drug back, because I do think there is an important role for it.
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Weisel K, et al. Abstract 8007. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.