Leukemia Research 99 (2020) 106476 Available online 4 November 2020 0145-2126/© 2020 Elsevier Ltd. All rights reserved. Deletions and amplifications of the IGH variable and constant regions:a novel prognostic parameter in patients with multiple myeloma Hadas Rabani a , Mira Ziv b , Noa Lavi c , Ariel Aviv d , Celia Suriu e , Adel Shalata b , Yarin Haddid b, 1 , Tamar Tadmor f, 1, * a Internal Medicine C, Bnai Zion Medical Center, Haifa, Israel b Winter Institute for Human Genetics, Bnai-Zion Medical Center, Affiliated With Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel c Hematology and Bone Marrow Transplantation Institute, Rambam Health Care Campus, Haifa, Israel d Hematology Unit, HaEmek Medical Center, Afula, Israel e Hematology Unit, Galilee Medical Center, Nahariya, Israel f Hematology Unit, Bnai Zion Medical Center, Haifa, and The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel A R T I C L E INFO Keywords: Multiple myeloma Immunoglobulin Constant region Immunoglobulin variable region Chromosome aberrations Prognosis ABSTRACT Cytogenetic abnormalities are a recognized factor in the pathogenesis of multiple myeloma (MM). While chro- mosomal translocations involving the IGH gene have been investigated and reported, the implications of de- letions or amplifications in the IGH gene have been less frequently examined. We conducted a retrospective analysis of 260 patients with MM from Northern Israel. Fluorescent in situ hybridization (FISH) analysis of separated CD-138 positive cells was done on bone marrow samples collected between 2016 and 2018. We used IGH break apart probes to identify IGH abnormalities and performed statistical analysis of clinical and prognostic features, comparing the different cytogenetic groups. Deletions in the variable region of the IGH (IGHv) were found in 17.3 % (n = 45) of patients and correlated with significantly worse progression free survival (PFS) after two years of follow up (p = 0.008), as well as with a worse response to 1st line treatment (p = 0.037). The median PFS was 7.1 and 17.7 months in patients with and without IGHv deletion, respectively. PFS differences remained significant (p = 0.017) in subgroup analysis of patients with high-risk cytogenetics (n = 108, 19 with IGHv deletion). Overall survival was not significantly different in the two groups. Constant region (IGHc) amplifications, were less frequently found (6.15 %, n = 16), yet significantly corre- lated with worse PFS after two years of follow up (p = 0.023). This difference remained valid in the high-risk subgroup (p = 0.001). In Conclusion, we identified that deletion of the IGH variable region and amplification in the IGH constant region, are both associated with poor prognosis and inferior outcome in MM. 1. Introduction Multiple Myeloma (MM) is a monoclonal plasma cell malignancy derived from post–germinal-center B cells [1]. Despite the significant progress in treatment, MM is still considered an incurable disease in most cases, with a median overall survival (OS) of 3–10 years, depending on disease stage and biology [2,3]. Cytogenetic abnormalities play a fundamental role in the pathobi- ology of MM and are broadly divided into two categories - hyperdiploidy and translocations. Hyperdiploidy presents mainly as trisomies of chromosomes 3,5,7,9,11,15,17 and 19, while translocations involve the immunoglobulin heavy chain (IGH) gene on chromosome 14, and the most frequent are t(11;14), t(4;14), t(6;14), t(14;16) and t(14;20) [4,5]. Hyperdiploidy is present in 42 % of MM cases, and correlate with a relatively better prognosis. Translocations are encountered in 30 % of cases, some of which are associated with poor prognosis. Generally, most patients display only one of these abnormalities [4–6]. Secondary cytogenetic abnormalities developing during the course of the disease provide a survival advantage to selected subclones, including Del(1p), Del(13q), Del(17p), Gain(1q) and MYC translocations * Corresponding author at: Hematology – Oncology Unit, Bnai-Zion Medical Center, 47, Golomb Street, Haifa 31048, Israel. E-mail address: tamar.tadmor@b-zion.org.il (T. Tadmor). 1 These authors contributed equally to the manuscript. Contents lists available at ScienceDirect Leukemia Research journal homepage: www.elsevier.com/locate/leukres https://doi.org/10.1016/j.leukres.2020.106476 Received 20 September 2020; Received in revised form 27 October 2020; Accepted 1 November 2020