Abstract 3970: Advancing multiple myeloma research: patient-derived 3D Organ-on-a-Chip models to reveal immunological mechanisms influencing cancer growth and resistance

Abstract Multiple myeloma (MM) is characterized by malignant plasma cells infiltrating the bone marrow. The standard induction therapy for MM includes combining bortezomib, lenalidomide and dexamethasone (VRd); this has recently expanded to include an anti-CD38 antibody, which has improved patient outcomes. Despite the recent advances in treatment, patients with MM commonly relapse and it is a disease that remains ultimately incurable. More advanced patient-derived 3D models would allow a greater understanding of the tumor microenvironment (TME) and how it changes during treatment. This is needed for the identification and validation of new biomarkers for this disease and could aid in predicting individual treatment responses. Longitudinal Olink proteomic data, generated by our group, from the plasma and bone marrow interstitial fluid (BMIF) of patients undergoing VRd induction therapy, allowed us to glean key insights into the changes specific to the bone marrow tumor microenvironment (TME) throughout therapy that can be validated in our 3D MM model system. Our longitudinal data shows elevated interleukin 16 (IL-16) in the BMIF of patients at diagnosis, which decreases following induction therapy. IL-16 is a proinflammatory cytokine that acts as a chemoattractant for CD4+ T cells, myeloid cells and eosinophils, and has also been shown to be essential for proliferation of MM cell lines. Extracellular IL-16 may contribute to tumor growth or influence immune cell recruitment to the bone marrow TME. Its increased presence in the BMIF compared to the plasma suggests a localized role within the bone marrow TME. To further investigate the role of IL-16 in the MM TME we developed a novel, patient-derived organ-on-a-chip model of multiple myeloma bone marrow. Using bone marrow mononuclear cells (BMMC) and donor matched bone marrow stromal cells (BMSC) we developed a complex TME on-chip using primary human cells. Using this model we examined the role of IL-16 and other differentially expressed growth factors on tumor development, hematopoietic stem cell differentiation and cytokine production in the TME. Preliminary data shows an increase in proliferation of malignant MM cells in the presence of IL-16, highlighting IL-16 as a potentially promising therapeutic target. Citation Format: Medbh A. Dillon, Kevin J. Lee, Cole G. Phalen, Aishwarya Chander, Imran McGrath, Love Tӓtting, Troy R. Torgerson, Melinda L. Angus-Hill. Advancing multiple myeloma research: patient-derived 3D Organ-on-a-Chip models to reveal immunological mechanisms influencing cancer growth and resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3970.