Aneuploidy Is Associated with Inferior Survival in Relapsed Refractory Multiple Myeloma Patients

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.4360-4360
• Main Authors: Ye, J Christine, Chen, Liying, Chen, Jason, Parkin, Brian, Polk, Avery, Kandarpa, Malathi, Cole, Craig E., Campagnaro, Erica L., Robinson, Dan, Wu, Yi-Mi, Talpaz, Moshe, Yesil, Jennifer, Auclair, Daniel, Bergsagel, P. Leif, Chinnaiyan, Arul, Baladandayuthapani, Veerabhadran
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-124135

Objective To identify the association between aneuploidy and clinical outcome in patients with relapsed and/or refractory multiple myeloma (RRMM) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. Background: Aneuploidy, defined by abnormal copy number changes of chromosomes, is one of the hallmarks in cancer, reflecting and also contributing to genome instability (Ye, Regan et al. 2018). Approximately 90% of cancers have gained or lost one or both arms of at least one chromosome (Taylor, Shih et al. 2018). In recent years, large scale sequencing efforts have extended aneuploidy study, identifying DNA somatic copy number alterations (SCNAs). Published data suggest aneuploidy has a stronger impact on prognosis than gene mutations in multiple myeloma (Walker, Boyle et al. 2015; Bolli, Biancon et al. 2018; Jamal-Haniani, Wilson et al. 2017). Methods: Fifty one RRMM patients from our institute participated in Clinical-Grade Molecular Profiling of Patients with Multiple Myeloma and Related Plasma Cell Malignancies (MMRF-002) from Multiple Myeloma Research Foundation (MMRF) between March 2016 and November 2018. Genomic DNA was obtained from CD138+ sorted myeloma cells and a peripheral blood sample from each patient. Capture exome sequencing on a targeted panel of 1500 genes was performed by the Illumina HiSeq 2500 (2x115bp paired-end reads, average 520X coverage). Copy number changes, loss of heterozygosity (LOH) and tumor purity were jointly estimated using an in-house pipeline for matched tumor/normal libraries. We assessed aneuploidy using chromosomal and arm level SCNAs which are determined by the median of SCNAs and summation of gain and loss of SCNAs for a given chromosomal arm, which are then used for a time-to-event analysis of overall survival (OS) of the patients. The differences between Kaplan-Meier overall survival curves were tested using the log-rank test. Hazard ratios (HR) were estimated from Cox proportional hazard regression. A threshold of significance was taken as p