B06: SUBCUTANEOUS TALQUETAMAB IN COMBINATION WITH DARATUMUMAB IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): PHASE 1B RESULTS
Authors: M Mateos, P Hari, N Bahlis, A Chari, NWCJ van de Donk, B Dholaria, AL Garfall, H Goldschmidt, KM Kortüm, A Krishnan, T Martin, D Morillo, A Oriol, D Reece, C Rodriguez, P Rodríguez-Otero, JF San-Miguel, SZ Usmani, R Verona, SXW Lin, TJ Prior, M Wade, B Weiss, JD Goldberg, E Askari
Journal: HemaSphere (2022)

MM remains incurable with most patients (pts) relapsing or becoming refractory to standard therapies, highlighting the need for novel agents. Talquetamab (Tal) is a bispecific antibody that binds to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on plasma cells with limited expression in healthy tissue, and CD3 to redirect T cells to GPRC5D-expressing MM cells. In the phase 1 MonumenTAL-1 study, an overall response rate of 70% at median 6.3-month follow-up was observed at the recommended phase 2 dose (RP2D) of Tal in pts with RRMM. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for treatment of MM. In preclinical studies, Dara enhanced Tal-mediated lysis of MM cells, suggesting the potential to increase clinical activity in pts with RRMM when the agents are combined. We report initial findings for pts with RRMM who received Tal + Dara in the phase 1b multicohort TRIMM-2 study (NCT04108195). Eligible pts (≥18 years) had MM 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 an IMiD. Pts who received anti-CD38 therapy ≤90 days were excluded. The primary objectives were to identify the RP2D of Tal in combination with Dara and to characterize the safety at the RP2D. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0 (cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS] graded per ASTCT guidelines). As of Jul 23, 2021, 23 pts received SC Tal + Dara in separate cohorts: Dara 1800 mg + Tal 400 μg/kg weekly (n=8), + Tal 400 μg/kg biweekly (n=5), and + Tal 800 μg/kg biweekly (n=10). Median follow-up across the cohorts was 2.9 months (range 0.3–11.2). Median age was 68 years (range 44–81), and 52.2% of pts were male. Pts had a median of 6 prior LOT (range 3–18); 82.6% were triple-class exposed (82.6% had prior Dara and 8.7% had prior isatuximab) and 73.9% were penta-drug exposed. Most frequently reported AEs (≥30%) were dysgeusia (52.2%; all grade 1/2), neutropenia (39.1%; grade 3/4 30.4%), thrombocytopenia (39.1%; grade 3/4 21.7%), anemia (34.8%; grade 3/4 21.7%), CRS (34.8%; all grade 1/2), and skin exfoliation (30.4%; all grade 1/2). Grade 3/4 AEs were reported in 78.3%. Median time to CRS onset was 2.5 days (range 2–4), and median duration was 2 days (range 1–3). Infections occurred in 34.8% of pts (grade 3/4 17.4%). Skin disorders were reported in 65.2% of pts (grade 3/4 13.0%), including nail disorders in 17.4% (all grade 1/2). Two ICANS events were reported (grade 1 [concurrent with CRS] and grade 3); both resolved and did not recur. One pt in the Dara 1800 mg + Tal 400 μg/kg biweekly cohort died from disease progression. Responses are shown in the Table. The median time to first response across the cohorts was 1.0 month (range 0.9–2.4), and median duration of response was not reached. Tal pharmacokinetics was similar to that reported in the MonumenTAL-1 study. Proinflammatory cytokine production and T cell activation were observed after Tal + Dara treatment. The combination of Tal with Dara was well tolerated, with a safety profile comparable to the monotherapies. The combination showed promising efficacy in pts with RRMM, supporting further clinical development of Tal + Dara combination therapy.