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Background T cell bispecific (TCB) therapies provide promising therapeutic efficacies for patients with relapsed/refractory multiple myeloma (RRMM) however a subset of patients do not respond initially or progress early. Several studies address the contribution of T cells in response to TCB, reporting baseline 1 or induced2 exhaustion as resistance mechanisms. As phenotypic and/or gene signatures are often used to define T cell exhaustion, functional characterisation of T cell performance is informative to further differentiate exhaustion from activation. Here, with a newly developed ex-vivo reverse translational assay, we evaluated baseline functional T cell status from RRMM patients enrolled in a phase I dose escalation of forimtamig, a GPRC5DxCD3 TCB (NCT04557150) to correlate with clinical responses.Methods Baseline bone marrow aspirate samples were collected from patients prior to treatment. Samples were treated ex-vivo using two forimtamig doses reflecting exposures measured in cycle 1: the patient-specific and a common higher exposure of 1nM (corresponding to the highest tested subcutaneous clinical dose of 7.2mg). An additional condition with spiked-in GPRC5D-expressing targets was assessed to normalise for inter-patient tumor burden heterogeneity. Readouts included cytokine secretion using a multiplex kit and tumor cell killing was assessed by flow cytometry. All patients provided informed consent.Results Upon ex-vivo treatment with forimtamig, T cells were capable of secreting cytokines and killing endogenous myeloma cells independently of patient response in the clinics, however a dose-dependent response was observed both ex-vivo and in pharmacodynamic analysis. Notably, T cells from non-responding patients showed an increased cytokine release after treatment with 1nM forimtamig compared to the patient-specific exposure (average 0.2nM-1.3nM), indicating a potential benefit from higher exposure. In the presence of spiked-in target cells, we confirmed similar levels of both cytokine secretion and cytotoxicity from responders and non-responder T-cells.Conclusions We developed an ex-vivo reverse translational model that enabled T cell functionality assessment in RRMM patients. T cell fitness was evident in both non-responding and responding patients, suggesting that T cell dysfunctionality may not be the resistance mechanism in the patient population in this analysis. An increase in forimtamig exposure (patient-specific dose to 1nM) correlated with a more efficacious potency, indicating opportunities to potentially increase T-cell functionality or individualized dosing strategies. Further investigation is needed to understand the immunological and resistance mechanisms which underpin the clinical response. The described reverse translational model can be utilized to test other therapeutic options/combinations to achieve better clinical responses.Acknowledgements Jan Attig, Stephan Schmeing, Emilio Yangueez, Llucia Alberti Servera, Inga Clausen, Hans J. Grote, Claudia Ferreira, Hans-Joachim Helms, Sara Belli, Vu-Long Tran, Carmelo Carlo-Stella, Caroline Hasselbalch Riley, Salomon Manier, Antonio Pinto, Paolo Corradini, Cyrille Hulin, Sung-Soo Yoon, Rakesh Popat, Simon Harrison, Sabrina Danilin, Joanne Hayworth, Grigori Singovski, Sara Belli, Jan Eckmann, Pablo Umana, Tanja Fauti, Steffen Dettling, Georgina Meneses-Lorente, Nassim Sleiman, Lisa Sach-Peltason.Trial Registration NCT04557150References Friedrich M, Neri P, Kehl N, et al. Cancer Cell. 2023;10:41(4):711–725Verkleij C, O’Neill C, Broekmans M, et al. Clin Cancer Research. 2024; 15:30(14):3006–3022