Abstract

Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk sequencing technologies. Here, we generated and analyzed single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enabled discovery of novel, patient-specific transcriptional changes. Using Bayesian Non-Negative Matrix Factorization, we discovered 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identified a signature that is uniformly lost in neoplastic cells across disease stages. Finally, we demonstrated that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, paving the way for exploration of personalized treatment approaches prior to malignant disease.