Both CART and bispecific antibody (BsAb), as T-cell directed therapies, have yielded impressive clinical responses in patients with relapsed, refractory multiple myeloma (MM) and are now FDA approved in standard of care (SOC) practice. However, durable remissions continue to be low, and most patients relapse in the first 1-3 years. Uncovering the underlying mechanisms of resistance is critical to improve durable remission of T-cell directed therapies. We have identified two novel, T-cell extrinsic, mechanisms of resistance for mechanistic studies and therapeutic development: 1) Myeloma cells intrinsic resistance to killing by entering into a dormant state; 2) Myeloma microenvironment suppression of T cell activities via bone marrow cancerassociated fibroblasts (BM-CAFs). We and others have shown that tumor cells can enter into a dormant, non-growing state after exposure to chemotherapy and radiation. These cells exhibit features of increased signaling in senescence, anti-apoptosis pathways, but are not permanently senescent or growth arrested. They can then re-enter into proliferation and contribute to disease relapse and progression. Thus, this therapy-induced dormancy (TID) state is a novel mechanism of tumor cell intrinsic resistance to therapy. We have found that myeloma cells can adopt this senescent and myeloid-like profile after treatment, and that increased presence of these TID-MM cells in the bone marrow of patients prior to CART infusion is associated with shorter PFS post CART. In addition, our group has recently published a novel mechanism for resistance to CART cells by BM-CAFs. Specifically, our studies indicate that BM-CAFs from patients with MM significantly inhibit CART cell functions in preclinical models through complex mechanisms that involve secretion of suppressive cytokines as well as expression of inhibitory and apoptosis proteins. This provides a rationale to directly target CAFs as a strategy to improve CART therapy. BM-CAFs in MM express high levels of fibroblast activating protein (FAP) and CS1 (also known as SLAMF7), and targeting both MM cells and BM-CAFs with dual BCMA-FAP CART cells or BCMA-CS1 CART cells is more potent compared to single-targeted BCMA-CART cells and is resistant to inhibition by BM-CAFs. Our additional preliminary studies demonstrate that a) dual targeting of MM and BM-CAFs by CART cells is safe in preclinical models, and b) targeting FAP can be enhanced through the utilization of BCMA-CART cells which secrete novel FAP-directed proteins. These preliminary data have informed our central hypothesis that resistance to BCMA-CART cell therapy is mediated by myeloma intrinsic mechanisms through the therapy-induced dormant MM cells and TME through CAF-mediated T-cell inhibition.