MonumenTAL-3: Phase 3 Trial of Talquetamab + Daratumumab ± Pomalidomide Versus Daratumumab + Pomalidomide + Dexamethasone in Relapsed/Refractory Multiple Myeloma Following ≥1 Prior Line of Therapy

Background: Patients with relapsed/refractory multiple myeloma (RRMM) after prior therapy with lenalidomide and a proteasome inhibitor (PI) are challenging to treat. Daratumumab, a human IgG1κ anti-CD38 monoclonal antibody, is approved in combination with pomalidomide and dexamethasone (DPd) for patients with RRMM after ≥1 prior line of therapy (LOT), including lenalidomide and a PI, but disease control could be improved. There is an unmet need for new, off-the-shelf therapeutic options with different mechanisms of action. Talquetamab (Tal) is a first-in-class, off-the-shelf, T-cell redirecting, bispecific antibody targeting both G protein-coupled receptor family C group 5 member D (GPCR5D) and CD3. In the phase 1/2 MonumenTAL-1 study (NCT03399799), Tal monotherapy had a manageable safety profile and showed encouraging efficacy in heavily pretreated patients with RRMM. The combination of Tal and daratumumab (Tal-D) in the phase 1b TRIMM-2 study (NCT04108195) showed manageable safety, with no overlapping toxicities and promising efficacy. The randomized, open-label, multicenter, phase 3 MonumenTAL-3 study will compare Tal-D (with or without pomalidomide [P]) versus DPd in patients with RRMM with ≥1 prior LOT. Study Design and Methods: Eligible patients are aged ≥18 years with documented MM per International Myeloma Working Group (IMWG), have measurable disease at screening, Eastern Cooperative Oncology Group performance status 0-2, received ≥1 prior LOT (including a PI and lenalidomide; patients with 1 prior LOT must be lenalidomide-refractory), and have progressive disease on or after their last regimen. Prior exposure to an anti-CD38 monoclonal antibody will be permitted, but patients who received prior GPRC5D-directed treatment or pomalidomide, or who are refractory to an anti-CD38 monoclonal antibody, will be excluded. Approximately 810 patients will be randomized 1:1:1 to receive 28-day cycles of Tal-DP, Tal-D, or DPd (stratified by International Staging System stage, prior daratumumab exposure, and number of prior LOT). Patients will receive subcutaneous Tal 0.8 mg/kg every other week following step-up doses. Daratumumab, pomalidomide, and dexamethasone will be administered per approved schedules. Patients will receive treatment until disease progression, start of subsequent anti-MM therapy, death, intolerable toxicity, withdrawal of consent, or end of study, whichever occurs first. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response, very good partial response or better, complete response or better, minimal residual disease negativity, PFS on next LOT (PFS2), overall survival, patient-reported outcomes, time to next treatment, and incidence and severity of adverse events (AEs). Response will be assessed per 2016 IMWG criteria. AEs will be graded by Common Terminology Criteria for AEs v5.0, except for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which will be graded by American Society for Transplantation and Cellular Therapy guidelines. The study will open for enrollment in October 2022. Results from this study will provide insights into the efficacy and safety of a combination therapy approach using Tal-DP or Tal-D versus DPd in patients with RRMM who received ≥1 prior LOT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal