AUTHOR=Morgan Heather T. , Derman Benjamin A. , Ma Hong , Kumar Shaji K. 

TITLE=Changing lanes: extending CAR T-cell therapy to high-risk plasma cell dyscrasias

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1558275

DOI=10.3389/fimmu.2025.1558275

ISSN=1664-3224

ABSTRACT=Chimeric antigen receptor (CAR) cellular therapies have advanced outcomes in challenging hematologic malignancies like leukemia, lymphoma, and multiple myeloma. Plasma cell-directed CAR T-cell therapies have been particularly beneficial in multiple myeloma, suggesting that these agents may have a role in other challenging plasma cell disorders such as systemic AL amyloidosis and plasma cell leukemia. AL amyloidosis is a monoclonal plasma cell disorder resulting in the deposition of protein fibrils that compromise end-organ function. Delays in diagnosis can result in end-organ dysfunction and organ failure, making designing and completing treatment difficult. Plasma cell leukemia (PCL) is a rare and highly challenging malignancy with dismal survival outcomes despite aggressive therapy. Both diagnoses are currently treated with regimens borrowed from myeloma: a combination of novel agents and chemotherapy induction, then autologous stem cell transplantation (ASCT), with the current practice trending towards consolidation and maintenance. Unfortunately, only 20% of AL amyloidosis patients are transplant-eligible at diagnosis. Those transplant-ineligible (TIE) patients are treated with combination induction chemotherapy, which may be limited by worsening disease-related end-organ dysfunction. Plasma cell leukemia patients are still very likely to relapse after this intensive and prolonged therapy. Despite the promise of a shorter course of therapy, CAR T-cell therapies directed against plasma cells have not been rigorously investigated in patients with AL amyloidosis or PCL; most trials of MM have excluded these patients. Herein, we describe current treatment paradigms for AL amyloidosis and PCL and review the evidence for CAR T-cell therapies in these challenging plasma cell disorders. Further investigation into CAR T-cell therapies for plasma cell disorders other than multiple myeloma is warranted.