Human preclinical multiple myeloma in vitro models for disease modeling and therapy screening.

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled expansion of malignant plasma cells within the bone marrow microenvironment. While suspension cultures of MM cell lines and murine models have been the cornerstone of research with MM pathogenesis, these conventional systems fail to recapitulate critical aspects of the human tumor microenvironment. Specifically, current models inadequately address key biological questions including mechanisms of drug resistance acquisition, immune evasion strategies, and the role of cellular crosstalk in disease progression. These limitations stem from the absence of physiologically relevant extracellular matrix architecture, lack of primary human stromal and immune cell populations, and inability to model the bone marrow niche with functional vasculature. Three-dimensional (3D) culture platforms have emerged to address these deficiencies by incorporating structural complexity and cellular heterogeneity. However, many existing 3D models remain insufficient for comprehensive MM modeling, as they typically lack integrated human-derived stromal compartments, functional immune surveillance mechanisms, and physiological vascular networks that collectively regulate MM pathobiology. Advanced humanized in vitro models-particularly those incorporating patient-derived cells within immunocompetent microenvironments-are needed to bridge the translational gap between preclinical findings and clinical outcomes. We analyze the evolution from conventional in suspension cultures to current organotypic systems while examining their applications in mechanistic studies and capabilities in therapeutic screening. Lastly, we outline the emerging challenges in model development and propose future research directions, with particular emphasis on establishing fully humanized, immunocompetent platforms that authentically reproduce the bone marrow ecosystem for predictive drug testing.