A new phase 3 randomized controlled trial has evaluated the efficacy and safety of belantamab mafodotin compared to pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma. The DREAMM-3 study, funded by GlaxoSmithKline (GSK), was published in The Lancet Haematology in October 2023.
The open-label study was conducted at 108 academic centers across 18 countries. Its purpose was to assess whether single-agent belantamab mafodotin, an antibody-drug conjugate targeting B-cell maturation antigen (BCMA), could improve progression-free survival compared to the standard combination of pomalidomide and dexamethasone in patients who had received at least two prior lines of therapy.
A total of 325 patients were enrolled and randomized in a 2:1 ratio to receive either belantamab mafodotin (n=218) or pomalidomide plus dexamethasone (n=107). Eligible patients had confirmed multiple myeloma according to International Myeloma Working Group criteria, an Eastern Cooperative Oncology Group performance status of 0-2, and had received at least two prior lines of therapy including lenalidomide and a proteasome inhibitor. Patients were required to have measurable disease and either be non-responsive or have progressive disease on or within 60 days of their last treatment.
Key exclusion criteria included prior pomalidomide or anti-BCMA therapy, allogeneic stem cell transplant, peripheral neuropathy grade 2 or worse, and active plasma cell leukemia. Patients with a history of anti-CD38 monoclonal antibody therapy were capped at 40% of enrollment to ensure a broader patient population.
The study population had a median age of 68 years, with 57% male and 43% female patients. The majority (78%) were White. Patients in the belantamab mafodotin group had received a median of 4 prior lines of therapy versus 3 lines in the pomalidomide-dexamethasone group. About one-third of patients in both groups were refractory to anti-CD38 monoclonal antibodies.
After a median follow-up of 11.5 months, the study did not meet its primary endpoint of improved progression-free survival with belantamab mafodotin. Median progression-free survival was 11.2 months in the belantamab mafodotin group compared to 7.0 months in the pomalidomide-dexamethasone group (hazard ratio 1.03, 95% CI 0.72-1.47, p=0.56). The 12-month progression-free survival rate was 48% for belantamab mafodotin versus 35% for pomalidomide-dexamethasone.
Overall survival data were immature at the time of analysis, with median overall survival of 21.2 months for belantamab mafodotin and 21.1 months for pomalidomide-dexamethasone (HR 1.14, 95% CI 0.77-1.68, p=0.75). Longer follow-up will be needed to determine any potential overall survival benefit.
While the primary endpoint was not met, belantamab mafodotin did show clinical activity. The overall response rate was 41% in the belantamab mafodotin group compared to 36% in the pomalidomide-dexamethasone group. Notably, more patients achieved a very good partial response or better (25% vs 8%) and complete response (10% vs 3%) with belantamab mafodotin. The median duration of response was not reached for belantamab mafodotin versus 8.5 months for pomalidomide-dexamethasone.
The safety profile of belantamab mafodotin was consistent with previous studies. The most common adverse events were thrombocytopenia (34%), blurred vision (40%), and anemia (29%). Grade 3-4 adverse events occurred in 77% of belantamab mafodotin patients versus 74% of pomalidomide-dexamethasone patients. Ocular toxicity, a known side effect of belantamab mafodotin, occurred in 66% of patients but led to treatment discontinuation in only 2%.
Interestingly, the incidence of grade 3 or higher infections was lower with belantamab mafodotin compared to pomalidomide-dexamethasone (13% vs 25%). This suggests belantamab mafodotin may pose less infection risk in this immunocompromised population.
Patient-reported outcomes showed that both treatments were generally well-tolerated, with over 80% of patients reporting no events or only mild/infrequent adverse events at each visit. A greater proportion of belantamab mafodotin patients had meaningful improvement in fatigue scores compared to the pomalidomide-dexamethasone group.
The study had several limitations. The open-label design could have introduced bias, although an independent review committee audit showed good concordance with investigator-assessed responses. The patient population was enriched for White patients due to the countries where recruitment occurred, potentially limiting generalizability. Additionally, as patients were naive to pomalidomide and BCMA-directed therapies, results may not apply to those previously treated with these agents.
Despite not meeting the primary endpoint, the authors concluded that belantamab mafodotin demonstrated clinical activity and a manageable safety profile in this heavily pretreated population. They suggest it could remain a viable anti-BCMA option, particularly for patients in whom increased infection susceptibility is a concern.
The investigators noted that while single-agent belantamab mafodotin did not improve progression-free survival in this trial, its use in combination with standard and novel agents is being investigated in ongoing studies. These include combinations with bortezomib/dexamethasone (DREAMM-6 and DREAMM-7) and pomalidomide/dexamethasone (ALGONQUIN and DREAMM-8).
The potential clinical impact of these findings is nuanced. While belantamab mafodotin did not demonstrate superiority over pomalidomide-dexamethasone, it appears to offer comparable efficacy with some potential advantages. The higher rates of deep responses (very good partial response or better) and lower infection risk could make it an attractive option for certain patients.
For clinicians treating relapsed/refractory multiple myeloma, belantamab mafodotin may be considered as an alternative to pomalidomide-dexamethasone in patients who have exhausted standard therapies like proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies. Its off-the-shelf availability and outpatient administration could be beneficial for patients without access to specialized centers.
However, the ocular toxicity associated with belantamab mafodotin requires careful management. While most events were reversible with dose modifications, patients require close monitoring with regular ophthalmic exams. This may impact the real-world utilization of the drug, particularly in settings where ophthalmology support is limited.
The comparable efficacy but distinct safety profile of belantamab mafodotin versus pomalidomide-dexamethasone highlights the importance of individualized treatment decisions in relapsed/refractory multiple myeloma. Factors such as prior therapies, comorbidities, and patient preferences will likely guide the choice between these options.
Looking ahead, the role of belantamab mafodotin may evolve as results from combination studies become available. If synergistic activity is demonstrated when combined with other agents, it could potentially move into earlier lines of therapy. Additionally, biomarker studies to identify patients most likely to benefit from belantamab mafodotin could help optimize its use.
In conclusion, while the DREAMM-3 trial did not meet its primary endpoint, it provides important data on the efficacy and safety of belantamab mafodotin in relapsed/refractory multiple myeloma. The results support its continued development and use as part of the treatment armamentarium for this challenging disease. As with all advances in multiple myeloma therapy, long-term follow-up and real-world data will be crucial to fully understand the place of belantamab mafodotin in clinical practice.
For the multiple myeloma community, these findings underscore both the progress made in developing novel therapies and the ongoing challenges in improving outcomes for relapsed/refractory patients. They also highlight the complexity of conducting and interpreting randomized trials in heavily pretreated populations, where heterogeneity in prior therapies and disease biology can impact results.
As research continues, the hope is that further refinement of BCMA-targeted approaches, including belantamab mafodotin and emerging modalities like CAR-T cells and bispecific antibodies, will translate into meaningful improvements in survival and quality of life for patients with relapsed/refractory multiple myeloma. The DREAMM-3 results, while not meeting the ambitious goal of superiority over an established regimen, represent another step forward in this ongoing effort.
References
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. doi:10.1016/S2352-3026(23)00243-0
