In the phase 1 MajesTEC-1 trial, teclistamab (Tec), a B-cell maturation antigen × CD3 T cell redirecting bispecific antibody, showed an overall response rate of 65% at 6.1-month follow-up. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for the treatment of MM. In MM cell lines, the lytic activity of Tec was enhanced by pretreatment and combination treatment with Dara; thus, the combination of both agents may improve efficacy in RRMM by targeting discrete yet complementary antigens. We present data on patients (pts) with RRMM who received Tec + Dara in the phase 1b TRIMM-2 study (NCT04108195).
Eligible pts were ≥18 years of age, had a MM diagnosis, and received ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD. Receipt of anti-CD38 therapy ≤90 days was not allowed. The primary objectives were to identify the RP2D for the Tec + Dara combination and to assess safety of the combination. This analysis focuses on subcutaneous (SC) cohorts in the study. Responses were assessed by IMWG criteria and adverse events (AEs) by CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] were graded per ASTCT guidelines).
33 pts received SC Tec + Dara in different dosing cohorts: Dara 1800 mg + Tec 1500 μg/kg weekly (n=21), + Tec 3000 μg/kg weekly (n=5), + Tec 300 mg biweekly starting Cycle 3 Day 1 (C3D1; Tec 150 mg weekly in C1–C2; n=2), and + Tec 3000 μg/kg biweekly (n=5). 9 pts in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort switched to Tec 3000 μg/kg biweekly dosing after C3D1. As of Jun 22, 2021, median follow-up across the cohorts was 3.6 months (range 0.1–10.4). Median age was 67 years (range 51–78) and 57.6% were female. Median number of prior LOT was 5 (range 2–16); 69.7% were triple-class exposed (prior Dara in all 69.7%) and 60.6% were penta-drug exposed. The most common AE was CRS (54.5%; all grade 1/2); median time to onset was 2 days (range 1–6), and median duration was 2 days (range 1–7). Other AEs (≥30%) were neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4 33.3%), anemia (36.4%; grade 3/4 24.2%), diarrhea (36.4%; grade 3/4 3.0%), nausea (30.3%; all grade 1/2), and pyrexia (30.3%; all grade 1/2). Overall, 66.7% of pts had grade 3/4 AEs. Infections occurred in 51.5% of pts (grade ≥3 24.2%). No ICANS events were reported. One pt in the Dara 1800 mg + Tec 3000 μg/kg weekly cohort died from treatment-unrelated bacterial pneumonia during C1, and 1 pt in the Dara 1800 mg + Tec 1500 μg/kg weekly cohort died from progressive disease. Responses are shown in the Table. Across the cohorts, median time to first response was 1.0 month (range 0–1.9). Median duration of response was not reached. Tec + Dara treatment led to proinflammatory cytokine production and T cell activation. The Tec pharmacokinetic profile was similar to that reported in the MajesTEC-1 study.
The combination of Tec + Dara had a manageable safety profile and showed preliminary efficacy in pretreated pts with MM. These findings warrant further investigation, and the randomized phase 3 MajesTEC-3 study will evaluate Tec + Dara vs Dara, pomalidomide, and dexamethasone or Dara, bortezomib, and dexamethasone in pts with RRMM.
