A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma
Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) are transforming treatment for relapsed or refractory multiple myeloma (RRMM). We analyze 61 RRMM patients receiving idecabtagene vicleucel (Ide-cel; n = 34) or ciltacabtagene autoleucel (Cilta-cel; n = 27) and find that Cilta-cel achieves higher complete response (CR) rates (78% vs. 38%) and longer progression-free survival. Using a longitudinal single-cell multi-omics atlas of 135 blood samples, we show that Cilta-cel induces expansion of CD4<sup>+</sup> cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8<sup>+</sup> T cells display impaired effector programs. Among non-B cells, plasmacytoid dendritic cells (pDCs) show the highest BCMA expression and BCMA-targeted agents eradicate a blastic plasmacytoid dendritic cell neoplasm line, suggesting a novel therapeutic avenue for this disease. Greater reductions in soluble BCMA correlate with enhanced CAR T expansion and systemic inflammation. These findings reveal cellular mechanisms driving differential efficacy and toxicity of BCMA-directed immunotherapy.
Authors
- Maik Friedrich (ORCID: https://orcid.org/0000-0002-7221-4222)
- Lukas Scheller (ORCID: https://orcid.org/0000-0002-0912-1808)
- Lorenz Christian Hofbauer (ORCID: https://orcid.org/0000-0002-8691-8423)
- Markus Kreuz (ORCID: https://orcid.org/0000-0002-0520-8391)
- Zsolt Sebestyén (ORCID: https://orcid.org/0000-0001-6184-7676)
- Farid Keramati (ORCID: https://orcid.org/0000-0002-3034-4133)
- Hermann Einsele (ORCID: https://orcid.org/0000-0002-7680-0819)
- Enrica Bach
- Miriam Alb (ORCID: https://orcid.org/0000-0001-6454-9906)
- Klaus Hans Metzeler (ORCID: https://orcid.org/0000-0003-3920-7490)
- Carmen Herling
- Péter Brázda (ORCID: https://orcid.org/0000-0002-0215-1692)
- Anja Grahnert (ORCID: https://orcid.org/0000-0001-5239-5735)
- Marco Herling (ORCID: https://orcid.org/0000-0001-7473-7476)
- Sabine Seiffert (ORCID: https://orcid.org/0000-0002-6850-4796)
- Vladan Vučinić (ORCID: https://orcid.org/0000-0002-8398-285X)
- Michael Rade (ORCID: https://orcid.org/0000-0001-6247-9289)
- Jonathan Scolnick
- Ulrike Koehl (ORCID: https://orcid.org/0000-0002-8159-9160)
- Kristin Reiche (ORCID: https://orcid.org/0000-0002-4452-4872)
- Song‐Yau Wang (ORCID: https://orcid.org/0000-0001-5433-8750)
- Jurgen H. E. Kuball (ORCID: https://orcid.org/0000-0002-3914-7806)
- Madlen Jentzsch (ORCID: https://orcid.org/0000-0002-2270-0804)
- Patrick Born (ORCID: https://orcid.org/0009-0002-8463-5179)
- Uwe Platzbecker (ORCID: https://orcid.org/0000-0003-1863-3239)
- Mirco Friedrich (ORCID: https://orcid.org/0000-0002-6401-3623)
- Heike Weidner (ORCID: https://orcid.org/0009-0001-6045-3349)
- Maximilian Merz (ORCID: https://orcid.org/0000-0002-2805-5973)
- David Fandrei (ORCID: https://orcid.org/0009-0006-4014-6030)
- Sandra Hoffmann (ORCID: https://orcid.org/0000-0003-1078-8412)
- Luise Fischer (ORCID: https://orcid.org/0009-0006-3619-2958)
- Georg‐Nikolaus Franke (ORCID: https://orcid.org/0000-0001-8239-002X)
- Ronny Baber
- Andreas Boldt
- Michael Hudecek
- Thomas C. Wiemers (ORCID: https://orcid.org/0009-0000-2053-3857)
Institutions
- Broad Institute (US)
- Utrecht University (NL)
- University Medical Center Utrecht (NL)
- University Hospital Leipzig (DE)
- Universitätsklinikum Würzburg (DE)
- Princess Máxima Center (NL)
- Fraunhofer Institute for Cell Therapy and Immunology (DE)
- University Hospital Carl Gustav Carus (DE)
- Leipzig University (DE)
Publication Details
- Journal
- Cancer Cell
- Published
- 2025-12-04
- DOI
- https://doi.org/10.1016/j.ccell.2025.10.014
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 1.05