Inflammatory microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma

Daratumumab and lenalidomide (DR) combination therapy has improved outcomes in multiple myeloma (MM), but some patients still experience poor responses. To understand the factors influencing treatment resistance, we performed single-cell RNA sequencing on bone marrow samples from 21 newly diagnosed MM patients enrolled in the IFM2017-03 trial, classifying them as complete responders (CR, n=11) or non-/poor responders (NR, n=10). NR patients exhibited pro-inflammatory bone marrow microenvironment (BME) characterized by elevated cytokine signaling. Classical and Nonclassical monocytes in NR patients displayed gene expression signals associated with impaired phagocytosis and interferon-associated monocytes upregulated NF-kB-related genes, while CD54 ^dim NK cells in NR patients expressed lower levels of CD16, a marker associated with antibody-dependent cellular cytotoxicity. Furthermore, tumor cells from NR patients also showed enhanced NF-kB activation, which was correlated with increased inflammatory gene expression and poor prognosis. A random forest model based on 34 NF-kB-related genes accurately distinguished CR from NR patients (AUC = 0.96), and a refined model using the top eight genes maintained strong predictive power for bone marrow (AUC = 0.92) and peripheral blood samples (AUC = 0.77). These findings suggest that an inflamed BME and NF-kB signaling contribute to DR resistance, offering potential targets for overcoming poor responses.