Juan Flores-Montero, Juan José Garcés, Xabier Agirre, Idoia Rodriguez, Rafael Del Orbe, Bruno Paiva, Paula Rodriguez-Otero, Felipe Prosper, Pethema, Maria-Victoria Mateos, Halima El Omri, Luzalba Sanoja-Flores, Rafael Valdés-Mas, Sara Rodriguez, Alberto Orfao, Joan Bladé, Miguel-García Álvarez, Jesús F. San Miguel, Noemi Puig, Laura Rosiñol, Luis Palomera, Carlos López-Otín, Albert Pérez-Montaña, Juan José Lahuerta, Maria-Teresa Cedena, Joaquin Martinez-Lopez, Rafael Rios, Leire Burgos, Gabriel Bretones, Maria-Jose Calasanz, Diego Alignani, Diana A. Puente, Pamela Millacoy, Ibai Goicoechea, Centro de Investigación Biomédica en Red Cáncer (España), Instituto de Salud Carlos III, Cancer Research UK, Asociación Española Contra el Cáncer, European Commission, Ministerio de Ciencia e Innovación (España), European Research Council, International Myeloma Foundation, Qatar National Research Fund, Leukemia Research Foundation, and Multiple Myeloma Research Foundation
Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood (PB) of virtually all MM cases and are prognostic, but their applicability for noninvasive screening has been poorly investigated. Here, we used next-generation flow (NGF) cytometry to isolate matched CTCs and BM tumor cells from 53 patients and compared their genetic profile. In eight cases, tumor cells from extramedullary (EM) plasmacytomas were also sorted and whole-exome sequencing was performed in the three spatially distributed tumor samples. CTCs were detectable by NGF in the PB of all patients with MM. Based on the cancer cell fraction of clonal and subclonal mutations, we found that ~22% of CTCs egressed from a BM (or EM) site distant from the matched BM aspirate. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy number alterations (≥95%) though not for translocations (39%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Noteworthy, ≥82% mutations present in BM and EM clones were detectable in CTCs. Altogether, these results support CTCs for noninvasive risk-stratification of MM patients based on their numbers and genetic profile., This study was supported by the Centro de Investigación Biomédica en Red—Área de Oncología—del Instituto de Salud Carlos III (CIBERONC; CB16/12/00236, CB16/12/00369, CB16/12/00489, and CB16/12/00400); by Cancer Research UK [C355/A26819] and FC AECC and AIRC under the Accelerator Award Program; by the Instituto de Salud Carlos III, FCAECC and co-financed by FEDER (ERANET-TRANSCAN-2 iMMunocell AC17/00101); the Spanish Ministry of Science and Innovation and co-financed by FSE (Torres Quevedo fellowship, PTQ-16-08623); the Black Swan Research Initiative of the International Myeloma Foundation; European Research Council (ERC) under the European Commission’s H2020 Framework Programme (MYELOMANEXT, 680200); the Qatar National Research Fund (QNRF) Award No. 7-916-3-237; the AACR-Millennium Fellowship in Multiple Myeloma Research (15-40-38-PAIV); the Leukemia Research Foundation; and the Multiple Myeloma Research Foundation (MMRF) under the 2019 Research Fellowship Award.