Belamaf Plus Standard Care Shows Progression-Free Survival Benefit in R/R MM

Belantamab mafodotin (belamaf) treatment combined with standard-care therapies showed a progression-free survival (PFS) benefit in patients with relapsed or refractory multiple myeloma (R/R MM). This is according to the results from the phase III DREAMM-7 and DREAMM-8 trials published in the New England Journal of Medicine.^1,2

In March 2023, the U.S. Food and Drug Administration (FDA) withdrew the biologics license for belamaf, which was indicated for the treatment of adults with R/R MM who had received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.³ The FDA revoked the license after the confirmatory DREAMM-3 trial missed its primary endpoint of superior PFS. The trial assessed the efficacy and safety of belamaf as a single agent versus pomalidomide plus low-​dose dexamethasone in patients with R/R MM.⁴

“It is important to have several active agents with a different mechanism of action available for the treatment of patients with MM,” said the first author of DREAMM-8 Meletios Athanasios Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece.

To assess the efficiency of belamaf in combination with standard-care therapies, DREAMM-7 evaluated belamaf, bortezomib, and dexamethasone (BVd) compared with daratumumab, bortezomib, and dexamethasone (DVd) in 494 patients who had progression of MM after at least one line of therapy.¹ The primary endpoint was PFS, and key secondary endpoints included overall survival (OS), response duration, and measurable residual disease (MRD)-negative status. The study randomly assigned 243 patients to receive BVd (median age = 65; 53% male) and 251 to DVd (median age = 64; 57% male).

At a median follow-up of 28.2 months, the median PFS was 36.6 months in the BVd group (95% CI 28.4 to not reached) and 13.4 months in the DVd group (95% CI 11.1-17.5), with a hazard ratio (HR) for disease progression or death of 0.41 (95% CI 0.31-0.53; p<0.001). OS at 18 months was 84% and 73% in the BVd and DVd groups, respectively. The median response duration was not fully mature, as more than half the responses in the BVd group were ongoing. Still, an analysis favored BVd in the restricted mean response duration (p<0.001). A complete response (CR) or better plus MRD-negative status occurred in 25% and 10% of the BVd and DVd groups, respectively. Most patients had grade 3 or higher adverse events (AEs) — 95% with BVd and 78% with DVd. Ocular events occurred more with BVd than DVd, at 79% versus 29%. Belamaf dose modifications managed such events, and cases of visual acuity typically resolved.

BVd proved superior to DVd in patients with R/R MM after at least one prior line of therapy, said the corresponding author of DREAMM-7 María-Victoria Mateos, MD, PhD, of the University Hospital of Salamanca in Spain. Dr. Mateos highlighted the following clinical implications of the results: “For patients with R/R MM who are naïve to anti-CD38 and eligible for anti-CD38 plus Vd (standard of care), belamaf plus Vd may be preferable based on the DREAMM-7 results. Most relapsed patients will have prior exposure to anti-CD38 with varying sensitivity and refractoriness. In such cases, BVd could be a suitable option. Elderly patients currently receiving firstline treatment with DaraRd [daratumumab, lenalidomide dexamethasone] will likely be bortezomib naïve at first relapse, making BVd an excellent choice.”

Meanwhile, DREAMM-8 compared belamaf, pomalidomide, and dexamethasone (BPd) with pomalidomide, bortezomib, and dexamethasone (PVd) in 302 lenalidomide-exposed patients with R/R MM after at least one line of therapy.² The primary endpoint was PFS. The researchers also assessed disease response and safety. The study randomly assigned 155 patients to receive BPd (median age = 6; 64% male) and 147 to PVd (median age = 68; 56% male).

At a median follow-up of 21.8 months, the 12-month estimated PFS with BPd was 71% (95% CI 63-78) and 51% with PVd (95% CI 42-60) with an HR for disease progression or death of 0.52 (95% CI 0.37-0.73; p<0.001). Data on OS were immature. A partial response or better to treatment was achieved by 77% of the BPd group and 72% in the PVd group, while 40% and 16%, respectively, reached a CR or better. Grade 3 or higher AEs occurred in 94% and 76% of the BPd and PVd groups, respectively. Ocular events occurred commonly in the BPd group, at 89% versus 30% in the PVd group. Belamaf dose modification managed such events. Ocular events led to treatment discontinuation in 9% of the BPd group and none in the PVd group.

BPd “is pertinent in today’s clinical practice for patients with myeloma,” Dr. Dimopoulos said. If belamaf regains FDA approval, BPd will be used because “it is easy to administer as a short outpatient intravenous infusion and as oral treatment. It is well suited for patients who are not eligible for CAR-T cell therapy and for whom treatment with bispecific monoclonal antibodies may be considered too toxic.”

Limitations to both trials included the lack of racial diversity with mainly white patients enrolled. The DREAMM-7 authors noted a potential for bias from the open-label design and a reporting bias of ocular events toward BVd because of the higher frequency of ocular examinations in this group. The DREAMM-8 authors noted the relatively short follow-up, limiting the interpretation of survival outcomes. The lack of approval for PVd within the U.S. was a potential limitation of the DREAMM-8 trial for this region.

If belamaf regains FDA approval, “it will serve as an additional option for our patients with R/R MM, alongside other B-cell maturation antigen (BCMA)-targeted therapies and conventional options like anti-CD38 with Kd [carfilzomib-​​dexamethasone] and pomalidomide-​based combinations,” Dr. Mateos said. “Patient- and disease-specific factors should be considered to make the right choice. The main advantages of belantamab-based combinations include being an off-the-shelf drug, no need for premedication, no hospitalization required, lower risk of infections compared to other BCMA-targeted therapies, and no impact on T-cell fitness.”

Any conflicts of interest declared by the authors can be found in the original articles.

References

1. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma [published online ahead of print, 2024 June 1]. N Engl J Med. doi: 10.1056/NEJMoa2405090.
2. Dimopoulos MA, Beksac M, Pour L, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma [published online ahead of print, 2024 June 2]. N Engl J Med. doi: 10.1056/NEJMoa2403407.
3. U.S. Food & Drug Administration. FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. March 20, 2023. Accessed July 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma.
4. Dimopoulos MA, Hungria VTM, Radinoff A, et al. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023;10(10):e801-e812.