CD70/CD27 signaling promotes the pathogenesis of multiple myeloma and represents a promising therapeutic target.

The increasing therapeutic options for multiple myeloma (MM) have significantly improved long-term survival for many patients. However, disease progression remains inevitable due to the emergence of drug-resistant myeloma cell populations, often culminating in extramedullary disease manifestations. In this study, we identified CD70-expressing myeloma cells as critical drivers of disease progression and propagation. CD70 expression in MM cells is an independent negative prognostic factor for overall survival. Mechanistically, CD70/CD27 signaling activates the MAPK/ERK and Wnt signaling pathways in MM cell lines and primary patient-derived MM samples, promoting increased cell cycling and proliferation. This proliferative advantage results in elevated CD70 expression in advanced MM stages, particularly in extramedullary myeloma. Functional inhibition of CD70/CD27 signaling, achieved either by generating CD70-knockout primary MM cells or with blocking monoclonal antibodies, completely abrogated tumor growth in xenotransplantation models. Furthermore, the ADCC-enhanced anti-CD70 antibody, cusatuzumab, demonstrated high efficacy in treating myeloma in xenotransplantation models. Collectively, these findings underscore the critical role of CD70/CD27 signaling in activating MAPK/ERK and Wnt pathways essential for MM progression. Targeting CD70 with blocking or ADCC-enhanced antibodies represents a promising therapeutic strategy, particularly for advanced MM stages characterized by high CD70 expression.