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Eight whole exome sequencing (WES) and one single cell RNA sequencing (scRNA-seq) were performed in order to assess dynamic genomic changes in temporal consecutive samples of one RRMM patient from the time of diagnosis to death (about 37\u00a0months). The 63-year-old female patient who suffered from MM (P1) had disease progression (PD) nine times from July 2017 [newly diagnosed (ND)] to Aug 2020 (death), and the force to drive branching-pattern evolution of malignant PCs was found to be sustained. The mutant-allele tumor heterogeneity (MATH) and tumor mutation burden (TMB) initially exhibited a downward trend, which was then upward throughout the course of the disease. Various somatic single nucleotide variants (SNVs) that had disappeared after the previous treatment were observed to reappear in later stages. Chromosomal instability (CIN) and homologous recombination deficiency (HRD) scores were observed to be increased during periods of all progression, especially in the period of extramedullary plasmacytoma. Finally, in combination with WES and scRNA-seq of P1-PD9 (the nineth PD), the intro-heterogeneity and gene regulatory networks of MM\u00a0cells were deciphered. As verified by the overall survival of MM patients in the MMRF CoMMpass and GSE24080 datasets, RUNX3 was identified as a potential driver for RRMM.<\/jats:p>","DOI":"10.3389\/fcell.2021.794144","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T07:11:21Z","timestamp":1641366681000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Single-Cell Transcriptomes Combining with Consecutive Genomics Reveal Clonal Evolution and Gene Regulatory Networks in Relapsed and Refractory Multiple Myeloma"],"prefix":"10.3389","volume":"9","author":[{"given":"Jiadai","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingli","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yifeng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yawen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panpan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiyang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jifeng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1038\/s41375-019-0590-x","article-title":"Monitoring the Cytogenetic Architecture of Minimal Residual Plasma Cells Indicates Therapy-Induced Clonal Selection in Multiple Myeloma","volume":"34","author":"An","year":"2020","journal-title":"Leukemia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1093\/bioinformatics\/btr670","article-title":"Control-FREEC: A Tool for Assessing Copy Number and Allelic Content Using Next-Generation Sequencing Data","volume":"28","author":"Boeva","year":"2012","journal-title":"Bioinformatics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.3389\/fimmu.2019.01823","article-title":"Implicating the Role of GILZ in Glucocorticoid Modulation of T-Cell Activation","volume":"10","author":"Cannarile","year":"2019","journal-title":"Front. 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