Advances in multiple myeloma treatment in 2024 included the return of belantamab mafodotin, new FDA approvals for daratumumab-hyaluronidase and CAR T-cell therapies, and promising research on isatuximab-based quadruplet therapy. These developments offer new options and improved outcomes for patients across different stages of the disease.
Belantamab Mafodotin's Second Chance
Belantamab mafodotin (Blenrep), an anti-B-cell maturation antigen (BCMA) monoclonal antibody, made a comeback after being withdrawn from the market in 2022. Initially granted accelerated approval in 2020 for relapsed or refractory multiple myeloma patients who had received at least four prior therapies, its withdrawal followed the DREAMM-3 confirmatory trial failing to meet the primary endpoint of progression-free survival (PFS).
However, the DREAMM-7 study showed that belantamab mafodotin, when combined with bortezomib (Velcade) and dexamethasone, led to a median PFS of 36.6 months compared with 13.4 months for daratumumab (Darzalex) plus bortezomib and dexamethasone (HR 0.41, 95% CI 0.31-0.53, P <0.00001). Furthermore, the DREAMM-7 study also met the secondary endpoint of improved overall survival. A second belantamab mafodotin-containing triplet, evaluated in the DREAMM-8 study, demonstrated a PFS benefit in relapsed/refractory myeloma, with 12-month PFS rates of 71% with belantamab mafodotin combined with pomalidomide (Pomalyst) and dexamethasone compared with 51% with pomalidomide, bortezomib, and dexamethasone (HR 0.52, 95% CI 0.37-0.73, P <0.001).
The FDA is again reviewing the drug as a treatment for myeloma.
FDA Approvals and Expanded Indications
In July, the FDA approved subcutaneous daratumumab-hyaluronidase (Darzalex Faspro) in combination with bortezomib, lenalidomide (Revlimid), and dexamethasone (VRd) for induction and consolidation in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant. This approval was based on the phase III PERSEUS trial, where the quadruplet therapy significantly improved the primary endpoint of PFS, reducing the risk of disease progression or death by 60% compared with VRd alone (HR 0.40, 95% CI 0.29-0.57, P <0.0001).
The FDA also expanded the labels of two CAR T-cell products for multiple myeloma in April, allowing their use in earlier lines of treatment for relapsed or refractory disease. Ciltacabtagene autoleucel (cilta-cel; Carvykti) is now approved as a second-line therapy for patients who are refractory to lenalidomide and whose prior line of therapy also included a proteasome inhibitor, based on the CARTITUDE-4 trial results. Idecabtagene vicleucel (ide-cel; Abecma) was approved as a third-line option for patients with triple-class-exposed disease, based on findings from the KarMMa-3 trial, which showed a significant improvement in PFS with the one-time infusion of ide-cel.
Isatuximab in Newly Diagnosed Disease
Two phase III trials presented at ASCO demonstrated that the anti-CD38 monoclonal antibody isatuximab combined with the standard VRd backbone significantly improved outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma. In the IMROZ trial, the estimated PFS rate at 60 months was 63.2% among patients treated with isatuximab-VRd compared with 45.2% for those treated with VRd alone (HR 0.60, 98.5% CI 0.41-0.88, P <0.001). In the BENEFIT trial, the isatuximab-VRd combination significantly improved minimal residual disease (MRD) negativity rates at 10-5 at 18 months compared with isatuximab, lenalidomide, and dexamethasone (53% vs 26%; OR 3.16, 95% CI 1.89-5.28, P <0.0001). These results support isatuximab-VRd as a potential new standard of care for transplant-ineligible patients with newly diagnosed multiple myeloma.
