A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma

Michael Rade; David Fandrei; Markus Kreuz; Sabine Seiffert; Anja Grahnert; Maik Friedrich; Thomas Wiemers; Patrick Born; Luise Fischer; Heike Weidner; Lorenz C Hofbauer; Ronny Baber; Song Yau Wang; Enrica Bach; Sandra Hoffmann; Jonathan Scolnick; Mirco Friedrich; Farid Keramati; Peter Brazda; Zsolt Sebestyen; Jürgen Kuball; Miriam Alb; Lukas Scheller; Michael Hudecek; Hermann Einsele; Klaus H Metzeler; Marco Herling; Carmen Diana Herling; Madlen Jentzsch; Georg-Nikolaus Franke; Andreas Boldt; Ulrike Köhl; Uwe Platzbecker; Vladan Vucinic; Kristin Reiche; Maximilian Merz

doi:10.1016/j.ccell.2025.10.014

A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma

Cancer Cell. 2025 Dec 4:S1535-6108(25)00490-8. doi: 10.1016/j.ccell.2025.10.014. Online ahead of print.

Authors

Michael Rade¹, David Fandrei², Markus Kreuz¹, Sabine Seiffert³, Anja Grahnert³, Maik Friedrich³, Thomas Wiemers⁴, Patrick Born⁴, Luise Fischer⁴, Heike Weidner⁵, Lorenz C Hofbauer⁵, Ronny Baber⁶, Song Yau Wang⁴, Enrica Bach⁴, Sandra Hoffmann⁴, Jonathan Scolnick⁷, Mirco Friedrich⁸, Farid Keramati⁹, Peter Brazda¹⁰, Zsolt Sebestyen¹¹, Jürgen Kuball¹¹, Miriam Alb¹², Lukas Scheller¹³, Michael Hudecek¹², Hermann Einsele¹³, Klaus H Metzeler⁴, Marco Herling⁴, Carmen Diana Herling⁴, Madlen Jentzsch⁴, Georg-Nikolaus Franke⁴, Andreas Boldt³, Ulrike Köhl¹⁴, Uwe Platzbecker¹⁵, Vladan Vucinic⁴, Kristin Reiche¹⁶, Maximilian Merz¹⁷

Affiliations

¹ Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.
² Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany; Department of Hematology, Cell Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany; Cancer Center Central Germany (CCCG) Leipzig-Jena, University Hospital of Leipzig, Leipzig, Germany.
³ Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig, Germany.
⁴ Department of Hematology, Cell Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany; Cancer Center Central Germany (CCCG) Leipzig-Jena, University Hospital of Leipzig, Leipzig, Germany.
⁵ Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III & Center for Healthy Aging, Medical Faculty and University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
⁶ Institute for Laboratory Medicine Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; Leipzig Medical Biobank, University Leipzig, Leipzig, Germany.
⁷ Singleron Biotechnologies, Singapore, Singapore.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
¹⁰ Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹¹ Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
¹² Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany; Department of Internal Medicine II, Chair of Cellular Immunotherapy, University Hospital Würzburg, Würzburg, Germany.
¹³ Department of Internal Medicine II, Chair of Cellular Immunotherapy, University Hospital Würzburg, Würzburg, Germany.
¹⁴ Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany; Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig, Germany; Cancer Center Central Germany (CCCG) Leipzig-Jena, University Hospital of Leipzig, Leipzig, Germany.
¹⁵ Department of Hematology, Cell Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany; Cancer Center Central Germany (CCCG) Leipzig-Jena, University Hospital of Leipzig, Leipzig, Germany; University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
¹⁶ Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany; Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig, Germany; Cancer Center Central Germany (CCCG) Leipzig-Jena, University Hospital of Leipzig, Leipzig, Germany; Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Dresden, Leipzig, Germany.
¹⁷ Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany; Department of Hematology, Cell Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany; Cancer Center Central Germany (CCCG) Leipzig-Jena, University Hospital of Leipzig, Leipzig, Germany; Myeloma and Cellular Therapy Services, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: merzm@mskcc.org.

PMID: 41349540
DOI: 10.1016/j.ccell.2025.10.014

Abstract

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⁺ cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8⁺ 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.

Keywords: B cell maturation antigen; T cell receptor; blastic plasmacytoid dendritic cell neoplasm; chimeric antigen receptor T cells; multiple myeloma; single-cell sequencing.