Further MonumenTAL-3 Follow-Up Needed for Triplet Regimen in Relapsed Myeloma

Peter Voorhees, MD, of Atrium Health Levine Cancer Institute, discusses data from the MonumenTAL-3 study (NCT05455320), a randomized controlled trial investigating talquetamab (Talvey)-based regimens for patients with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy. Enrolled patients were required to have prior exposure to lenalidomide and a proteasome inhibitor, with no history of GPRC5D-targeted therapy or pomalidomide use. Although patients could have been exposed to an anti-CD38 antibody in earlier lines, they could not be refractory to it.

According to Voorhees, the trial demonstrated overwhelming efficacy for the experimental arms compared with the control standard of daratumumab (Darzalex), pomalidomide (Pomalyst), and dexamethasone (DPd). The talquetamab, daratumumab, and pomalidomide triplet arm reduced the risk of disease progression or death by 72%. Similarly, the talquetamab and daratumumab doublet arm demonstrated exceptional performance, reducing the risk of progression or death by 67%. Both outcomes achieved high statistical significance, showing consistent progression-free survival (PFS) benefits across multiple high-risk, clinically relevant subsets, including older patients, those with previous daratumumab exposure, ISS stage III disease, high-risk cytogenetics, and soft tissue plasmacytomas.

Despite the incremental PFS and overall survival gains provided by adding pomalidomide, Voorhees noted that the trial was not powered to directly contrast the 2 experimental arms, and the differences between them remain subtle. Furthermore, appending pomalidomide altered the risk-benefit calculus by introducing sharper toxicities, notably higher rates of grade 3 or 4 treatment-emergent adverse events, grade 3 or 4 neutropenia, and severe infections. Based on the current median follow-up of 2 years, Voorhees suggested the talquetamab-daratumumab doublet could be a preferred choice in early relapse if approved, considering its superior tolerability and balanced risk profile. However, longer-term follow-up and subsequent subgroup analyses will evaluate if specific patient populations derive enough additional benefit to justify the triplet's toxicity profile.