Abstract
Daratumumab-lenalidomide (DR) combination therapy improves multiple myeloma (MM) outcomes, yet some patients respond poorly. We examined 21 DR pre-treatment samples from the IFM2017-03 phase 3 trial using single-cell and bulk multiomics approaches to identify determinants of response. Analysis of the bone marrow environment revealed a coordinated inflammatory state across immune and myeloma cells associated with DR resistance. We identified upregulated NF-κB signaling genes in monocytes of non-responders, alongside increased proinflammatory ISG + T cells and attenuated NK cell CD16 expression, suggesting an impairment of antibody-dependent cellular cytotoxicity essential for daratumumab efficacy. Concurrently, myeloma cells displayed enhanced NF-κB activation, supporting convergent tumor and immune inflammatory programs. We further developed an eight-gene NF-κB-related signature that robustly predicted treatment response in independent bone marrow (n = 28, AUC = 0.81) and peripheral blood (n = 40, AUC = 0.77) samples. Our study underscores an NF-κB-associated inflammatory axis underlying poor DR response and suggests that targeting inflammatory pathways a potential therapeutic avenue warranting further investigation.