CO20 | Immune dysregulation in multiple myeloma: uncovering the role of non-malignant B cells

B cells are emerging as key contributors to the tumor microenvironment (TME), with growing evidence supporting their functional diversity and prognostic significance. However, their role in plasma cell (PC) dyscrasias’ evolution, including monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM, remains poorly understood. In this scenario, our study aims to investigate the functional properties and B cell receptor (BCR) repertoire changes of B cells in the TME of PC neoplasms.Single cell (sc) 5’ RNAseq coupled with scBCRseq was performed on the CD138- cell fraction of 41 bone marrow aspirate samples collected from 35 patients at diagnosis (7 MGUS, 13 SMM, and 15 MM) and at progression to overt MM (6 paired samples). A control cohort of 12 healthy donors (HDs) (4 internally sourced, 8 from a public repository) was included. Bioinformatic analysis was conducted using the Seurat pipeline, Gene Set Enrichment Analysis with ClusterProfiler, interactome analysis with Multinichenet, and BCR repertoire profiling applying scRepertoire and Immcantation workflow.We analyzed a total of 131,814 CD138⁻ cells, of which 11,716 were labelled as B cells according to the BoneMarrowMap reference atlas. In MM, compared to asymptomatic stages, there was a significant depletion of precursor stages such as pro- and pre-B cells (p