Abstract 470: Chromosomal instability and bad prognosis both connote a multiple myeloma (MM) sub-type carrying 13qCN loss and 1qCN gain
Authors: Terragna Carolina , Martello Marina , Poletti Andrea , Solli Vincenza , Borsi Enrica , Termini Rosalinda , Pantani Lucia , Zamagni Elena , Marzocchi Giulia , Tacchetti Paola , Testoni Nicoletta , Rocchi Serena , Cifarelli Luca , Dozza Luca , Martinelli Giovanni , Cavo Michele 
Published: August 2019

Abstract
BACKGROUND MM patients (pts) are characterized by a prevalence of aneuploidies and Copy Number Alterations (CNAs) broadly scattered over the whole genome. Along with translocations and/or single nucleotide variants, they account for the MM-distinctive genomic heterogeneity, which characterizes the onset of symptomatic MM and identifies each pts.
AIM. To deeply explore the genomic landscape of newly diagnosed, homogeneously treated MM pts, to assess the prognostic relevance of whole genome aneuploidies, CNAs, and structural aberrations.
PATIENTS AND METHODS 344 highly purified BM CD138+ samples were profiled by SNPs array. R scripts were employed to analyse genomic data. Pts, enrolled in the EMN02 phase III trial, were randomized to receive VMP (121 pts) or high-dose MEL and autologous stem cell transplantation (223 pts), after bortezomib-based induction. At a median follow-up of 46 months (m), the estimated PFS and OS rates were 55% and 83%, respectively.
RESULTS To evaluate the contribution of each genomic variables to the overall pts variability, a Principal Component Analysis of the whole genome’s numerical and structural aberrations was performed, highlighting that a “common ground” of at least 4 chromosomal aberrations (hyperdiploidy, H, 13qCN loss, IgH-t and 1qCN gains) was sufficient to describe and resume the MM overall genomic heterogeneity. Therefore, since 13qCN loss and 1qCN gains co-segregate, 3 pts sub-types might be identified, partially overlapping, even though well-defined by the presence of either H, or IgH-t or 13qCN loss and 1qCN gain. Outcomes of the latter MM sub-type was explored. Pts carrying 13qCN loss and 1qCN gain were characterized by the presence of several small deletions in MM-critical genes (YAP1, TRAF3, CYLD), and by the markedly de-regulated expression of CCND2 and CCND1 (as evaluated by the analysis of CoMMpass-derived RNAseq expression dataset). Their 46-m PFS and OS estimates were shorter as compared to that of patients carrying either just one or any of these CNAs (PFS: 39%, 44% and 73%, respectively; p=0.0001. OS: 68%, 83% AND 91%; p=0.0001). PFS and OS hazard ratios (HR) of pts carrying 13qCN loss and 1qCN gain (PFS: 1.76; OS: 2.24) were comparable to that of pts carrying either del(17p) (PFS: 2.1; OS: 2.1) or t(4;14) (PFS: 1.80; OS: 1.7), resulting as an independent factor predicting both PFS and OS in a Cox multivariate analysis. Survival data were confirmed on additional SNPs array data derived from 151 unrelated MM pts not included in the EMN02 trial, as well as on 700 pts, whose CNAs data were extrapolated from the MMRF CoMMpass Study dataset.
CONCLUSIONS We propose a simple way to stratify MM pts, according to the detection of 2 CNAs, which is able to select pts with high (25%) and with low (40%) risk of progression and/or death, allowing to predict the clinical outcome in most MM pts. Supported by AIRC, Fond. del Monte Bo-Ra, Fond. Berlucchi, BO-AIL, Harmony
Citation Format: Carolina Terragna, Marina Martello, Andrea Poletti, Vincenza Solli, Enrica Borsi, Rosalinda Termini, Lucia Pantani, Elena Zamagni, Giulia Marzocchi, Paola Tacchetti, Nicoletta Testoni, Serena Rocchi, Luca Cifarelli, Luca Dozza, Giovanni Martinelli, Michele Cavo. Chromosomal instability and bad prognosis both connote a multiple myeloma (MM) sub-type carrying 13qCN loss and 1qCN gain [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 470.