Circulating tumor cells in myeloma are a compound biomarker for bone marrow high-risk genomic alterations and tumor load.

High levels of circulating tumor cells (CTC) are a powerful predictor of poor outcomes in newly diagnosed multiple myeloma, yet the mechanistic underpinnings of this correlation remain unknown. To investigate whether CTC-related pathobiology is driven by a specific circulating tumor cell subset, paired bone marrow and blood samples from newly-diagnosed multiple myeloma patients were analyzed by single-cell transcriptomics and whole-genome sequencing. This revealed that down to the individual clone level, CTCs and paired bone marrow cells are transcriptionally similar, without evidence for a distinct circulating population. In contrast, bone marrow myeloma cells from patients with high CTC levels showed increased proliferation and unbalanced primary genetic events, including enrichment for MAF and CCND translocations. To investigate impact of heterogenic genomic events on CTC levels, whole-exome and bulk-RNA sequencing from the MMRF CoMMpass dataset were analyzed and validated in our in-house datasets. Bone marrow tumor cells from patients with high CTC levels were uniformly characterized by transcriptomic signatures of proliferation. Additionally, CTC levels were uniquely dependent on primary genomic events, as well as high-risk secondary genomic events, including amplification1q, deletion1p, deletion13q, biallelic TP53 mutations, and increased APOBEC-induced mutations even in patients without MAF translocations. Finally, we developed a model that predicts the impact of genetic alterations and tumor burden on CTC levels. In sum, we show that CTC are the net result of tumor burden, primary translocations, and secondary genomic events, making CTC a powerful biomarker for genomics-driven high-risk disease in newly diagnosed myeloma patients.