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Background:Multiple Myeloma (MM) is a malignancy of mature plasma cells, primarily affecting patients over 65, with a 5-year survival rate of ~62%. Aging alters the bone marrow (BM) microenvironment, including remodeling of the extracellular matrix (ECM), which may promote tumor-supportive functions of mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs). However, determining the impact of aging-related matrix remodeling on MM onset/progression remains challenging due to the absence of microphysiological systems that preserve the tumorigenic phenotype of MM cells in vitro. We hypothesize that recapitulating aged BM ECM may overcome these limitations by providing a physiologically relevant microenvironment that sustains MM cell behavior and models tumor-supportive functions. Additionally, we expect that interleukin-6 (IL-6), an inflammatory cytokine elevated in both the inflammaging BM microenvironment and MM, preferentially expands MM-associated MSCs without affecting HSCs. Methods:Cryopreserved tumor-associated MSCs and HSCs were cultured on tissue culture plastic (TCP), young ECM (≤25 y/o), or aged ECM (≥60 y/o), in either α-MEM or IMDM media, with or without IL-6. HSC cluster formation was observed, and cells were analyzed using Cytospin with Giemsa-May-Grünwald staining. Results:MM-derived HSCs, cultured on aged ECM, but not young, exhibited myelopoietic skewing. In contrast, young ECM supplemented with IL-6 promoted MSC expansion, suggesting a synergistic effect in developing patient-derived stromal models. Adherent MSCs were harvested and expanded on TCP to produce ECM. Conclusion:ECM-based microphysiological systems offer a promising, scalable approach for recapitulating aging- and MM-associated remodeling of the BM microenvironment. Understanding how aged ECM drives myeloid skewing may reveal therapeutic targets to delay/prevent MM progression. The observed myeloid bias in MM-derived HSCs cultured on aged ECM may reflect physiologically relevant disruptions in immunoregulatory cell populations. Future work will test whether ECM from MM patient-derived MSCs preserves tumor-specific phenotypes to advance translational models for MM drug discovery.