Inflammatory microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma
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Daratumumab and lenalidomide (DR) combination therapy improves multiple myeloma outcomes, yet some patients respond poorly. We examined 56 DR pre-treatment samples from the IFM2017 Phase 3 trial using multiomics approaches to identify determinants of response. Analysis of bone marrow environment revealed critical synergy between inflamed myeloma cells and inflammatory immune microenvironment contributing to treatment failure. We identified non-responders exhibiting inflammatory signatures with impaired monocyte phagocytosis, upregulated NF-kB signaling in monocytes, increased pro-inflammatory ISG+ T cells, and attenuated NK cell CD16 expression—undermining antibody-dependent cellular cytotoxicity essential for daratumumab efficacy. Concurrently, myeloma cells displayed enhanced NF-kB activation, creating an inflammatory circuit. We developed a model based on 34 NF-kB-related genes (AUC=0.96) discriminating responders from non-responders. A refined eight-gene signature was robustly validated using bulk RNA sequencing in bone marrow and peripheral blood cohorts (AUCs=0.92 and 0.77, respectively). These findings suggest anti-inflammatory strategies may enhance treatment efficacy.
