Genomics Define Malignant Transformation in Myeloma Precursor Conditions
Abstract
Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify malignant transformation in MGUS and SMM. We introduce the concept of genomic MM and genomic MGUS to differentiate the subsets of MGUS and SMM that are biologically malignant with genomic features indistinguishable from MM from the subset that is premalignant and unlikely to progress to malignancy. Importantly, we find that most SMM has biological features of malignant transformation indistinguishable from MM. As expected, this subset that we consider having genomic MM is associated with a high risk of progression to MM although some patients remained progression-free beyond 5 years. Conversely, 60% of MGUS and 10% of SMM have no evidence of malignant transformation (genomic MGUS), with no progression during follow-up. Integration of genomic features with the 2/20/20 International Myeloma Working Group model significantly improved the prediction of progression among genomic MM. These findings support the use of genomic criteria to refine the classification and the risk stratification in myeloma precursor conditions.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (44)
Francesco Maura
Memorial Sloan Kettering Cancer Center, New York
P. Leif Bergsagel
Mayo Clinic Arizona, Scottsdale
Bachisio Ziccheddu
Memorial Sloan Kettering Cancer Center, United States
Shaji Kumar
Kylee Maclachlan
2Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Andriy Derkach
Juan-Jose Garces
Memorial Sloan Kettering Cancer Center
Ross Firestone
1Memorial Sloan Kettering Cancer Center, Myeloma Service, Department of Medicine, New York, United States
Esteban Braggio
2Department of Medicine, Mayo Clinic, Phoenix, AZ
Yan Asmann
Michael Durante
1Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL
Benjamin T. Diamond
Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
Marios Papadimitriou
1Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, United States
Malin Hultcrantz
1Memorial Sloan Kettering Cancer Center, Myeloma Service, Department of Medicine, New York, United States
Alessio Marella
7University of Milan, Milano, Italy
Giancarlo Castellano
5Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Akihiro Maeda
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Marta Lionetti
7University of Milan, Milano, Italy
Antonio Matera
7University of Milan, Milano, Italy
Stefania Pioggia
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Matteo Claudio Da Vià
2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Hematology Unit, Milan, Italy
Claudio de Magistris
6Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
Daniel Leongamornlert
Danny DeAvila
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Praneeth Reddy Sudalagunta
1H. Lee Moffitt Cancer Center & Research Institute, Tampa, United States
Rafael Renatino Canevarolo
1H. Lee Moffitt Cancer Center & Research Institute, Tampa, United States
Erin M. Siegel
Phaedra Agius
Jamie Teer
9Moffitt Cancer Center, Tampa, United States
Andrew McPherson
Yusuke Yamashita
National Museum of Japanese History
Ariosto S. Silva
Patrick Blaney
1Multiple Myeloma Research Program, Perlmutter Cancer Center, NYU Langone Health, New York, NY
Rachid Baz
1Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
Krina K. Patel
The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States
Peter Campbell
Gareth Morgan
Rafael Fonseca
IDOMED Vista Carioca, RIO DE JANEIRO, Brazil
Ola Landgren
Robert Z. Orlowski
The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Kenneth H. Shain
Niccolò Bolli
1Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Saad Usmani
8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
S. Vincent Rajkumar