Genetic interrogation of circulating multiple myeloma cells at single-cell resolution.

Lohr JG1,2,3, Kim S4, Gould J4, Knoechel B4,2,3, Drier Y4,3,5, Cotton MJ4,5,6, Gray D4, Birrer N5, Wong B4, Ha G4,2, Zhang CZ4,2, Guo G4,2,3, Meyerson M4,2,3, Yee AJ3,5, Boehm JS4, Raje N3,5, Golub TR1,2,3,6.

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Abstract

Multiple myeloma (MM) remains an incurable disease, with a treatment-refractory state eventually developing in all patients. Constant clonal evolution and genetic heterogeneity of MM are a likely explanation for the emergence of drug-resistant disease. Monitoring of MM genomic evolution on therapy by serial bone marrow biopsy is unfortunately impractical because it involves an invasive and painful procedure. We describe how noninvasive and highly sensitive isolation and characterization of circulating tumor cells (CTCs) from peripheral blood at single-cell resolution recapitulate MM in the bone marrow. We demonstrate that CTCs provide the same genetic information as bone marrow MM cells and even reveal mutations with greater sensitivity than bone marrow biopsies in some cases. Single CTC RNA sequencing enables classification of MM and quantitative assessment of genes that are relevant for prognosis. We propose that the genomic characterization of CTCs should be included in clinical trials to follow the emergence of resistant subclones after MM therapy.