Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes. I hypothesized that engineered secretion of the pro-inflammatory cytokine interleukin-18 (IL-18) and multi-antigen targeting could improve CAR T cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed. In contrast, IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type I and II interferon signaling, and utilized macrophages to mediate anti-myeloma activity. Simultaneous targeting of weakly expressed BCMA and BAFF-R with dual-CAR T cells enhanced T cell:target cell avidity, increased overall CAR signal strength, and stimulated anti-myeloma activity. Dual-antigen targeting augmented CAR T cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. These results demonstrate that combination of engineered IL-18 secretion and multi-antigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.