Clonal Evolution Paths Significantly Impact the Outcome of Myeloma
Authors: Qin Xiaoqi , An Gang , Hu Lin-ping , Qin Yu , Xu Yan , Feng Xiaoyan , Zang Meirong , Deng Shuhui , Sui Weiwei , Yi Shuhua , Li Zengjun , Yang Lin-hua , Cheng Tao , Wang Jianxiang , Qiu Lugui 
Published: October 2019

Abstract
Background
Multiple myeloma is a malignancy of clone plasma cells that were composed of various multisteps development and had different molecular genetical variation in different phases in the course of disease. Clonal evolution promotes the disease development from prophase to advanced stage. We investigated the paths of clonal evolution in a cohort myeloma patients by a unique multicolor FISH (mFISH) to identify the clonal architecture of different time points, and first reported the survival and prognostic value of various clonal evolution paths.
Methods
Totally 85 myeloma patients with CD138+ cells at diagnosis versous relapse or former relapse versous latter relapse were enrolled in this study between January 2004 and December 2014. Firstly, the clonal evolution were analyzed by conventional iFISH (cFISH) with a panel probes of 1q21, RB-1 and TP53. The clonal architecture of different time points were detected by mFISH in 62 samples from different time points of selected 25 patients among the 85 patients. The survival significance and prognostic value of 3 different clonal evolution paths identified by mFISH were analyzed.
Results: 1). Clonal evolution were detected in 34/85(40%) cases by cFISH analysis. The survival analysis showed that patients with clonal evolution had significant shorter over survival (OS) than those with clonal stabilization. The meadian OS of these 2 groups were 42.67 (95% CI:32.15-53.19) and 71.46 (95%CI:58.99-83.93) months respectively, the difference between these 2 groups was significant (p=0.010). Comparing the survival since post relapse/clonal evolution, significant difference (p=0.003) also existed in these 2 groups with a median survival of 14.79 (95% CI:10.01-19.56) months and 37.61 (95%CI:27.30-47.92) months respectively.
2). Three clonal evolution paths were identified by mFISH in different phase samples from 25 myeloma patients. 36% (9/25) of them were clonal stabilization, 32% (8/25) were linear clonal evolution, 32% (8/25) were branching clonal evolution. mFISH had more powerful efficacy of clonal evolution detection than cFISH. Of these 25 cases, 14 cases were clonal stabilization and 11 were clonal evolution identified by cFISH. 7/14 (50%) with clonal stabilization by cFISH were identified into clonal evolution by mFISH, 1 with linear evolution and 6 with branching evolution. The 11 cases with clonal evolution identified by cFISH were further classified into 7 with linear evolution and 4 with branching evolution by mFISH detection.
3). Our results indicated that clonal evolution type had significant impact on survival of myeloma patients. The median OS of patients with clonal stabilization, linear evolution and branching evolution were 87.00 (95%CI:74.53-99.47), 24.99 (95% CI:16.58-33.39) and 35.70 (95% CI:27.10-44.30) months respectively. There were significant difference among these 3 groups (p=0.004). The median survival post relapse/clonal evolution in these 3 groups were 34.00 (95%CI:20.14-47.86), 8.06 (95% CI:4.91-11.22) and 22.75 (95% CI:13.49-32.01) months, the difference among them was significant (p=0.007).
Conclusions
mFISH is a simple and clinical practicable tool for clonal detection and analysis of myeloma. Our results firstly demonstrated that the clonal evolution type had significant impact on survival of patients with myeloma. According to the 3 different clonal evolution paths, individualized treatment strategy would be required for different patients with myeloma.

Disclosures
No relevant conflicts of interest to declare.