Genotypic identification of polyclonal plasma cells in plasma cell dyscrasias shows an aberrant single-cell phenotype with clinical implications

Multiple Myeloma (MM) is driven by clonal plasma cell (PC)-intrinsic factors and changes in the tumorigenic microenvironment (TME). To investigate if residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNAseq and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 18 healthy donors (HDs). Out of n= 213,074 CD138pos PCs, 42,717 were genotypically identified as pPCs. Compared to HDs, we detected quantitative and qualitative differences in pPCs of patients showing immunoparesis, where we showed a pro-inflammatory status, driven by specific cellular interactions with TME. Finally, we derived a “hPC signature” that, once inferred in the CoMMpass dataset, was predictive of PFS and OS. Our findings show that genotypic, single-cell identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications. ### Competing Interest Statement N.B. received honoraria for Amgen, GSK, Janssen, Jazz, Pfizer, Takeda. M.C.D.V. served as Advisory Board for Takeda, and on Speakers Bureau for Janssen and GSK. F.P. received honoraria during the last two years for lectures from Novartis, Bristol-Myers Squibb, Abbvie, GSK, Janssen, AOP Orphan and for advisory boards from Novartis, Bristol-Myers Squibb/ Celgene, GSK, Abbvie, AOP Orphan, Janssen, Karyiopharma, Kyowa Kirin and MEI, Sumitomo, Kartos. The remaining Authors declare no competing financial interest.