Multiple myeloma, a cancer of bone marrow-resident plasma cells, is the 2nd-most common hematological malignancy. However, despite the advent of immunotherapies like chimeric antigen receptor T (CAR-T) cells, which gained FDA approval in March 2021, relapse is nearly universally inevitable. The bone marrow (BM) microenvironment influences how MM cell survive, proliferate, and interact with stromal cells and how treatment resistance and relapses arise; yet it is unclear which BM niches (endosteal, central marrow, and perivascular) interact with MM and how various cells of the BM give rise to MM phenotypes and pathophysiology. Therefore, it is important to recapitulate each niche in any in vitro MM model. The overall hypothesis of the proposed work is that a 3D, multi-niche, microvascularized culture system will accurately model primary MM behavior and allow us to study MM interactions with stromal cells in the BM as well as model the responses to therapeutic cells. To that end, a microphysiologic, microvascularized model of human MM is proposed to enable the introduction of various agents in order to study MM’s response to external stimuli. The overall objective is to investigate the heterogeneity within and among MM samples and create a physiologically relevant model of MM that accurately models the behavior of adoptively-transferred CAR-T cells. We shall do this in 3 specific aims: 1) Create and characterize a microvascularized, microphysiological human bone marrow model to recapitulate the tumor microenvironment of multiple myeloma. 2) Study the interaction of CAR-T cell subsets with the MM model. 3) Compare the behavior of CAR-T cell subsets within the MM-chip to an in vivo model of MM. If successful, the proposed work could be used to study the role of the BM microenvironment in multiple myeloma survival and therapeutic evasion and may eventually be used to better-inform the rational design of next-generation MM therapeutics.