Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes
Mark Bustoros, Shankara Anand, Romanos Sklavenitis‐Pistofidis, Robert Redd, Eileen M. Boyle, Benny Zhitomirsky, Andrew Dunford, Yu‐Tzu Tai, Selina J Chavda, Cody J. Boehner, Carl Jannes Neuse, Mahshid Rahmat, Ankit K. Dutta, Tineke Casneuf, Raluca Verona, Efstathis Kastritis, Lorenzo Trippa, Chip Stewart, Brian A. Walker, Faith E. Davies, Meletios Α. Dimopoulos, P. Leif Bergsagel, Kwee Yong, Gareth J. Morgan, François Aguet, Gad Getz, Irene M. Ghobrial
Abstract
Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with significant heterogeneity in disease progression. Existing clinical models of progression risk do not fully capture this heterogeneity. Here we integrate 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identify six distinct genetic subtypes. These subtypes are differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three genetic subtypes are associated with increased risk of progression to active MM in both the primary and validation cohorts, indicating they can be used to better predict high and low-risk patients within the currently used clinical risk stratification models.