High-risk cytogenetics in multiple myeloma: Further scrutiny of deletions within the IGH gene region enhances risk stratification

Multiple myeloma is a clonal malignancy of plasma cells in the bone marrow. Risk stratification is partly based on cytogenetic findings that include abnormalities of theIGHlocus as determined by fluorescence in situ hybridization (FISH), such as rearrangements that result in either standard-risk or high-risk gene fusions.IGHdeletions have been evaluated as a group in multiple myeloma patients with respect to cumulative outcomes but have provided limited guidance. Whether these deletions have the potential to result in gene fusions and thus further stratify patients is unknown. We identified 229IGHdeletions in patients referred for plasma cell dyscrasia genetic testing over 5.5 years. Follow-up was conducted on 208 of the deletions with dual fusion FISH probes for standard-risk (IGH-CCND1) and high-riskIGHgene fusions (IGH-FGFR3,IGH-MAF,IGH-MAFB). Of all deletions identified with follow-up, 44 (21%) resulted in a gene fusion as detected by FISH, 15 (7%) of which were fusion partners associated with high-risk multiple myeloma. All fusion-positive 3 '-IGHdeletions (6 fusions) resulted in high-riskIGH-FGFR3fusions. Of the 15 high-risk fusion-positive cases, eight were without other high-risk cytogenetic findings. This study is the first to evaluate the presence ofIGHgene fusions upon identification ofIGHdeletions and to characterize the deletion locus. Importantly, these findings indicate that follow-up FISH studies with dual fusion probes should be standard of care whenIGHdeletions are identified in multiple myeloma.