Phenotypic and genomic analysis of multiple myeloma minimal residual disease clonal plasma cells: a new model to understand chemoresistance [HuGene-1_0 Expression]

Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) relates to inferior survival in multiple myeloma (MM). MRD PCs are therefore a minor clone able to recapitulate the initial tumor burden at relapse and accordingly, its characterization may represent a unique model to understand chemoresistance; unfortunately, the MRD clone has never been biologically investigated. Here, we compared the antigenic profile of MRD vs. diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study, and showed that the MRD clone is enriched by cells over-expressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4) and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs. diagnostic PCs showed identical copy number alterations (CNAs) in 3/8 cases, 2 patients with linear acquisition of additional CNAs in MRD clonal PCs, and 3 cases with variable acquisition and loss of CNAs over time. The MRD clone showed significant downregulation of genes particularly related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and identifies chemoresistant PCs in vitro. Together, we show that therapy-induced clonal selection is already present at the MRD stage, in which chemoresistant PCs show a specific phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. Gene expression profiling (GEP) was performed in matched diagnostic and MRD clonal PCs from 7 cases with adequate RNA extracted from CD138+ and patient-specific phenotypically aberrant FACS-purified tumor cells, respectively.