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 J. Dunford; Yu Tzu Tai; Selina J. Chavda; Cody Boehner; Carl Jannes Neuse; Mahshid Rahmat; Ankit Dutta; Tineke Casneuf; Raluca Verona; Efstathis Kastritis; Lorenzo Trippa; Chip Stewart; Brian A. Walker; Faith E. Davies; Meletios Athanasios Dimopoulos; P. Leif Bergsagel; Kwee Yong; Gareth J. Morgan; François Aguet; Gad Getz; Irene M. Ghobrial

doi:10.1038/s41467-022-30694-w

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 J. Dunford, Yu Tzu Tai, Selina J. Chavda, Cody Boehner, Carl Jannes Neuse, Mahshid Rahmat, Ankit Dutta, Tineke Casneuf, Raluca Verona, Efstathis Kastritis, Lorenzo Trippa, Chip Stewart, Brian A. Walker, Faith E. DaviesMeletios Athanasios Dimopoulos, P. Leif Bergsagel, Kwee Yong, Gareth J. Morgan, François Aguet, Gad Getz, Irene M. Ghobrial

Hematology/Oncology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	3449
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-30694-w
State	Published - Dec 2022

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Bustoros, M., Anand, S., Sklavenitis-Pistofidis, R., Redd, R., Boyle, E. M., Zhitomirsky, B., Dunford, A. J., Tai, Y. T., Chavda, S. J., Boehner, C., Neuse, C. J., Rahmat, M., Dutta, A., Casneuf, T., Verona, R., Kastritis, E., Trippa, L., Stewart, C., Walker, B. A., ... Ghobrial, I. M. (2022). Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes. Nature communications, 13(1), Article 3449. https://doi.org/10.1038/s41467-022-30694-w

Bustoros, M, Anand, S, Sklavenitis-Pistofidis, R, Redd, R, Boyle, EM, Zhitomirsky, B, Dunford, AJ, Tai, YT, Chavda, SJ, Boehner, C, Neuse, CJ, Rahmat, M, Dutta, A, Casneuf, T, Verona, R, Kastritis, E, Trippa, L, Stewart, C, Walker, BA, Davies, FE, Dimopoulos, MA, Bergsagel, PL, Yong, K, Morgan, GJ, Aguet, F, Getz, G & Ghobrial, IM 2022, 'Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes', Nature communications, vol. 13, no. 1, 3449. https://doi.org/10.1038/s41467-022-30694-w

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title = "Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes",

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.",

author = "Mark Bustoros and Shankara Anand and Romanos Sklavenitis-Pistofidis and Robert Redd and Boyle, {Eileen M.} and Benny Zhitomirsky and Dunford, {Andrew J.} and Tai, {Yu Tzu} and Chavda, {Selina J.} and Cody Boehner and Neuse, {Carl Jannes} and Mahshid Rahmat and Ankit Dutta and Tineke Casneuf and Raluca Verona and Efstathis Kastritis and Lorenzo Trippa and Chip Stewart and Walker, {Brian A.} and Davies, {Faith E.} and Dimopoulos, {Meletios Athanasios} and Bergsagel, {P. Leif} and Kwee Yong and Morgan, {Gareth J.} and Fran{\c c}ois Aguet and Gad Getz and Ghobrial, {Irene M.}",

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doi = "10.1038/s41467-022-30694-w",

language = "English (US)",

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AU - Bustoros, Mark

AU - Anand, Shankara

AU - Sklavenitis-Pistofidis, Romanos

AU - Redd, Robert

AU - Boyle, Eileen M.

AU - Zhitomirsky, Benny

AU - Dunford, Andrew J.

AU - Tai, Yu Tzu

AU - Chavda, Selina J.

AU - Boehner, Cody

AU - Neuse, Carl Jannes

AU - Rahmat, Mahshid

AU - Dutta, Ankit

AU - Casneuf, Tineke

AU - Verona, Raluca

AU - Kastritis, Efstathis

AU - Trippa, Lorenzo

AU - Stewart, Chip

AU - Walker, Brian A.

AU - Davies, Faith E.

AU - Dimopoulos, Meletios Athanasios

AU - Bergsagel, P. Leif

AU - Yong, Kwee

AU - Morgan, Gareth J.

AU - Aguet, François

AU - Getz, Gad

AU - Ghobrial, Irene M.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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Genetic subtypes of smoldering multiple myeloma are associated with distinct pathogenic phenotypes and clinical outcomes

Abstract

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