Multinational phase 3 trial of talquetamab-daratumumab in relapsed or refractory myeloma

Talquetamab is a bispecific antibody targeting GPRC5D and CD3, leading to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma (RRMM) in phase 1 and phase 2 trials, with a limited effect on normal B cells. The multinational phase 3 MonumenTAL trial evaluated the combination of talquetamab and daratumumab in RRMM patients who had received at least one line of therapy. Patients were randomized to talquetamab plus daratumumab and pomalidomide (Tal-DP; n=287), talquetamab plus daratumumab (Tal-D; n=287), or daratumumab plus pomalidomide and dexamethasone (DPd; n=290). The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee. At an interim analysis after median 24.6 months of follow-up, 24-months PFS rates were 81.3% with Tal-DP, 77.6% with Tal-D, and 51.2% with DPd (Tal-DP versus DPd HR 0.28; Tal-D versus DPd HR 0.33; p<0.001 for both comparisons). Overall survival rate at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (Tal-DP versus DPd HR 0.47; 95% CI 0.30-0.73; Tal-D versus DPd 0.51; 0.33-0.78). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively, with fatal adverse events in 1.8%, 4.0%, and 4.6%. The authors conclude that among RRMM patients who had received at least one line of therapy, both Tal-DP and Tal-D led to significantly longer PFS than DPd.