Genetic Subtypes of Smoldering Multiple Myeloma are associated with Distinct Pathogenic Phenotypes and Clinical Outcomes

• Published in: bioRxiv
• Main Authors: Bustoros, Mark, Shankara Anand, Romanos Sklavenitis-Pistofidis, Redd, Robert, Boyle, Eileen M, Zhitomirsky, Benny, Dunford, Andrew J, Yu-Tzu Tai, Chavda, Selina J, Boehner, Cody, Neuse, Carl Jannes, Rahmat, Mahshid, Dutta, Ankit, Casneuf, Tineke, Verona, Raluca, Kastritis, Efstathis, Trippa, Lorenzo, Stewart, Chip, Walker, Brian A, Davies, Faith E, Dimopoulos, Meletios-Athanasios, Bergsagel, Leif, Kwee Yong, Morgan, Gareth J, Aguet, Francios, Getz, Gad, Ghobrial, Irene M
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 11.12.2021
• Subjects: Clinical outcomes; Multiple myeloma; Patent applications; Patients; Phenotypes; Research funding; Risk groups; Transcription
• DOI: 10.1101/2021.12.10.471975

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 integrated 42 genetic alterations from 214 SMM patients using unsupervised binary matrix factorization (BMF) clustering and identified six distinct genetic subtypes. These subtypes were differentially associated with established MM-related RNA signatures, oncogenic and immune transcriptional profiles, and evolving clinical biomarkers. Three subtypes were 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 model. Competing Interest Statement There was no commercial funding for this study. M.B has an advisory role and received honoraria from Takeda and has received honoraria from Takeda, Janssen, and Bristol Myers Squibb (BMS). E.K has received honoraria and research funding from Amgen, Genesis Pharma, Janssen, Takeda, and Prothena. R.J.S is on the Data and Safety Monitoring Board of Juno and Celgene; has consulting roles with Gilead, Merck, and Astellas; and is on the Board of Directors of Kiadis. M.A.D has received honoraria from Amgen, Celgene, Janssen, and Takeda. I.M.G has a consulting and advisory role with GSK and Aptitude; and has consulting roles with Sanofi, Janssen, Takeda, AbbVie, Genentech, BMS, Curio Science, and Oncopeptides. G.G. is a founder, consultant and holds privately held equity in Scorpion Therapeutics, received research funding from IBM and Pharmacyclics, and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig, MSIdetect, POLYSOLVER, and TensorQTL.