Differentiation stage of myeloma plasma cells: biological and clinical significance

The notion that plasma cells (PCs) are terminally-differentiated has prevented intensive research in multiple myeloma (MM) about their phenotypic plasticity and differentiation. Here, we demonstrated in healthy individuals (n=20) that the CD19-CD81 expression axis identifies three bone marrow (BM)PC subsets with distinct age-prevalence, proliferation, replication-history, immunoglobulin-production, and phenotype, consistent with progressively increased differentiation from CD19+CD81+ into CD19-CD81+ and CD19-CD81- BMPCs. Afterwards, we demonstrated in 225 newly-diagnosed MM patients that, comparing to normal BMPC counterparts, 59% had fully-differentiated (CD19-CD81-) clones, 38% intermediate-differentiated (CD19-CD81+), and 3% less-differentiated (CD19+CD81+) clones. The latter patients had dismal outcome, and PC differentiation emerged as an independent prognostic marker for progression-free (HR:1.7;P=.005) and overall survival (HR:2.1;P=.006). Longitudinal comparison of diagnostic vs. minimal-residual-disease samples (n=40) unraveled that in 20% of patients, less-differentiated PCs subclones become enriched after therapy-induced pressure. We also revealed that CD81 expression is epigenetically regulated, that less-differentiated clonal PCs retain high expression of genes related to preceding B-cell stages (e.g.:PAX5), and show distinct mutation profile vs. fully-differentiated PC clones within individual patients. Together, we shed new light into PC plasticity and demonstrated that MM patients harboring less-differentiated PCs have dismal survival, which might be related to higher chemoresistant potential plus different molecular and genomic profiles