Background Talquetamab is a T-cell redirecting bispecific antibody targeting G protein-coupled receptor family C group 5 member D and CD3. Daratumumab is an anti-CD38 monoclonal antibody with direct on-tumor and immunomodulatory actions. The phase 1b TRIMM-2 (NCT04108195) trial showed that talquetamab + daratumumab had deep (overall response rate [ORR] of 71–84%) and durable responses, with promising ORRs in unmet need subgroups (anti-CD38 refractory and prior T-cell redirection exposed), and a manageable safety profile in patients with relapsed/refractory multiple myeloma (RRMM). We present pharmacodynamic results from TRIMM-2 to support and elucidate the potential immunomodulatory mechanisms of action (MOA) of talquetamab + daratumumab.

Methods Patients had MM, ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD and had not received anti-CD38 therapy in ≤90 days. Patients received the recommended phase 2 doses of talquetamab, 0.4 mg/kg weekly or 0.8 mg/kg biweekly with step-up doses, + daratumumab 1800 mg per the approved schedule. Whole blood from patients in TRIMM-2 was analyzed for immune populations by flow cytometry. T-cell clonality was analyzed by T-cell receptor sequencing.

Results Patients who received talquetamab + daratumumab demonstrated T-cell redistribution (early reduction in peripheral CD3+ T cells) and subsequent T-cell recovery, consistent with the MOA of each agent. A high level of clonal expansion was observed at cycle 3, day 1 vs baseline, including a significant increase in the fraction of newly detected clones, indicative of antigen-specific T-cell activation. Talquetamab + daratumumab led to a moderate increase in effector memory CD8+ T cells and induction of T-cell activation, as evidenced by an increase in LAG-3+, TIM-3+, and PD-1+ CD8+ T cells in the first cycle. An initial reduction of CD38+CD8+ T cells was observed after daratumumab administration; however, following talquetamab administration, induction of CD38+CD8+ T cells was observed, indicative of T-cell activation. Consistent with daratumumab’s MOA, there was a notable reduction in immunosuppressive CD38+ regulatory T cells (Tregs) with the combination and a sustained reduction in natural killer cells. There was no reduction in total CD19+ B cells.

Conclusions The pharmacodynamic profile of talquetamab + daratumumab was consistent with the respective MOAs and showed induction of T-cell activation, an increase in T-cell clonality, and reduction of immunosuppressive CD38+ Tregs. These data support the promising efficacy of this off-the-shelf immunotherapy combination in patients with RRMM.

Acknowledgements This study was funded by Janssen Research & Development, LLC. Medical writing support was provided by Rachael Smith, PhD, of Eloquent Scientific Solutions, and funded by Janssen Global Services, LLC.

Trial Registration NCT04108195

Ethics Approval Conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization’s Good Clinical Practice guidelines. Protocol/amendments were approved by each site’s Institutional Review Board. All patients provided informed written consent.