Clonotypic and Transcriptomic Evolution of Myeloma

Published in Cancer Cell

Abstract

Multiple myeloma remains an incurable disease, and the cellular and molecular evolution from precursor conditions, 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 microenvironment 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 stratification, biomarker discovery, and possible clinical applications.

Main points:

• Multiple myeloma precursors exhibit high degree of transcriptional heterogeneity
• The HY and non-HY subtypes are transcriptionally and immunologically distinct
• Early-stage tumors favor linear evolution; branching evolution arises with expansion

Reference:

Dang M., Wang R., …Ndacayisaba L.J., …et al., 2023 Jun 12. Single Cell Clonotypic and Transcriptional Evolution of Multiple Myeloma Precursor Disease. Cancer Cell. doi.org/10.1016/j.ccell.2023.05.007