Inflammatory bone marrow microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma
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.
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BibTeX
@article{cheng2026inflammatory,
title = {{Inflammatory bone marrow microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma}},
author = {Wenwen Cheng and Silvia Gaggero and Lama Hasan Bou Issa and Aïcha Ouelkdite and Guillaume Escure and Adeline Cozzani and Yanick Njosse Tchantchou and Noémie Carlier and Emilie Wauquier and Gauthier Decool and Rémi Tilmont and Benjamin Podvin and Malo Leprohon and Mojtaba Shekarkar and Léa Fléchon and Angélina Kasprowicz and Sophie Groux-Degroote and Jérôme Moreaux and Bertrand Arnulf and Jill Corre and Céline Villenet and Ludovic Martinet and Xavier Leleu and Martin Figeac and Thierry Facon and Wenfei Jin and Suman Mitra and Salomon Manier},
journal = {Biomarker Research},
year = {2026},
month = sep,
doi = {10.1186/s40364-026-00992-2},
url = {https://hal.science/hal-05745245v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Inflammatory bone marrow microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma
AU - Wenwen Cheng
AU - Silvia Gaggero
AU - Lama Hasan Bou Issa
AU - Aïcha Ouelkdite
AU - Guillaume Escure
AU - Adeline Cozzani
AU - Yanick Njosse Tchantchou
AU - Noémie Carlier
AU - Emilie Wauquier
AU - Gauthier Decool
AU - Rémi Tilmont
AU - Benjamin Podvin
AU - Malo Leprohon
AU - Mojtaba Shekarkar
AU - Léa Fléchon
AU - Angélina Kasprowicz
AU - Sophie Groux-Degroote
AU - Jérôme Moreaux
AU - Bertrand Arnulf
AU - Jill Corre
AU - Céline Villenet
AU - Ludovic Martinet
AU - Xavier Leleu
AU - Martin Figeac
AU - Thierry Facon
AU - Wenfei Jin
AU - Suman Mitra
AU - Salomon Manier
PY - 2026
DA - 2026/09/05
JO - Biomarker Research
DO - 10.1186/s40364-026-00992-2
UR - https://hal.science/hal-05745245v1
AB - 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.
SN - 2050-7771
ER -