Single cell clonotypic and transcriptional evolution of multiple myeloma precursor disease

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor con-ditions, including monoclonal gammopathy of undetermined significance and smoldering multiple myeloma, is incompletely understood. Here, we combine single-cell RNA and B cell receptor sequencing from fifty-two patients with myeloma precursors in comparison with myeloma and normal donors. Our comprehensive analysis reveals early genomic drivers of malignant transformation, distinct transcriptional features, and divergent clonal expansion in hyperdiploid versus non-hyperdiploid samples. Additionally, we observe intra-patient heterogeneity with potential therapeutic implications and identify distinct patterns of evolution from myeloma precursor disease to myeloma. We also demonstrate distinctive characteristics of the micro -environment associated with specific genomic changes in myeloma cells. These findings add to our knowledge about myeloma precursor disease progression, providing valuable insights into patient risk strat-ification, biomarker discovery, and possible clinical applications.

Automated summary

In this study, single-cell RNA and B cell receptor sequencing were used to analyze data from 52 patients with myeloma precursors. The study revealed early genomic drivers, distinct transcriptional features, and different clonal expansion patterns in hyperdiploid and non-hyperdiploid samples. Intra-patient heterogeneity was observed, along with unique patterns of evolution from myeloma precursor disease to myeloma. Additionally, distinctive characteristics of the microenvironment associated with specific genomic changes in myeloma cells were identified. These findings provide valuable insights into myeloma precursor disease progression and have implications for patient risk stratification, biomarker discovery, and potential clinical applications.