Spatial profiling of extramedullary multiple myeloma demonstrates immune-excluded and suppressive tumor microenvironment

Extramedullary myeloma (EMD) exhibits aggressive clinical behavior and resistance to immunotherapies, yet its immune microenvironment remains poorly defined. Solitary plasmacytoma (SPM), a localized plasma cell neoplasm with favorable outcomes, provides a comparator regarding immune control. Imaging mass cytometry was performed on two EMD and two SPM biopsies for single-cell phenotyping and spatial mapping. Composition, checkpoint receptor expression, nearest-neighbor distances, and cell-cell interactions were compared between entities. Cell proportions were similar between groups; spatial analyses revealed reorganization of immune niches in EMD, with increased separation of plasma cells from dendritic and helper T cells. Interaction modeling showed an organized immune microenvironment in EMD with reduced interaction of malignant plasma cells with effector immune populations. In SPM, we found an evenly distributed immune architecture. EMD demonstrated higher expression of inhibitory receptors, including TIGIT, PD-1, PD-L1, and TIM-3 on both helper and cytotoxic T cells, consistent with an exhausted phenotype. This analysis demonstrates that EMD is characterized by spatial decoupling of effector cells from antigen presentation and malignant plasma cells, together with enhanced regulatory interactions. These findings suggest that a spatically excluded immune architecture contributes to immune escape in EMD and may contribute to the limited responsiveness to current immunotherapies.