Findings of the multicohort phase 1 TRIMM-2 trial showed that the G-protein–coupled receptor family C group 5 member D x CD3 bispecific antibody talquetamab in combination with daratumumab therapy was well-tolerated and resulted in promising antitumor activity in patients with RRMM, supporting further evaluation of this combination.
Based on preclinical evidence that the addition of the anti-CD38 monoclonal antibody daratumumab enhanced multiple myeloma (MM) cell killing mediated by the G-protein–coupled receptor family C group 5 member D x CD3 bispecific antibody talquetamab, the combination was evaluated in the phase 1b multicohort study (TRIMM-2; NCT04108195) in patients with relapsed/refractory multiple myeloma (RRMM). Preliminary results of the trial were reported at the 2021 ASH Annual Meeting and summarized here.
The study enrolled patients aged ≥18 years with a diagnosis of MM, who had received ≥3 previous lines of therapy, had previous exposure or were refractory to a proteasome inhibitor and immunomodulatory drug, but had no previous exposure to anti-CD38 therapy in the past 90 days. Eligible patients received daratumumab (1800 mg) plus subcutaneous talquetamab (administered with step-up dosing in 3 cohorts: 400 µg/kg weekly, 400 µg/kg biweekly, 800 µg/kg biweekly) in 28-day cycles. The primary objectives were to identify the recommended phase 2 dose (RP2D) of talquetamab plus daratumumab and to characterize the safety of talquetamab plus daratumumab at the RP2D. The data cutoff date was September 7, 2021.
A total of 29 patients received subcutaneous talquetamab plus daratumumab in 3 separate cohorts: daratumumab 1800 mg plus talquetamab 400 µg/kg weekly (N = 9), daratumumab 1800 mg plus talquetamab 400 µg/kg biweekly (N = 5), and daratumumab 1800 mg plus talquetamab 800 µg/kg biweekly (N = 15). Across the 3 cohorts, the median age was 66 years and 55.2% were female. Patients were heavily pretreated and had received a median of 6 previous lines of therapy; 79.3% were triple-class–exposed (82.6% had received daratumumab before, and 8.7% had received isatuximab before) and 65.5% were penta-drug–exposed. The median follow-up across the 3 cohorts was 2.9 months.
Across the 3 cohorts, any grade adverse events (AEs) were reported in 95.7% of patients; the most common reported AEs that occurred in ≥20% of patients were cytokine release syndrome (CRS; 55.2%), dysgeusia (48.3%), neutropenia (41.4%), thrombocytopenia (34.5%), infections (34.5%), anemia (31.0%), and skin exfoliation (27.6%). Grade 3/4 AEs occurred in 78.3% of patients and included neutropenia (31%), thrombocytopenia (20.7%), anemia (20.7%), and infections (10%). All CRS events were grade 1/2; the median time to CRS onset was 2 days, and the median duration was 2 days. Skin disorders were reported in 65% of patients (grade 3/4: 10.3%), including nail disorders in 31% (all grade 1/2). Two events of immune effector-cell–associated neurotoxicity syndrome were reported; one was a grade 1 event, and another was a grade 3 event, both of which resolved. One death as a result of disease progression was reported in the daratumumab 1800-mg plus talquetamab 400-μg/kg biweekly cohort.
Patients evaluable for efficacy analysis had received ≥1 study treatments and 1 postbaseline response evaluation. In the daratumumab 1800-mg plus talquetamab 400-µg/kg weekly cohort (N = 7), 2 patients achieved a complete response or better. In the daratumumab 1800-mg plus talquetamab 400-µg/kg biweekly cohort (N = 5), 1 patient achieved a complete response or better and 3 patients achieved a very good partial response or better. In the daratumumab 1800-mg plus talquetamab 800-µg/kg biweekly cohort (N = 9), 1 patient achieved a complete response or better, 6 patients achieved a very good partial response or better, and 7 achieved a partial response or better. The median time to first response across the talquetamab plus daratumumab cohorts was 1.0 month (range, 0.9-2.4 months), and median duration of response was not reached. Consistent with the pharmacokinetic profile of talquetamab monotherapy, the talquetamab plus daratumumab combination treatment resulted in proinflammatory cytokine production and T-cell activation.
Findings of the multicohort phase 1 TRIMM-2 trial showed that talquetamab plus daratumumab combination therapy was well-tolerated and resulted in promising antitumor activity in patients with RRMM, supporting further evaluation of this combination.
Source: Chari A, Hari P, Bahlis NJ, et al. Phase 1b results for subcutaneous talquetamab plus daratumumab in patients with relapsed/refractory multiple myeloma. Blood. 2021;138(suppl 1):161.