A comprehensive real-world analysis of belantamab mafodotin treatment in heavily pretreated multiple myeloma patients has demonstrated maintained efficacy despite the drug's withdrawal from commercial use, providing critical insights as combination therapies prepare for market reentry.
The multicenter retrospective study, conducted by the US Myeloma Innovations Research Collaborative, analyzed 81 patients with relapsed refractory multiple myeloma (RRMM) treated with belantamab mafodotin monotherapy between October 2019 and September 2023. The patient population represented a significantly higher-risk cohort than those enrolled in the original pivotal trials, with 67% of patients meeting exclusion criteria for the DREAMM-2 study.
Patient Population and Disease Characteristics
The study included patients with a median age of 67 years who had received a median of 5 prior lines of therapy. Notably, 92% were triple-class refractory, 45% were penta-class refractory, and 15% had previously failed BCMA-directed therapies. More than half (57%) had high-risk cytogenetics, 37% presented with extramedullary disease, and 37% had an Eastern Cooperative Oncology Group performance status of 2-4.
These baseline characteristics represented a substantially more challenging patient population compared to the DREAMM-2 trial, with higher rates of baseline cytopenias (24%), renal insufficiency (43%), and poor performance status that would have excluded them from the original registration study.
Efficacy Outcomes
Despite the high-risk patient characteristics, belantamab mafodotin demonstrated notable clinical activity. The best overall response rate reached 40%, with 15% of patients achieving complete response or better. Partial response and very good partial response were observed in 17% and 7% of patients, respectively.
Response rates varied significantly across patient subgroups, with lower activity observed in those with extramedullary disease (23%), BCMA-refractory disease (17%), and penta-refractory disease (24%). The median time to first response was 21 days, with a median time to best response of 42 days. Among the 32 responding patients, the median duration of response was 13 months.
With a median follow-up of 11.3 months, the median progression-free survival was 5 months and median overall survival was 12 months for the entire population. Patients with high-risk features showed shorter survival outcomes, with median progression-free survival of 5 months for high-risk cytogenetics, 3 months for ECOG 2-4, and 2 months for extramedullary disease.
Safety Profile and Tolerability
Ocular toxicity remained the most significant treatment-related adverse event, affecting 69% of patients with any-grade keratopathy. Grade 3 or worse ocular events occurred in 43% of patients, with a median time to onset of 21 days. Visual decline to less than 20/50 and less than 20/200 occurred in 32% and 21% of patients, respectively.
The median time to improvement to grade 1 or complete resolution of ocular toxicity was 42 days, and importantly, no patients developed permanent blindness. However, ocular toxicity led to treatment discontinuation in 53% of patients, highlighting its impact on treatment tolerability.
Hematologic toxicities included grade 3+ neutropenia (20%), anemia (28%), and thrombocytopenia (31%). Infections occurred in 27% of patients, with 17% experiencing severe infections. Despite the presence of baseline cytopenias and organ dysfunction, there was no significant increase in severe toxicities compared to the original clinical trials.
Predictors of Outcome
Multivariable analysis identified extramedullary disease as the only clinical variable significantly associated with both inferior progression-free survival (HR = 1.97, 95% CI [1.11, 3.50], p = 0.0205) and overall survival (HR = 3.05, 95% CI [1.71, 5.45], p = 0.0002).
The poor outcomes in patients with extramedullary disease likely reflect the aggressive nature of this disease manifestation and the challenges of achieving adequate drug penetration and immune activation in large tumor masses outside the bone marrow compartment.
Clinical Implications
The study's findings are particularly relevant given the recent positive results from the DREAMM-7 and DREAMM-8 phase III trials, which demonstrated significant improvements with belantamab mafodotin combination therapies compared to standard-of-care treatments. These combination approaches may help address the tolerability challenges observed with monotherapy while maintaining efficacy.
The researchers noted that despite several high-risk disease features in their real-world population, belantamab mafodotin demonstrated comparable efficacy to the pivotal DREAMM-2 trial (overall response rate 40% versus 31%; progression-free survival 5 months versus 2.9 months) without significantly increased toxicity risks.
At the time of last follow-up, 58 patients (72%) had experienced disease progression, with common salvage therapies including alkylating agents (23%), selinexor combinations (19%), and T-cell-directed therapies (16%). A total of 60 patients (74%) had died, with 68% of deaths related to disease progression.
The study represents one of the largest real-world analyses of belantamab mafodotin monotherapy and provides valuable insights for clinicians as combination therapies prepare for regulatory approval and clinical implementation. The maintained efficacy in high-risk patients who would have been excluded from clinical trials supports broader therapeutic application, while the detailed toxicity profile informs patient selection and monitoring strategies.
