Expression Signature of Myeloma Residual Cells Is Characterized By Genes Associated with Proliferation, Epigenetic Modification, and Stem Cell Maintenance

Background Despite significant progress in the treatment of multiple myeloma (MM), 30% of patients relapse within 3 years of diagnosis. Recent data indicate that intervention before relapse would benefit most patients with high-risk MM and a significant proportion (38%) of low-risk MM patients. Residual MM cells are responsible for relapse, have been described as drug resistant and as having stem cell-like characteristics including altered cell metabolism, increased drug efflux, ALDH1 activity, and myeloma propagating activity. We sought to molecularly characterize residual myeloma plasma cells (MMPCs) and identify novel biomarkers and therapeutic targets of resistant MM cells. Methods Patient samples. Residual samples were collected at least 3 months after start of therapy (range 4 mths-11yrs), had low tumor burden (0.6-4.4% BM MMPC), 2 were in VGPR or better, 7 had PR, and 3 had not responded. Of the 12 cases analyzed, 2 had relapsed > 1 yr prior to residual sample. RNAseq analysis. Paired MMPCs at diagnosis and during residual disease (n=12) and 4 healthy donors were interrogated by RNAseq. Genes with at least 2-fold difference between groups and at a statistical significance