S183: NOVEL COMBINATION IMMUNOTHERAPY FOR THE TREATMENT OF RELAPSED/REFRACTORY MULTIPLE MYELOMA: UPDATED PHASE 1B RESULTS FOR TALQUETAMAB (A GPRC5D X CD3 BISPECIFIC ANTIBODY) IN COMBINATION WITH DARATUMUMAB
N. W. van de Donk, Nizar J. Bahlis, MV Mateos, Katja Weisel, Bhagirathbhai Dholaria, Alfred L. Garfall, Hartmut Goldschmidt, Thomas G. Martin, Daniel Morillo, Donna Reece, David D. Hurd, Paula Rodríguez‐Otero, Manisha Bhutani, Anita D’Souza, Albert Oriol, Elham Askari, Jesús F. San Miguel, K. Martin Kortüm, Deeksha Vishwamitra, Shun Xin Wang Lin, Thomas J. Prior, Lien Vandenberk, M.-A. D. Smit, Judith D. Goldberg, Ralph Wäsch, Ajai Chari
Abstract
Background: Talquetamab (tal; JNJ-64407564) is a first-in-class, bispecific IgG4 antibody that binds both to G protein-coupled receptor family C group 5 member D (GPRC5D), a receptor highly expressed on malignant plasma cells but with limited expression in healthy tissue, and CD3 to mediate T-cell–activated lysis of GPRC5D+ multiple myeloma (MM) cells. Daratumumab (dara) is an anti-CD38 mAb with direct on-tumor and immunomodulatory actions. Initial clinical results from the phase 1b multicohort TRIMM-2 study identified the recommended phase 2 doses (RP2Ds) of tal as 400 μg/kg weekly or 800 μg/kg Q2W and support the combination of tal + dara for the treatment of RRMM, with manageable safety, no overlapping toxicities, and promising efficacy. Aims: Here we report updated results for both RP2Ds of tal + dara in TRIMM-2 with additional patients (pts) and longer follow-up. Methods: Eligible MM pts (aged ≥18 years) had received ≥3 prior lines of therapy (LOT; including a PI and IMiD) or were double refractory to a PI and an IMiD, and could not have received anti-CD38 therapy within 90 days. Pts received dara SC 1800 mg per approved schedule and tal (400 μg/kg weekly or 800 μg/kg Q2W) with step-up dosing. The primary objectives were to identify the RP2D(s) of tal for combination therapy and evaluate safety of the combination. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Responses were assessed by IMWG criteria. Results: At data cutoff (Jan 13, 2022, N=46), median follow-up was 4.0 months (range 0.4-16.3), median age was 65 years (range 47-81), and 48% were female. Pts received a median of 5 prior LOT (range 2-16); 83% were triple-class exposed, 61% penta-drug exposed, 37% anti-BCMA non–CAR-T exposed, and 4% anti-BCMA CAR-T exposed. 96% of pts had ≥1 AE (gr 3/4: 67%). The most frequently reported AEs (≥30% across tal + dara cohorts) were CRS (65%; all gr 1/2; median time to onset: 2 days; median duration: 2 days), dysgeusia (57%), thrombocytopenia (35%; gr 3/4: 20%), anemia (39%; gr 3/4: 20%), and dry mouth (44%). Infections occurred in 50% of pts (gr 3/4: 13%). Skin disorders were reported in 72% of pts (gr 3/4: 11%): skin exfoliation in 26% (all gr 1/2) and nail disorders in 11% (all gr 1/2). Two ICANS events were reported in the 800 Q2W group (both gr 1 and resolved within 1 day). 3 pts discontinued due to AEs. Response rates were consistent across both RP2Ds supporting their equivalence (Table). Median time to first response across dosing cohorts was 0.95 months (range 0.9-9.7); median duration of response was not reached. Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed with tal + dara, supporting potential synergy of the combination in pts with prior anti-CD38 exposure. Updated results will be presented. Image:Summary/Conclusion: Longer follow-up with additional patients shows comparable efficacy and safety across both RP2Ds, with no new safety signals, strengthening the benefit-risk profile of tal + dara as a novel immunotherapy-based approach for heavily pretreated pts with RRMM.