The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma

Daratumumab, an anti-CD38 monoclonal antibody, is an effective therapy for plasma cell myeloma (PCM). However, many initial responders relapse. We compared paired samples from subjects pre-therapy and then acquired resistance to daratumumab. We first used single-cell RNA sequencing and digital spatial profiler (DSP). The proportion of cytotoxic CD8-positive T-cells with an exhaustion phenotype and an IFN-γ signature increased in resistance compared with pre-therapy samples, whilst the proportion of NK-cells decreased and had an increased inhibitory phenotype. Transcription of CD38 in neoplastic plasma cells decreased. Numbers of immune cells in cancer centre defined by DSP were significantly decreased in parallel with an increased exhaustion signature. The acquired resistance signature and elevated PCM subset phenotype were associated with worse prognosis in 4 external cohorts (GSE24080, GSE136337, GSE57317, and coMMpass). Using single-cell regulatory network inference, we identified MYC regulation as a key activated factor for acquired resistance in neoplastic plasma cells by intersecting the top 20 upregulated regulons and upregulated genes in acquired resistance. Furthermore, data from in vitro and in vivo experiments indicate that IFN-γ secreted by cells of bone marrow immune ecosystem activates MYC, which correlates with acquired daratumumab resistance. Our data provide insights into acquired daratumumab resistance and suggest potential therapeutic strategies.