Circulating tumor cells (CTCs) have emerged as a key prognostic factor in newly diagnosed multiple myeloma (NDMM). However, it remains unclear if high CTC counts represent a mere surrogate of tumor burden or might reflect a distinct genomic or transcriptomic entity. In this study, we characterized the genomic and transcriptomic features associated with CTC burden and assessed their combined prognostic value in NDMM patients. We analyzed 540 NDMM patients from the CoMMpass dataset with available baseline CTC information and matched bone marrow transcriptomic (n = 374) and genomic (n = 460) sequencing data. We then validated the results on an external cohort of 135 NDMM patients with CTCs enumerated by next-generation flow cytometry. Higher CTC levels were significantly associated with high-risk clinical features (e.g., ISS or IMS/IMWG 2024). Furthermore, genomic analyses revealed that high CTC counts were associated with complex genomic features such as chromothripsis, APOBEC mutagenesis, and loss of key tumor suppressors, typically linked to high-risk disease. Transcriptomic analyses revealed that elevated CTCs were enriched in cell cycle and proliferation (PR) genes while presenting a reduced association with immune response. Importantly, CTCs also emerged as a surrogate for PR transcriptomic signatures and demonstrated prognostic superiority, potentially simplifying application in the clinical setting. Elevated CTC levels reflect aggressive biological features of multiple myeloma and outperform prognostic markers such as PR signatures. Integrating CTC data into genomic and transcriptomic classifiers could enhance risk stratification and provide a streamlined and powerful tool for clinical decision-making in NDMM.

Department of Biology and Ecology Faculty of Science University of Ostrava Ostrava Czech Republic

Department of Hematooncology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematooncology University Hospital Ostrava Ostrava Czech Republic

Department of Medical Physics Memorial Sloan Kettering Cancer Center New York New York USA

Icahn School of Medicine at Mount Sinai Tisch Cancer Institute New York City New York USA

Integrated Cancer Genomics Division Translational Genomics Research Institute Phoenix Arizona USA

Multiple Myeloma Research Foundation Norwalk Connecticut USA

Myeloma Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York USA

Sylvester Comprehensive Cancer Center Sylvester Myeloma Institute University of Miami Miami Florida USA

See more in PubMed

Garcés J‐J, Simicek M, Vicari M, et al. Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination. Leukemia. 2020;34(2):589‐603. 10.1038/s41375-019-0588-4 PubMed DOI

Rodriguez‐Otero P, Paiva B, San‐Miguel JF. Roadmap to cure multiple myeloma. Cancer Treat Rev. 2021;100:102284. 10.1016/j.ctrv.2021.102284 PubMed DOI

Sanoja‐Flores L, Flores‐Montero J, Garcés JJ, et al. Next generation flow for minimally‐invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC). Blood Cancer J. 2018;8(12):117. 10.1038/s41408-018-0153-9 PubMed DOI PMC

Garcés J‐J, Cedena M‐T, Puig N, et al. Circulating tumor cells for the staging of patients with newly diagnosed transplant‐eligible multiple myeloma. J Clin Oncol. 2022;40(27):3151‐3161. 10.1200/jco.21.01365 PubMed DOI

Bertamini L, Oliva S, Rota‐Scalabrini D, et al. High levels of circulating tumor plasma cells as a key hallmark of aggressive disease in transplant‐eligible patients with newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(27):3120‐3131. 10.1200/jco.21.01393 PubMed DOI

Termini R, Žihala D, Terpos E, et al. Circulating tumor and immune cells for minimally invasive risk stratification of smoldering multiple myeloma. Clin Cancer Res. 2022;28(21):4771‐4781. 10.1158/1078-0432.ccr-22-1594 PubMed DOI

Jelinek T, Bezdekova R, Zihala D, et al. More than 2% of circulating tumor plasma cells defines plasma cell leukemia–like multiple myeloma. J Clin Oncol. 2023;41(7):1383‐1392. 10.1200/jco.22.01226 PubMed DOI PMC

Zhan F, Huang Y, Colla S, et al. The molecular classification of multiple myeloma. Blood. 2006;108(6):2020‐2028. 10.1182/blood-2005-11-013458 PubMed DOI PMC

Bruinink DHo, Kuiper R, Duin Mv, et al. Identification of high‐risk multiple myeloma with a plasma cell leukemia‐like transcriptomic profile. J Clin Oncol. 2022;40(27):3132‐3150. 10.1200/jco.21.01217 PubMed DOI PMC

Skerget S, Penaherrera D, Chari A, et al. Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes. Nat Genet. 2024;56(9):1878‐1889. 10.1038/s41588-024-01853-0 PubMed DOI PMC

Mishima Y, Paiva B, Shi J, et al. The mutational landscape of circulating tumor cells in multiple myeloma. Cell Rep. 2017;19(1):218‐224. 10.1016/j.celrep.2017.03.025 PubMed DOI PMC

Ledergor G, Weiner A, Zada M, et al. Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma. Nat Med. 2018;24(12):1867‐1876. 10.1038/s41591-018-0269-2 PubMed DOI

Garcés J‐J, Bretones G, Burgos L, et al. Circulating tumor cells for comprehensive and multiregional non‐invasive genetic characterization of multiple myeloma. Leukemia. 2020;34(11):3007‐3018. 10.1038/s41375-020-0883-0 PubMed DOI

Dutta AK, Alberge J‐B, Lightbody ED, et al. MinimuMM‐seq: genome sequencing of circulating tumor cells for minimally invasive molecular characterization of multiple myeloma pathology. Cancer Discov. 2022;13(2):348‐363. 10.1158/2159-8290.cd-22-0482 PubMed DOI

Foulk B, Schaffer M, Gross S, et al. Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders. Br J Haematol. 2018;180(1):71‐81. 10.1111/bjh.15003 PubMed DOI

Flores‐Montero J, Sanoja‐Flores L, Paiva B, et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017;31(10):2094‐2103. 10.1038/leu.2017.29 PubMed DOI PMC

Jelinek T, Nenarokov S, Sevcikova T, et al. Insights into biological mechanisms responsible for egression of circulating tumor plasma cells (CTCs) in multiple myeloma. Blood. 2024;144(suppl 1):3270.

Garcés J‐J, Termini R, Martín‐Sánchez E, et al. Biological and clinical significance of undetectable circulating tumor cells (CTCs) in patients (Pts) with multiple myeloma (MM). Blood. 2023;142(suppl 1):646. 10.1182/blood-2023-186411 DOI

Kostopoulos IV, Ntanasis‐Stathopoulos I, Rousakis P, et al. Low circulating tumor cell levels correlate with favorable outcomes and distinct biological features in multiple myeloma. Am J Hematol. 2024;99(10):1887‐1896. 10.1002/ajh.27414 PubMed DOI

Avet‐Loiseau H, Davies FE, Samur MK, et al. International Myeloma Society/International Myeloma Working Group consensus recommendations on the definition of high‐risk multiple myeloma. J Clin Oncol. 2025;43(24):2739‐2751. PubMed

Maura F, Rajanna AR, Ziccheddu B, et al. Genomic classification and individualized prognosis in multiple myeloma. J Clin Oncol. 2024;42:JCO2301277. 10.1200/jco.23.01277 PubMed DOI PMC

Maclachlan KH, Rustad EH, Derkach A, et al. Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma. Nat Commun. 2021;12(1):5172. 10.1038/s41467-021-25469-8 PubMed DOI PMC

Rustad EH, Yellapantula VD, Glodzik D, et al. Revealing the impact of structural variants in multiple myeloma. Blood Cancer Discov. 2020;1(3):bloodcandisc.0132.2020. 10.1158/2643-3230.bcd-20-0132 PubMed DOI PMC

Anz D, Mueller W, Golic M, et al. CD103 is a hallmark of tumor‐infiltrating regulatory T cells. Int J Cancer. 2011;129(10):2417‐2426. 10.1002/ijc.25902 PubMed DOI

Venkataraman G, Aguhar C, Kreitman RJ, Yuan CM, Stetler‐Stevenson M. Characteristic CD103 and CD123 expression pattern defines hairy cell leukemia: usefulness of CD123 and CD103 in the diagnosis of mature B‐cell lymphoproliferative disorders. Am J Clin Path. 2011;136(4):625‐630. 10.1309/ajcpkum9j4ixcweu PubMed DOI PMC

Morgan EA, Pihan GA, Said JW, et al. Profile of CD103 expression in T‐cell neoplasms: immunoreactivity is not restricted to enteropathy‐associated T‐cell lymphoma. Am J Surg Pathol. 2014;38(11):1557‐1570. 10.1097/pas.0000000000000296 PubMed DOI

Suzuki S, Komiya K, Tsuda S, et al. Type I‐conventional dendritic cells support the progression of multiple myeloma in the bone marrow. Front Immunol. 2024;15:1444821. 10.3389/fimmu.2024.1444821 PubMed DOI PMC

Papadimitriou M, Tauro M, Panahi A, et al. Replication stress induces hyper‐apobec mutagenesis in multiple myeloma. Blood. 2024;144(suppl 1):3276. 10.1182/blood-2024-211173 DOI

Fokkema C, de Jong MME, Tahri S, et al. High levels of circulating tumor cells are associated with increased bone marrow proliferation in newly diagnosed multiple myeloma patients. Blood. 2021;138(suppl 1):1566. 10.1182/blood-2021-145971 DOI

Zanwar S, Jevremovic D, Kapoor P, et al. Clonal plasma cell proportion in the synthetic phase identifies a unique high‐risk cohort in multiple myeloma. Blood Cancer J. 2025;15(1):20. 10.1038/s41408-025-01232-w PubMed DOI PMC