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

Nat Commun. 2022 Jun 15;13(1):3449. doi: 10.1038/s41467-022-30694-w.

Authors

Mark Bustoros^#^{1

2}, Shankara Anand^#^{3

4}, Romanos Sklavenitis-Pistofidis^{1

3}, Robert Redd⁵, Eileen M Boyle⁶, Benny Zhitomirsky³, Andrew J Dunford³, Yu-Tzu Tai¹, Selina J Chavda⁷, Cody Boehner¹, Carl Jannes Neuse^{1

8}, Mahshid Rahmat¹, Ankit Dutta¹, Tineke Casneuf⁹, Raluca Verona¹⁰, Efstathis Kastritis¹¹, Lorenzo Trippa⁵, Chip Stewart³, Brian A Walker¹², Faith E Davies⁶, Meletios-Athanasios Dimopoulos¹¹, P Leif Bergsagel¹³, Kwee Yong⁷, Gareth J Morgan⁶, François Aguet³, Gad Getz^#^{14

15}, Irene M Ghobrial^#^{16

17}

Affiliations

¹ Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
² Division of Hematology & Medical Oncology, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
³ Broad Institute of MIT & Harvard, Cambridge, MA, USA.
⁴ Boston University School of Medicine, Boston, MA, USA.
⁵ Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
⁷ Division of Hematology, University College London, London, UK.
⁸ University of Münster Medical School, Münster, Germany.
⁹ Janssen Research and Development, Beerse, Belgium.
¹⁰ Janssen Research and Development, Spring House, PA, USA.
¹¹ Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.
¹² Melvin and Bren Simon Comprehensive Cancer Center, Indiana University, Indianapolis, IN, USA.
¹³ Division of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
¹⁴ Broad Institute of MIT & Harvard, Cambridge, MA, USA. gadgetz@broadinstitute.org.
¹⁵ Department of Pathology, Massachusetts General Hospital Cancer Center, Boston, MA, USA. gadgetz@broadinstitute.org.
¹⁶ Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA. Irene_Ghobrial@dfci.harvard.edu.
¹⁷ Broad Institute of MIT & Harvard, Cambridge, MA, USA. Irene_Ghobrial@dfci.harvard.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Disease Progression
Humans
Multiple Myeloma* / genetics
Phenotype
Risk
Risk Factors
Smoldering Multiple Myeloma* / genetics

Abstract

Publication types

MeSH terms

Grants and funding