The clonal evolution during long-term clinical course of multiple myeloma
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CASE REPORT
The clonal evolution during long‑term clinical course of multiple myeloma Yuko Mishima1,2 · Yuji Mishima2 · Yuko Shirouchi1 · Noriko Nishimura1 · Masahiro Yokoyama1 · Takashi Okabe1 · Norihito Inoue1 · Hideki Uryu1 · Takanori Fukuta1 · Kiyohiko Hatake3 · Yasuhito Terui1,2 Received: 26 May 2020 / Revised: 18 August 2020 / Accepted: 21 August 2020 © Japanese Society of Hematology 2020
Abstract Somatic gene mutations related to acceleration disease and clonal evolution in multiple myeloma strongly influence severe clinical outcomes. In this study, we traced the transition of somatic mutations during the clinical course of myeloma patients over a long-term follow-up period (8.5 year average). Seven myeloma cases treated with immuno-chemotherapy at our institution were analyzed with clinical courses and the results of FISH and G-band analyses. Furthermore, the target sequences in regard to 121 genes, related to driver mutations or acceleration of disease in myeloma, were performed using bone marrow myeloma samples by next-generation sequencing, Ion Proton™ System. We detected a relationship between an increase in the dominant mutated gene (e.g., TP53, DIS3, FAM46C, KDM6B, and EGR1) and poor prognosis. In particular, clonal escalation of the TP53 mutation could not be overcome by any treatment. The selection of a combination treatment conducted in conjunction with the monitoring of gene mutations is appropriate for long-term survival. Our data demonstrate that long-term follow-up of somatic gene mutations during the clinical course of myeloma is helpful in the development of an effective treatment strategy. Keywords Multiple myeloma · Gene mutation · Clonal evolution · Resistance for therapy · Somatic gene mutation analysis
Introduction The biology of multiple myeloma (MM) is complicated, and genetic alterations are heterogeneous. Various theories regarding the patterns of clonal evolution have been considered [1–4]. Weinhold et al. reported that the first ‘big bang’ of initial inter- and intra-clonal heterogeneity occurs Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-02979-7) contains supplementary material, which is available to authorized users. * Yuko Mishima [email protected] 1
Department of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3‑8‑31, Ariake, Koto‑ku, Tokyo 135‑8550, Japan
2
Division of Clinical Research, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
3
Department of Hematology, International University of Health and Welfare, School of Medicine, Mita Hospital, Tokyo, Japan
in normal plasma cells, at which point the clinical status moves to monoclonal gammopathy of unknown significance (MGUS) or smoldering myeloma [5]. During MGUS and smoldering myeloma, the clonal evolution gradually progresses [5, 6]. Additionally, a secondary driver event, such as MYC translation, other driver mutations take place, at which point the dis
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