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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	586-603.e9
Journal	Cancer Cell
Volume	44
Issue number	3
Early online date	4 Dec 2025
DOIs	https://doi.org/10.1016/j.ccell.2025.10.014
Publication status	Published - 9 Mar 2026

Keywords

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

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Rade, M., Fandrei, D., Kreuz, M., Seiffert, S., Grahnert, A., Friedrich, M., Wiemers, T., Born, P., Fischer, L., Weidner, H., Hofbauer, L. C., Baber, R., Wang, S. Y., Bach, E., Hoffmann, S., Scolnick, J., Friedrich, M., Keramati, F., Brazda, P., ... Merz, M. (2026). A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma. Cancer Cell, 44(3), 586-603.e9. https://doi.org/10.1016/j.ccell.2025.10.014

@article{7d19b81d702d461ba42ba9bfca9ede41,

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

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, blastic plasmacytoid dendritic cell neoplasm, chimeric antigen receptor T cells, multiple myeloma, single-cell sequencing, T cell receptor",

author = "Michael Rade and David Fandrei and Markus Kreuz and Sabine Seiffert and Anja Grahnert and Maik Friedrich and Thomas Wiemers and Patrick Born and Luise Fischer and Heike Weidner and Hofbauer, \{Lorenz C.\} and Ronny Baber and Wang, \{Song Yau\} and Enrica Bach and Sandra Hoffmann and Jonathan Scolnick and Mirco Friedrich and Farid Keramati and Peter Brazda and Zsolt Sebestyen and J{\"u}rgen Kuball and Miriam Alb and Lukas Scheller and Michael Hudecek and Hermann Einsele and Metzeler, \{Klaus H.\} and Marco Herling and Herling, \{Carmen Diana\} and Madlen Jentzsch and Franke, \{Georg Nikolaus\} and Andreas Boldt and Ulrike K{\"o}hl and Uwe Platzbecker and Vladan Vucinic and Kristin Reiche and Maximilian Merz",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2026",

month = mar,

day = "9",

doi = "10.1016/j.ccell.2025.10.014",

language = "English",

volume = "44",

pages = "586--603.e9",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

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Rade, M, Fandrei, D, Kreuz, M, Seiffert, S, Grahnert, A, Friedrich, M, Wiemers, T, Born, P, Fischer, L, Weidner, H, Hofbauer, LC, Baber, R, Wang, SY, Bach, E, Hoffmann, S, Scolnick, J, Friedrich, M, Keramati, F , Brazda, P , Sebestyen, Z , Kuball, J, Alb, M, Scheller, L, Hudecek, M, Einsele, H, Metzeler, KH, Herling, M, Herling, CD, Jentzsch, M, Franke, GN, Boldt, A, Köhl, U, Platzbecker, U, Vucinic, V, Reiche, K & Merz, M 2026, 'A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma', Cancer Cell, vol. 44, no. 3, pp. 586-603.e9. https://doi.org/10.1016/j.ccell.2025.10.014

TY - JOUR

T1 - A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma

AU - Rade, Michael

AU - Fandrei, David

AU - Kreuz, Markus

AU - Seiffert, Sabine

AU - Grahnert, Anja

AU - Friedrich, Maik

AU - Wiemers, Thomas

AU - Born, Patrick

AU - Fischer, Luise

AU - Weidner, Heike

AU - Hofbauer, Lorenz C.

AU - Baber, Ronny

AU - Wang, Song Yau

AU - Bach, Enrica

AU - Hoffmann, Sandra

AU - Scolnick, Jonathan

AU - Friedrich, Mirco

AU - Keramati, Farid

AU - Brazda, Peter

AU - Sebestyen, Zsolt

AU - Kuball, Jürgen

AU - Alb, Miriam

AU - Scheller, Lukas

AU - Hudecek, Michael

AU - Einsele, Hermann

AU - Metzeler, Klaus H.

AU - Herling, Marco

AU - Herling, Carmen Diana

AU - Jentzsch, Madlen

AU - Franke, Georg Nikolaus

AU - Boldt, Andreas

AU - Köhl, Ulrike

AU - Platzbecker, Uwe

AU - Vucinic, Vladan

AU - Reiche, Kristin

AU - Merz, Maximilian

PY - 2026/3/9

Y1 - 2026/3/9

N2 - 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.

AB - 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.

KW - B cell maturation antigen

KW - blastic plasmacytoid dendritic cell neoplasm

KW - chimeric antigen receptor T cells

KW - multiple myeloma

KW - single-cell sequencing

KW - T cell receptor

UR - https://www.scopus.com/pages/publications/105024198746

U2 - 10.1016/j.ccell.2025.10.014

DO - 10.1016/j.ccell.2025.10.014

M3 - Article

C2 - 41349540

SN - 1535-6108

VL - 44

SP - 586-603.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

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