In multiple myeloma, plasma cells multiply uncontrollably in the bone marrow, disrupting the growth of healthy blood-forming cells. If the disease recurs after treatment or if the treatment is unsuccessful, CAR-T cell therapy can be used. In this innovative and personalized cancer immunotherapy, immune cells (T cells) are removed from patients and genetically modified in the laboratory so that they can better recognize and attack cancer cells. The body's own modified cells (CAR-T cells) are then re-administered by infusion. They become active in the body, attack cancer cells, destroy them, and continue to multiply. This is why careful monitoring of patients during and after treatment with CAR-T cell therapy is particularly important.

A research team led by Leipzig University Hospital and the Fraunhofer Institute for Cell Therapy and Immunology IZI has conducted a recent study to analyze in more detail how such living drugs work in the body over a longer period of time. The scientists investigated two CAR-T cell therapies that target the B-cell maturation antigen (BCMA). BCMA is present on the surface of diseased plasma cells and is therefore well suited as a target structure for therapeutic approaches.

The study examined 61 heavily pretreated patients: 34 received CAR T-cell therapy with idecabtagene vicleucel (Ide-Cel) and 27 received therapy with ciltacabtagene autoleucel (Cilta-Cel). Treatment with Cilta-cel led to complete remission in significantly more patients (78% compared to 38% with Ide-cel). In addition, longer progression-free survival was achieved, meaning that the disease remained under control for longer.

Until now, it was assumed that the better treatment success was primarily due to the fact that Cilta-cel has two BCMA-binding domains. However, the reasons for the improved destruction of tumor cells and the different side effects of Cilta-cel and Ide-cel are still not well understood. Therefore, the project team performed single-cell multiomics analyses of a total of 135 blood samples. Such studies allow the molecular properties of individual cells to be recorded over a longer period of time and cell changes to be tracked in detail. It was found that therapy with Cilta-cel causes the proliferation of certain immune cells (CD4⁺ cytotoxic CAR-T cells), which are important for fighting cancer but can also cause side effects.

Dr. Kristin Reiche, head of the Medical Bioinformatics Department at Fraunhofer IZI, explains: "The pharmacokinetics, i.e., how the human body interacts with the two CAR-T cell therapies, differ. Cilta-cel shows a delayed onset of expansion but achieves higher cell counts, which means that the CAR-T cells initially multiply more slowly but more strongly overall. For this reason, cytokine release syndrome, a possible side effect of the therapy, may also occur later."

Prof. Dr. Maximilian Merz, who led the study as senior physician and head of the Multiple Myeloma Department at Leipzig University Hospital together with Dr. Reiche, adds: "Such findings are very important for the treatment of patients. We were able to show that tumor burden, T-cell fitness, and general inflammation in the body also play an important role in the success of CAR-T cell therapy."

The studies conducted are part of the CERTAINTY project. Funded by the European Union, the project aims to develop a virtual patient twin that will improve treatment with personalized cancer immunotherapies in the future.

The results of the study have been published in the journal Cancer Cell. They could serve as a comprehensive resource for identifying clinically actionable biomarkers to optimize patient selection, therapy monitoring, and immune monitoring.

The study “A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma” can be viewed here: https://doi.org/10.1016/j.ccell.2025.10.014 ]

Partners involved in the study

• Fraunhofer Institute for Cell Therapy and Immunology IZI
• University Hospital Leipzig
• University Leipzig
• University Hospital Carl Gustav Carus Dresden at TU Dresden
• Singleron Biotechnologies, Singapore
• Broad Institute of MIT and Harvard, Cambridge, USA
• Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
• University Utrecht, Niederlande
• University Hospital Würzburg
• University Hospital Jena
• Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI)
• Memorial Sloan Kettering Cancer Center, New York, USA