Immunotherapy has shown efficacy in relapsed multiple myeloma (MM). However, these therapies may depend on a functional tumor immune microenvironment (iTME) for their efficacy. Characterizing the evolution of the iTME over the disease course is necessary to optimize the timing of immunotherapies. We performed mass cytometry, cytokine analysis, and RNA sequencing on bone marrow samples from 39 (13 newly diagnosed [NDMM], 11 relapsed pre-daratumumab exposure [RMM], and 13 triple-refractory [TRMM]) MM patients. Three distinct cellular iTME clusters were identified; cluster 1 comprised mainly of NDMM and RMM patients; and clusters 2 and 3 comprised primarily of TRMM patients. We showed that naive T cells were decreased in clusters 2 and 3, cluster 2 was characterized by increased senescent T cells, and cluster 3 by decreased early memory T cells. Plasma cells in clusters 2 and 3 upregulated E2F transcription factors and MYC proliferation pathways, and downregulated interferon, TGF-beta, interleuking-6, and TNF-αlpha signaling pathways compared to cluster 1. This study suggests that the MM iTME becomes increasingly dysfunctional with therapy whereas the MM clone may be less dependent on inflammation-mediated growth pathways and less sensitive to IFN-mediated immunosurveillance. Our findings may explain the decreased sensitivity of TRMM patients to novel immunotherapies.
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