Ex Vivo Treatment Response Prediction in Multiple Myeloma: Assay Formats, Clinical Correlation, and Future Directions.

Ex vivo functional testing for multiple myeloma is rapidly evolving, yet no single assay has reached the level of reliability and clinical utility needed for routine decision-making. Existing approaches generally fall into three categories: 2D cultures, 3D models, and dynamic systems. Each contributes valuable but incomplete insight into therapeutic response. Among these, 2D assays remain the most mature, with the most extensive clinical correlations to date, though their simplified architecture limits their ability to reflect the full complexity of the bone marrow microenvironment. However, 3D systems, including spheroids and matrix-based organoids, offer improved preservation of tumor heterogeneity and microenvironmental cues. These platforms show emerging clinical relevance and may hold advantages over traditional 2D formats, and validation efforts are developing. Dynamic systems, including microfluidic models and perfused bone-marrow mimetics, represent the most physiologically ambitious category, yet their technical intricacy and early stage of development have so far limited broad clinical correlation. Altogether, the current landscape highlights substantial progress but lacks an optimal assay. In this review, we take the unique approach of examining published ex vivo tests that have demonstrated a level of clinical correlation. We evaluate their respective formats, strengths and limitations, and discuss considerations for what an ideal future assay may encompass.