Inflammatory bone marrow microenvironment impairs the therapeutic effect of daratumumab-lenalidomide in multiple myeloma
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.
Authors
- Malo Leprohon
- Aïcha Ouelkdite
- Gauthier Decool (ORCID: https://orcid.org/0000-0003-3379-1083)
- Benjamin Podvin (ORCID: https://orcid.org/0000-0002-0616-8694)
- Silvia Gaggero (ORCID: https://orcid.org/0000-0002-2685-1108)
- Ludovic Martinet (ORCID: https://orcid.org/0000-0002-0867-7724)
- Jérôme Moreaux (ORCID: https://orcid.org/0000-0002-5717-3207)
- Jill Corre (ORCID: https://orcid.org/0000-0003-1580-6106)
- Sophie Groux‐Degroote (ORCID: https://orcid.org/0000-0002-9964-6519)
- Guillaume Escure (ORCID: https://orcid.org/0000-0002-3151-9441)
- Rémi Tilmont (ORCID: https://orcid.org/0000-0003-1739-2162)
- Wenfei Jin (ORCID: https://orcid.org/0000-0002-0028-3739)
- Angélina Kasprowicz
- Céline Villenet
- Lama Hasan Bou Issa (ORCID: https://orcid.org/0000-0002-2561-9980)
- Adeline Cozzani (ORCID: https://orcid.org/0000-0001-5837-0459)
- Yanick Njosse Tchantchou
- Emilie Wauquier
- Léa Fléchon
- Thierry Facon
- Wenwen Cheng
- Xavier Leleu
- Bertrand Arnulf
- Suman Mitra
- Noémie Carlier
- Martin Figeac
- Mojtaba Shekarkar
- Salomon Manier
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Universitaire de France (FR)
- Université de Lille (FR)
- Centre Hospitalier Universitaire de Lille (FR)
- Southern University of Science and Technology (CN)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Lille’s Cardiology Hospital (FR)
- Shanghai Institute of Nutrition and Health (CN)
- Centre Hospitalier Universitaire de Poitiers (FR)
- Unité de Glycobiologie Structurale et Fonctionnelle (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Hôpital Saint-Louis (FR)
- Institut de Génétique Humaine (FR)
- Institut de Biologie de Lille (FR)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Biomarker Research
- Published
- 2026-09-05
- DOI
- https://doi.org/10.1186/s40364-026-00992-2
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Johnson and Johnson