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

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

Free article

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

Michael Rade et al. Cancer Cell. 2025.

Free article

. 2025 Dec 4:S1535-6108(25)00490-8.

doi: 10.1016/j.ccell.2025.10.014. Online ahead of print.

Authors

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.

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Conflict of interest statement

Declaration of interests M.M.: advisory boards, honoraria and research support for/from Amgen, BMS, Celgene, Gilead, Janssen, Stemline, SpringWorks, Sanofi, Takeda. M.H: advisory boards and honoraria for/from Abbvie, Beigene, Jazz, Janssen, Stemline Menarini Takeda; research support from EDO-Mundipharma, Janpix, Novartis, Roche. U.K.: consultant and/or speaker fees from AstraZeneca, Affimed, Glycostem, GammaDelta, Zelluna, Miltenyi Biotec, Novartis Pharma, Bristol-Myers Squibb. K.H.M.: consultancy, honoraria and/or research support from BMS, AbbVie, Pfizer, Otsuka, Janssen, Novartis. K.R.: honoraria from Novartis. L.S.: honoraria from Swedish Orphan Biovitrum. L.S., M.H. and M.A.: patent applications and granted patents related to CAR T technologies. M.H.: co-founder and equity owner of T-CURX GmbH;honoraria from Celgene/BMS, Janssen, Kite/Gilead. H.E.: honoraria from Pfizer, Amgen, Janssen, Sanofi, BMS. U.P.: consultancy, honoraria and/or research funding from Syros, Silence Therapeutics, Takeda, Servier, Novartis, Jazz, Celgene, FibroGen, Roche, Merck, Amgen, AbbVie, Curis, Janssen Biotech, BeiGene, Geron, MDS Foundation (membership on an entity’s Board of Directors or advisory committees), Bristol-Myers Squibb (consultancy, honoraria, membership on an entity’s Board of Directors or advisory committees, other, travel support, medical writing support, research funding). M.J.: honoraria from Novartis, Amgen, Pfizer, Blueprint Medicine, BMS, Jazz. L.C.H.:funding for clinical trials from Alexion, Amolyte, Ascendis to his institution, and honoraria from Ascendis, Amgen, UCB for consultancies and adboards to himself. V.V.: advisory boards for Janssen Cilag, BMS Celgene, MSD, Novartis, Sobi, Caribou and honoraria from Novartis, Gilead Kite, BMS Celgene, Janssen Cilag, Sobi, Amgen, Abbvie, Takeda. All other authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Research Materials