Extramedullary disease shapes toxicity risk in BCMA CAR T therapy

Multiple myeloma is a cancer of plasma cells, immune cells that normally reside in the bone marrow and produce antibodies to fight infection. Many modern treatments for advanced multiple myeloma target B-cell maturation antigen (BCMA), a protein found at high levels on the surface of myeloma cells but largely absent from most healthy tissues. By engineering a patient’s own immune cells to recognize BCMA, CAR T cell therapies have led to deep and sometimes long-lasting responses. However, not all patients benefit equally, highlighting the need to better understand factors that influence both treatment effectiveness and safety.

One particularly aggressive presentation, known as extramedullary disease (EMD), occurs when myeloma cells spread outside the bone marrow into soft tissues. Patients with EMD tend to have poorer outcomes, and prior studies have shown that they respond less well to BCMA-directed CAR T therapy. What has been less clear is whether EMD also changes the safety profile of these treatments—specifically, whether it puts patients at higher risk for treatment-related toxicities and complications.

In a retrospective study recently published in Haematologica, researchers from Dr. Jordan Gauthier’s group examined outcomes in patients with multiple myeloma treated with the BCMA-targeted CAR T therapies idecabtagene vicleucel (Abecma) or ciltacabtagene autoleucel (Carvykti) at a single institution. By comparing patients with and without active EMD, the team evaluated not only treatment efficacy and survival, but also immune-related toxicities, blood count recovery, and infectious complications. Their findings reveal that EMD is linked to significantly higher toxicity, slower recovery of blood counts, and worse survival—uncovering an important and previously underappreciated risk factor in CAR T-treated myeloma patients.

These toxicities included immune effector cell–associated neurotoxicity syndrome (ICANS), which affects the brain and nervous system, and early immune effector cell–associated hematotoxicity (eICAHT), marked by prolonged suppression of blood cell production following treatment. They also examined the potential effects on cytokine release syndrome (CRS), which can cause symptoms ranging from flu-like fever and fatigue to severe organ dysfunction. While the incidence of CRS was similar between groups, patients with EMD took longer to recover.

“While EMD has long been recognized as a marker of poor efficacy with BCMA CAR T-cell therapy, our study is the first to clearly demonstrate that EMD is also a major determinant of treatment-related toxicity,” shared lead author Dr. Andrew Portuguese. “We show that patients with EMD experience disproportionately severe neurotoxicity, prolonged and profound hematologic toxicity, higher infectious complications, and markedly increased non-relapse mortality. These findings shift EMD from being viewed solely as a predictor of resistance to also being a critical safety risk factor, with direct implications for patient selection, supportive care, and risk stratification in real-world CAR T practice.”

In other words, the study suggests that EMD changes how patients tolerate CAR T therapy, not just whether it works. Patients with EMD were more likely to develop serious neurologic side effects and prolonged suppression of blood counts, which in turn increased their risk of infection and treatment-related death. These complications often required intensive supportive care, including longer hospital stays, repeated transfusions, and extended courses of antibiotics. The authors propose that this heightened vulnerability may stem from a pre-existing inflammatory and clotting imbalance in EMD patients, indicated by elevated inflammatory markers even before treatment, which may leave patients less able to tolerate the intense immune activation triggered by CAR T cells.

“Our findings raise important questions about the biological mechanisms linking EMD to immune-mediated toxicity. The heightened baseline inflammation and coagulopathy observed in EMD patients suggest that tumor-driven systemic immune dysregulation may prime patients for severe CAR T-associated toxicities,” suggests Dr. Portuguese. “Moving forward, our research will focus on integrating tissue-based analyses of EMD with peripheral biomarkers to better define these mechanisms, as well as evaluating risk-adapted strategies such as targeted cytoreduction, enhanced infection prophylaxis, and early supportive interventions to improve the safety of CAR T therapy in this high-risk population.”

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Andrew Portuguese, Emily Liang, Danai Dima, Rahul Banerjee, Mary Kwok, Alexandre Hirayama, Mazyar Shadman, Lawrence Fong, and Jordan Gauthier contributed to this research.

The spotlighted research was funded by Kuni Foundation, Swim Across America and the National Institutes of Health.

Portuguese AJ, Liang EC, Huang JJ, Jeon Y, Dima D, Banerjee R, Kwok M, Cicero KI, Hirayama AV, Basom R, Khouderchah C, Shadman M, Fong L, Cowan AJ, Gauthier J. 2025. Extramedullary disease is associated with severe toxicities following B-cell maturation antigen CAR T-cell therapy in multiple myeloma. Haematologica. DOI: 10.3324/haematol.2025.287985.