- Review
Overcoming Microenvironment-Driven Resistance to CAR-T Therapy in Multiple Myeloma
- Gabriel Saez,
- Randy Khusial and
- Heather Kissel
- + 3 authors
B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for relapsed or refractory multiple myeloma (MM), with products such as idecabtagene vicleucel and ciltacabtagene autoleucel achieving high initial response rates, and in selected patient populations, durable treatment-free remission. However, a substantial proportion of patients still experience relapse, including antigen-positive progression, highlighting persistent limitations in long-term disease control across diverse clinical settings. An increasing body of evidence indicates that resistance to CAR-T therapy in MM is driven not only by tumor-intrinsic factors, but also by extrinsic pressures imposed by the bone marrow microenvironment (BMME). This review integrates current understanding of tumor-niche interactions that impair CAR-T persistence, trafficking, and effector function, including immunosuppressive cellular networks, inhibitory cytokine signaling, metabolic constraints, stromal adhesion, antigen modulation, and marrow remodeling. This review further examines emerging therapeutic strategies and next-generation CAR-T platforms.
5 March 2026




![Conceptual framework for managing TDLNs in the immunotherapy era [14]. Effective immune checkpoint blockade depends on an intact tumor–lymph node axis, in which TDLNs function as active immune organs that coordinate antigen presentation, expansion of Tpex cells, and effector recirculation. Traditional strategies—elective ND and broad-field elective nodal irradiation—achieve regional control but may simultaneously ablate or chronically damage non-involved nodal basins, creating an “immune desert neck” that attenuates immunotherapy efficacy. HNC, head and neck cancer; ICI, immune checkpoint inhibitor; IO, immunotherapy; LN, lymph node.](https://mdpi-res.com/cdn-cgi/image/w=281,h=192/https://mdpi-res.com/lymphatics/lymphatics-04-00013/article_deploy/html/images/lymphatics-04-00013-g001-550.jpg)
