How CAR T-cell therapies target myeloma at the molecular level

Graphical abstract. Credit: Cancer Cell (2025). DOI: 10.1016/j.ccell.2025.10.014

In multiple myeloma, plasma cells proliferate uncontrollably in the bone marrow, disrupting the growth of healthy blood-forming cells. If the disease recurs after treatment or fails to respond, CAR T-cell therapy may be considered. In this innovative and personalized form of cancer immunotherapy, immune cells (T cells) are taken from the patient and genetically modified in the laboratory to enhance their ability to recognize and attack cancer cells. The modified autologous cells (CAR T cells) are then reinfused into the patient. Once active in the body, they seek out and destroy malignant cells.

A research team led by Leipzig University Medical Center and the Fraunhofer Institute for Cell Therapy and Immunology IZI has examined in greater detail how such living, cell-based therapies act in the body over an extended period. The researchers analyzed two CAR T-cell therapies directed against the B-cell maturation antigen (BCMA). BCMA is present on the surface of malignant plasma cells and is therefore a suitable target for therapeutic approaches. The paper is published in the journal Cancer Cell.

The study involved 61 patients: 34 received CAR T-cell therapy with idecabtagene vicleucel (ide-cel) and 27 were treated with ciltacabtagene autoleucel (cilta-cel). Treatment with cilta-cel led to complete remission in a substantially higher proportion of patients—78% compared with 38% for ide-cel. It was also associated with longer progression-free survival, meaning that disease control was maintained for a longer period.

Professor Maximilian Merz, who led the study in his role as senior physician and head of the Multiple Myeloma Unit at the University of Leipzig Medical Center, emphasizes, “Such insights are highly important for patient care. We were able to show that tumor burden, T-cell fitness and overall systemic inflammation play a major role in determining the success of CAR T-cell therapy.”

The reasons for the improved efficacy and the differing side-effect profiles of the two products are still poorly understood. The project team at the University of Leipzig Medical Center and the Fraunhofer IZI therefore carried out single-cell multi-omics analyses on a total of 135 blood samples. Such investigations make it possible to capture the molecular characteristics of individual cells over an extended period and to track cellular changes in detail. The analyses showed that treatment with cilta-cel induces the expansion of certain immune cells that are important for combating cancer but can also give rise to side effects.

Dr. Kristin Reiche, head of the Department of Medical Bioinformatics at the Fraunhofer IZI, explains, “The pharmacokinetics—in other words, how the human body interacts with the two CAR T-cell therapies—differ. Cilta-cel exhibits a delayed onset of expansion but reaches higher cell numbers overall, meaning that CAR T cells proliferate more slowly at first but ultimately more extensively. For this reason, cytokine release syndrome, a possible side effect of the therapy, may also occur later.”

In addition to CAR-T cell therapies, bispecific antibodies have also revolutionized the treatment of multiple myeloma in recent years—three of the four bispecific antibodies currently approved in Germany likewise target the surface molecule BCMA. However, the two therapeutic approaches work in different ways, exhibit distinct pharmacokinetic properties and are currently used without a clearly defined treatment sequence. In this new project, the researchers aim to use comprehensive multi-omics analyses of samples from relapsed myeloma patients to investigate how CAR-T cells and bispecific antibodies might be optimally combined or aligned with one another in the future.

Study reveals why some myeloma patients stay cancer-free for years after CAR T therapy