Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120)

• Published in: Haematologica (Roma) 2015-09, Vol.100 (9), p.1214-1221
• Main Authors: Khan, Rashid, Dhodapkar, Madhav, Rosenthal, Adam, Heuck, Christoph, Papanikolaou, Xenofon, Qu, Pingping, van Rhee, Frits, Zangari, Maurizio, Jethava, Yogesh, Epstein, Joshua, Yaccoby, Shmuel, Hoering, Antje, Crowley, John, Petty, Nathan, Bailey, Clyde, Morgan, Gareth, Barlogie, Bart
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Bone Marrow - pathology; Female; Genes, Neoplasm; Genomic Instability; Humans; Male; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Neoplasm Proteins - genetics; Prospective Studies
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2015.124651

Multiple myeloma is preceded by an asymptomatic phase, comprising monoclonal gammopathy of uncertain significance and smoldering myeloma. Compared to the former, smoldering myeloma has a higher and non-uniform rate of progression to clinical myeloma, reflecting a subset of patients with higher risk. We evaluated the gene expression profile of smoldering myeloma plasma cells among 105 patients enrolled in a prospective observational trial at our institution, with a view to identifying a high-risk signature. Baseline clinical, bone marrow, cytogenetic and radiologic data were evaluated for their potential to predict time to therapy for symptomatic myeloma. A gene signature derived from four genes, at an optimal binary cut-point of 9.28, identified 14 patients (13%) with a 2-year therapy risk of 85.7%. Conversely, a low four-gene score (< 9.28) combined with baseline monoclonal protein < 3 g/dL and albumin ≥ 3.5 g/dL identified 61 patients with low-risk smoldering myeloma with a 5.0% chance of progression at 2 years. The top 40 probe sets showed concordance with indices of chromosome instability. These data demonstrate high discriminatory power of a gene-based assay and suggest a role for dysregulation of mitotic checkpoints in the context of genomic instability as a hallmark of high-risk smoldering myeloma.