Umair Munawar, Xiang Zhou, Sabrina Prommersberger, Silvia Nerreter, Cornelia Vogt, Maximilian J. Steinhardt, Marietta Truger, Julia Mersi, Eva Teufel, Seungbin Han, Larissa Haertle, Nicole Banholzer, Patrick Eiring, Sophia Danhof, Miguel Angel Navarro-Aguadero, Adrian Fernandez-Martin, Alejandra Ortiz-Ruiz, Santiago Barrio, Miguel Gallardo, Antonio Valeri, Eva Castellano, Peter Raab, Maximilian Rudert, Claudia Haferlach, Markus Sauer, Michael Hudecek, J. Martinez-Lopez, Johannes Waldschmidt, Hermann Einsele, Leo Rasche, K. Martin Kortüm

• The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to beThe treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the FADD/BID axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.…