Wenwen Cheng, Silvia Gaggero, Lama Hasan Bou Issa, Aïcha Ouelkdite, Guillaume Escure, Adeline Cozzani, Yanick Njosse Tchantchou, Noémie Carlier, Emilie Wauquier, Gauthier Decool, Rémi Tilmont, Benjamin Podvin, Malo Leprohon, Mojtaba Shekarkar, Léa Fléchon, Angélina Kasprowicz, Sophie Groux-Degroote, Jérôme Moreaux, Bertrand Arnulf, Jill Corre, Céline Villenet, Ludovic Martinet, Xavier Leleu, Martin Figeac, Thierry Facon, Wenfei Jin, Suman Mitra, Salomon Manier
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.