The anti-BCMA belantamab mafodotin (belamaf), plus pomalidomide and dexamethasone (Pd), produced durable responses in patients with relapsed or refractory multiple myeloma (MM), but adverse ocular effects were common though manageable, researchers reported in a new paper in Nature Medicine.
The results of the phase I/II ALGONQUIN trial — mainly intended to evaluate dose-limiting toxicities, identify a recommended phase II dose, and assess overall response rates (ORRs) — are reason to hold out promise for the drug, which was withdrawn from marketing after its phase III results as a single agent didn’t meet its primary endpoint.
“The results demonstrated that the combination of belantamab mafodotin plus Pd has promising efficacy for patients with relapsed MM, comparable with the anti-BCMA bispecific antibodies and ide-cel [chimeric antigen receptor] T-cell therapy, and an improvement over other Pd-based combinations,” said Suzanne Trudel, MD, MSc, lead investigator and professor of medicine at the University of Toronto in Canada. “The main clinical challenge, however, is undoubtedly belamaf-related ocular toxicity. Regular monitoring and examinations with an eye care professional are essential.”
In the trial, researchers identified the recommended phase II dose as 2.5 mg/kg every eight weeks, after balancing efficacy and tolerability. At this dose, which 38 patients received, the ORR was 85.3%, with at least a very good partial response seen in 75.7% of patients and an estimated two-year progression-free survival (PFS) of 52.8% at a median follow-up of 13.9 months.
Ocular adverse events (AEs) were common; a decrease in best corrected visual acuity was seen in 71.1% and keratopathy in 65.8%. Fatigue was also seen in 57.9% of patients and infections in 47.4% — 7.9% of which were at least grade 3. About 40% of patients experienced thrombocytopenia.
The corneal toxicities that have been reported with the drug have been found to be reversible with dose holds, Dr. Trudel said. No patients receiving the recommended phase II dose discontinued because of ocular effects, and no irreversible loss of complete vision has been reported, researchers said.
The corneal toxicities that have been reported with the drug have been found to be reversible with dose holds.
The patients in the study had tried a median of three regimens, and more than half (55.2%) were triple-class refractory, researchers reported.
“Once patients are triple-class exposed or refractory, outcomes with currently and widely available therapeutics are almost universally poor,” Dr. Trudel said.
But the combination with Pd might be effective for these patients, the findings suggest. In the pivotal single-agent trial that did not meet its PFS endpoint because of early progression, the drug showed a durable response, and the median duration of response was not reached at the time of the trial’s analysis.
“It has been postulated that the durability of response observed in the DREAMM studies reflects the ability of belamaf to induce immunogenic cell death,” the researchers wrote. “It seems logical, therefore, that incorporating belamaf in combination with other active anti-MM agents may induce more rapid disease control to mitigate early progression while extending the clear duration of response benefit. Indeed, the results of the ALGONQUIN study demonstrate a doubling of responses and a corresponding improvement of PFS.”
But the regimen would require vigilance, especially in light of the eye involvement, Dr. Trudel said.
“Clinicians must be knowledgeable in interpreting ocular examination results, as well as managing ocular toxicity with respect to both symptom awareness and belamaf dose modifications,” she said. “It is important to note, however, that corneal AEs are reversible and that longer dosing intervals may represent a significant step forward in mitigating the corneal toxicities of belamaf.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Trudel S, McCurdy A, Louzada ML, et al. Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial. Nat Med. 2024;30(2):543-551.
Perspectives
Belamaf, a BCMA-targeting antibody-drug conjugate, was granted accelerated approval by the U.S. Food and Drug Administration after the phase II DREAMM-2 study in patients with relapsed or refractory MM (R/R MM) and showed a 32% ORR with a median duration of response of 12.5 months.1 However, it was later withdrawn from the U.S. market due to failure to demonstrate superiority in PFS compared to Pd in the phase III DREAMM-3 trial.
Considering the benefit of Pd plus immunotherapy, particularly in patients previously exposed to anti-CD38 monoclonal antibodies, the ALGONQUIN trial evaluates the safety and efficacy of belamaf in combination with Pd for R/R MM treatment.2
Alternative BCMA-targeted strategies include bispecific antibodies and CAR T-cell therapy. Despite their high efficacy, these approaches pose challenges, such as the need for treatment in specialized centers as a result of immune-related side effects like cytokine release syndrome and neurotoxicity. CAR T-cell therapy faces additional obstacles, including wait times for T-cell production, limited capacity, and manufacturing failures, which make it unsuitable for rapidly progressing patients. Both bispecific antibodies and CAR T-cell therapy are associated with a high rate of grade 3-4 infections, affecting more than 70% of patients, compared to the 21% observed in this study. An off-the-shelf belamaf regimen provides an attractive alternative, with its relatively low infection rate and infrequent need for infusion.
The phase III DREAMM-8 confirmatory study comparing Pd plus belamaf to Pd plus daratumumab is underway. Recent phase III data from the DREAMM-7 trial demonstrated a significant PFS benefit with belamaf plus bortezomib and dexamethasone (BorDex) compared to daratumumab plus BorDex in R/R MM.3 Belamaf combinations are expected to re-enter the U.S. market soon.
Attaya Suvannasankha, MD
Indiana University School of Medicine
Indianapolis, Indiana
References
- Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221.
- Trudel S, McCurdy A, Louzada ML, et al. Belantamab mafodotin, pomalidomide and dexamethasone in refractory multiple myeloma: a phase 1/2 trial. Nat Med. 2024;30(2):543-551.
- Mateos M, Robak P, Hus M, et al. Results from the randomized phase III DREAMM-7 study of belantamab mafodotin (belamaf) + bortezomib, and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(36 suppl).
