Regimen confers ‘clinically meaningful’ PFS benefit in relapsed multiple myeloma
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CHICAGO — The addition of belantamab mafodotin to pomalidomide and dexamethasone improved outcomes compared with standard care for patients with relapsed or refractory multiple myeloma, according to data presented at ASCO Annual Meeting.
Researchers reported a 47% improvement in 1-year PFS with the experimental regimen at the time of a prespecified interim analysis of the randomized phase 3 DREAMM-8 trial.
“We evaluated [this combination] in a pan-Canadian study called the ALGONQUIN study, and we saw very impressive results among patients who were more heavily pretreated than those in DREAMM-8,” Suzanne Trudel, MSc, MD, associate professor at Princess Margaret Cancer Centre, told Healio. “Based on those findings, we had a feeling [the regimen] would perform quite well, and it really delivered. The benefit certainly is statistically significant and I would say it also is really clinically meaningful.”
Treatment advances — including triplet or quadruplet regimens that include anti-CD38 antibodies, proteasome inhibitors and immunomodulators — have improved survival outcomes among patients with newly diagnosed multiple myeloma. However, the majority of patients still relapse, according to study background.
Front-line therapy with lenalidomide (Revlimid, Bristol Myers Squibb) also has resulted in a greater proportion of patients who have lenalidomide-refractory disease at first relapse.
“Currently, our approach has been to use those same classes for treatment of relapse, and the results have been suboptimal,” Trudel said. “There is a need for new treatment regimens that incorporate new drugs with novel mechanisms of action.”
The FDA granted accelerated approval to belantamab mafodotin (Blenrep, GSK) — an antibody-drug conjugate comprised of a humanized B-cell maturation antigen (BCMA) monoclonal antibody conjugated to the cytotoxic agent auristatin F via a noncleavable linker — 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 regulatory agency made full approval contingent on confirmed clinical benefit in the randomized phase 3 DREAMM-3 trial. However, results showed belantamab mafodotin monotherapy failed to confer significant improvement in PFS compared with pomalidomide (Pomalyst, Bristol Myers Squibb) plus dexamethasone. This prompted GSK to announce it would begin the process of withdrawing belantamab mafodotin from the U.S. market for that indication.
Trudel and colleagues conducted the randomized phase 3 DREAMM-8 trial to compare two regimens for 302 lenalidomide-exposed patients who had relapsed or refractory multiple myeloma after one line of therapy.
Researchers assigned 155 patients to the BPd regimen, which consisted of belantamab mafodotin plus pomalidomide and dexamethasone.
The other 147 patients received the PVd regimen, which consisted of bortezomib, pomalidomide and dexamethasone.
PFS served as the primary endpoint. Investigators also assessed response and safety.
Median follow-up was 21.8 months (range, < 0.1 to 39.2).
Results showed estimated 12-month PFS rates of 71% (95% CI, 63-78) with BPd vs. 51% (95% CI, 42-60) with PVd (HR = 0.52; 95% CI, 0.37-0.73).
A higher percentage of patients assigned the BPd regimen responded to treatment (77% vs. 72%) and achieved complete response (40% vs. 16%).
OS results remained immature. Median OS had not been reached in either group.
“I’m very optimistic because of the durability of responses we’ve seen,” Trudel said. “At this point, median follow-up is quite short. If the duration of response continues, I think the OS benefit will be more robust with further follow-up.”
More patients in the BPd group experienced grade 3 or higher adverse events (94% vs. 76%).
Ocular toxicity also was higher in the BPd group (any grade, 89% vs. 30%; grade 3/grade 4, 43% vs. 2%). Belantamab mafodotin dose modifications controlled ocular events, Trudel said.
“With protocol-specified dose modification and dose reductions, the discontinuation rate for ocular events was low at 9%,” Trudel said. “When we looked at patients who experienced bilateral decreased visual acuity — an objective measure of ocular toxicity — around 92% demonstrated improvement in symptoms and around 81% returned to baseline at the time of data [cutoff], so that shows this is manageable and reversible.”
The most common non-ocular events in the BPd group were neutropenia, thrombocytopenia and infection. When researchers adjusted for treatment exposure, rates of grade 3/grade 4 neutropenia and thrombocytopenia were equivalent between groups, and the rate of grade 3/grade 4 infections was slightly higher in the BPd group (35% vs. 28%), Trudel said.
“Taken together with the results from DREAMM-7 — which combined belantamab mafodotin with bortezomib and dexamethasone — these data highlight the potential of belantamab mafodotin-containing triplets to address an unmet need for novel regimens to treat patients with multiple myeloma at first relapse,” Trudel said.
Moving forward, there will be opportunities to evaluate belantamab mafodotin in combination with other agents, including bispecifics that target different antigens or anti-CD38 therapies, she added.
Perspective
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Oreofe O. Odejide, MD, FACP
The findings of the DREAMM-8 trial are really striking. They demonstrate that the first-in-class BCMA-targeted antibody-drug conjugate belantamab mafodotin plus pomalidomide and dexamethasone is significantly more effective than pomalidomide, bortezomib and dexamethasone, cutting the risk for disease progression or death by nearly half among patients with relapsed or refractory multiple myeloma.
There have been several advances in the care of patients with multiple myeloma over the past several years that involve inclusion of multiple agents as front-line treatments. Although they have improved outcomes, when patients relapse, they may not respond as well to other anti-myeloma treatments, so there is an unmet need for novel combination therapies in the relapsed setting. Based on these findings, belantamab mafodotin plus pomalidomide and dexamethasone is poised to be a new treatment option for patients with relapsed or refractory myeloma.
Perspective
Back to TopRobert Rifkin, MD, FACP
In multiple myeloma, we’ve always done doublets vs. triplets and triplets always win. Then we do triplets vs. quadruplets and quadruplets always win. But that means patients are getting exposed to lots of things.
This gives patients exposure to something they wouldn’t have seen. That is important, because how many immunomodulatory drugs, proteasome inhibitors or anti-CD38 agents can you have? This also is a great way to target BCMA, which is on almost every myeloma cell, in a way other than a bispecific antibody or chimeric antigen receptor T-cell therapies.
I hope this means we'll have another good BCMA-targeting drug that we now know how to dose. The toxicity appears manageable and the responses are unbelievable. They’re deep and sustained.
Treating the ocular toxicity is a bit hard but, like everything else in oncology, the key to giving this drug is education. Clinicians need to become familiar with it and get comfortable with it. Dose and schedule are what it’s all about. Once someone learns when to hold or reduce a dose, I’d hope they’d be less afraid to use a really effective agent.
Perspective
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Tulio E. Rodriguez, MD
Despite the implementation of highly efficacious induction therapies, typically consisting of triple-agent or quadruple-agent regimens, relapse remains inevitable for most individuals with multiple myeloma. Hence, many patients are exposed to medications encompassing most of the currently available mechanisms of action by the time they experience their first relapse.
The findings from the DREAMM-8 study validate the use of a regimen incorporating the antibody-drug conjugate belantamab mafodotin, offering a novel mechanism of action as an alternative for patients after their first relapse. The study compares two triplet regimens, diverging from the common approach of placing triplets against double-drug regimens frequently reported in myeloma studies. The combination of belantamab, pomalidomide, and dexamethasone (BPd) demonstrated superior PFS compared to the standard of care regimen of bortezomib, pomalidomide, and dexamethasone in patients with multiple myeloma at first relapse and beyond. Most individuals enrolled in the trial have received a median of 3 prior lines of therapies.
Ocular toxicity continues to pose a challenge when using belantamab — most participants in DREAMM-8 who received the agent experienced this side effect. This issue will remain a focal point for further studies.
Additionally, the efficacy of sequentially employing other BCMA-targeted therapies like chimeric antigen receptor T-cells or bispecific T-cell engagers will warrant investigation should this drug receive approval for patients with myeloma patients after first relapse. The study provides valuable insights into the efficacy and safety of BPd for treatment of multiple myeloma after first relapse and beyond and underscores the challenge of belantamab-related ocular toxicity and the potential implications in sequential use of other BCMA-targeted therapies.
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Trudel S, et al. Abstract LBA105. Presented at: ASCO Annual Meeting; May 31-June 4, 2024; Chicago.
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