Spatial imaging unlocks the potential of charting multiple myeloma and extramedullary disease.

Extramedullary disease (EMD) in multiple myeloma (MM) represents a significant clinical challenge, with a limited understanding of the spatial architecture and its pathobiological impact. To address this unmet need, we examined 10 matched samples from bone marrow (BM) and cognate EMD sites. This investigation provides critical insights into the distinct features of EMD, offering potential avenues for more effective diagnosis and targeted therapies. To this aim, we employed MACSima™ Imaging Cyclic Staining (MICS) to unveil distinct biomarker expression profiles as companion diagnostics for a personalized therapeutic approach for MM. We observed elevated BCL-2 levels in EMD plasma cells (p < 0.0001), indicating the potential of BCL-2 inhibitors to target anti-apoptotic pathways in select cases. The higher expression of EZH2 in EMD compared to BM (p < 0.0001) highlights its role in sustaining aggressive tumor phenotypes and supports the use of epigenetic-targeting agents in key situations. In contrast, CD3 + T-cell distance was significantly higher in EMD, reflecting impaired immune surveillance (p < 0.0001). Across the cohort, our analysis revealed significant differences between BM and EMD regarding the expression and spatial organization of key markers. CD38 expression was markedly reduced in EMD plasma cells (p < 0.0001). These findings underscore profound biological heterogeneity in MM and its BM emancipated disease phenotype, emphasizing dysfunctional apoptosis, immune evasion and resistance to CD38-targeting therapies in EMD, conceivably informing future validations. By integrating high-dimensional data, this study provides insights into potential druggable vulnerabilities for crafted interventions, particularly challenging in EMD cases.