OA-03: Bispecific T-cell engager response is driven by pre-treatment CD8+ effector memory cells and inhibited by TIGIT+ Tregs in relapsed/refractory multiple myeloma

Introduction: Teclistamab (Tec) is a CD3 x BCMA bispecific antibody approved for treating relapsed/refractory (RR) multiple myeloma (MM) based on the results of the MajesTEC-1 trial (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022), where patients with exposure to prior anti-BCMA therapy were excluded. While the therapy demonstrated impressive efficacy, little is known about clinical and patient-specific immunophenotypic predictors of response to therapy. Additionally, the efficacy of Tec in patients with prior anti-BCMA therapy exposure has yet to be assessed.

Methods: We performed an IRB-approved study profiling the peripheral blood T-cell repertoire from pre-treatment PBMC samples from a 14-patient sub cohort (9 responders, 5 non-responders) of commercial Tec patients via high-dimensional spectral cytometry using a 33-color panel including lineage (CD4, CD8, CD25, CD127, CD45RA, CD45RO, CCR7, CD62L, CD28, CD95), exhaustion (PD-1, LAG3, TIM3, CTLA-4, TIGIT, OX-40, 4-1BB, ICOS, BTLA, CD57), and activation markers (CD69, HLA-DR, CD25, CD27) among others. We also performed a retrospective analysis of clinical outcomes for 41 commercial Tec patients (7 median prior lines of therapy, 23/41 (56%) with prior anti-BCMA therapy exposure) treated as of 05/01/2023. Results were correlated to MM cell BCMA expression.

Results: Tec responders had enrichment for both CD8+ effector memory T-cells (>6-fold increase, p = 0.03) and CD8+ effector memory cells re-expressing CD45RA (>5-fold increase, p = 0.02). Tec non-responders were enriched for TIGIT+ Tregs (3-fold increase, p = 0.03). No differences between PD-1, CTLA-4, LAG-3 or TIM-3 expression were observed in responders vs non-responders. Clinical outcome analysis identified a high CD8+:CD4+ ratio as predictive of response, and CRS during step-up dosing was strongly associated with Tec efficacy. Among the 31/41 response evaluable patients, the overall response rate for commercial Tec patients with prior anti-BCMA therapy exposure was 58% (11/19 patients) and was similar for anti-BCMA therapy naïve patients. No differences in BCMA expression were noted between responding and non-responding patients or between anti-BCMA exposed and anti-BCMA therapy naïve patients.

Conclusions: Tec is an effective therapy in RRMM even in patients with prior anti-BCMA therapy exposure. A pre-Tec T-cell population enriched with highly cytotoxic effector T-cells associates with response to therapy, while suppressive TIGIT+ Tregs associate with nonresponse, suggesting a potential therapeutic role for TIGIT blockade or CD25+ cell depletion to enhance the therapeutic efficacy of Tec and other bispecific antibodies. Clinical and translational data from additional enrolled patients will be presented at the meeting.