Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

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Publication Details

Journal
Nature Genetics
Published
2024-08-19
DOI
https://doi.org/10.1038/s41588-024-01853-0
Citations
63
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
28.63

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article

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes

Sheri Skerget, Hearn Jay Cho, Rafaël Fonseca, Mattia D’Agostino et al.
63 citations
Nature Genetics
Multiple Myeloma Research and Treatments
28.63
article

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes

Sheri Skerget, Hearn Jay Cho, Rafaël Fonseca, Mattia D’Agostino, Martin Boateng, Ajai Chari, Saad Z. Usmani, Erica E. Tassone, Michael L. Grossbard, Daniel C. Rohrer, Jeffrey L. Wolf, Venkata D. Yellapantula, Suman Kambhampati, Larry J. Anderson, Sagar Lonial, David S. Siegel, Hakan Kaya, Ravi Vij, Allyson Harroff, Rebecca Silbermann, Lori Cuyugan, Sundar Jagannath, Andrea Donnelly, Winnie S. Liang, Carlos Fernandes da Silva, Kenneth Carl Anderson, Cristina Gasparetto, Darla Liles, Jeffrey A. Zonder, Adrienne Helland, Joan Bargay, Moshe Yair Levy, Miguel Á. Conde, Jyothi Dodlapati, Mary DeRome, Carlos Fernández de Larrea, Marie Shieh, Rebecca Reiman, Kathleen J. Yost, Scott D. Jewell, Caitlin Costello, Robert M. Rifkin, Alex R. Menter, Mark Evan Graham, Brooks A. Benard, Gregory Orloff, Norma Carmen Gutierrez, Anabelle Chinea, Jesús G. Berdeja, Maureen Toone, Charles Kuzma, Pam Kidd, Carter Milner, Carmen Martínez‐Chamorro, Albert Oriol, Daniel Auclair, William B. Solomon, Andrzej J. Jakubowiak, João L. Ascensão, William Wachsman, Hani Hassoun, Austin Christofferson, Jackie McDonald, Michael P. Chu, Miguel‐Teodoro Hernández, Sara Nasser, Shaker R. Dakhil, Michaël Sébag, Nizar Jacques Bahlis, Spencer H. Shao, Fabio Volterra, Kimberly Collison, Ahmet Kurdoglu, Jennifer Stumph, Miquel Granell, David W. Craig, Leonard Klein, Rubén Niesvizky, Isabel Krsnik, Pablo Rios, Gemma Azaceta, Saulias Girnius, Jessica L. Aldrich, Robert F. Anderson, John D. Carpten, Eugènia Abella, Suzanne Trudel, Daniel Peñaherrera, Alex Blanski, DeQuincy Andrew Lewis, Meghan Kirchhoff, Jonathan J. Keats, Kristi Stephenson, Jonathan Adkins, Matthew A. Lunning, Bryce Turner, Shari Kyman, Antònia Sampol, Siva Mannem, Vivek Roy, Adedayo A. Onitilo, Paula Rodríguez, Megan Washington, Kenneth R. Meehan, Gerald C Hsu, Rama Balaraman, Justinian Ngaiza, Madhuri Yalamachili, May Matkiwsky, Kyle McBride, Barbara Zaugg, Donald Richards, Fredrick Min, C. S. Miller, Ronald G. Steis, Michael Bär, Juan Vazquez Paganini, Shaji Kumar, Christophe Legendre, Shanti Srinivas, Wayne Harris, Don Benson, Dilip Patel, Robert Robles, Jennifer Rogers, Brianne Livermore, Sumeet Chandra
article en
63 citations

Abstract

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Nature GeneticsVol. 56(9)
Grand Rapids Community College (US), Saint Barnabas Medical Center (US), Translational Genomics Research Institute (US), Dartmouth–Hitchcock Medical Center (US), Marshfield Clinic (US), San Francisco VA Medical Center (US), Van Andel Institute (US), Hackensack University Medical Center (US), Peninsula Regional Medical Center (US), Maimonides Medical Center (US), Memorial Sloan Kettering Cancer Center (US), Kaiser Permanente (US), Spectrum Health (US), Emory University (US), Oregon Health & Science University (US), East Carolina University (US), Cotton (United States) (US), Washington University in St. Louis (US), Cornell University (US), Texas Oncology (US), Hospital Universitario de Canarias (ES), Hospital de Sant Pau (ES), WinnMed (US), Multiple Myeloma Research Foundation (US), Princess Margaret Cancer Centre (CA), Jackson Memorial Hospital (US), University of Mississippi Medical Center (US), University of California San Diego (US), Hospital Son Llatzer (ES), University of Chicago Medical Center (US), Hospital Universitario Nuestra Señora de Candelaria (ES), Royal Victoria Hospital (CA), The Barbara Ann Karmanos Cancer Institute (US), St. Francis Hospital (US), Levine Cancer Institute (US), Sarah Cannon (US), Waverly Hematology Oncology (US), Cancer Care Northwest (US), Hospital Universitario Puerta de Hierro Majadahonda (ES), Hospital Universitario Quirónsalud Madrid (ES), Cancer Center of Kansas (US), Randolph Health (US), University of California San Francisco Medical Center (US), Baylor Medical Center at Garland (US), Hospital Clínic de Barcelona (ES), Precision for Medicine (United States) (US), Alberta Cancer Foundation (CA), Central Texas Veterans Health Care System (US), Dana-Farber Cancer Institute (US), East Orange VA Medical Center (US), Regional Cancer Center (US), Cancer Care Specialists of Illinois (US), Virginia Cancer Specialists (US), Mayo Clinic in Arizona (US), Bennett Aerospace (United States) (US), Mayo Clinic Hospital (US), Sharp HealthCare Foundation (US), Hospital Del Mar (ES), University of California San Diego Medical Center (US), Instituto de Investigación Biomédica de Salamanca (ES), Dana-Farber/Harvard Cancer Center (US), Clinica Universidad de Navarra (ES), Hospital Clínico Universitario Lozano Blesa (ES), FirstHealth of the Carolinas (US), Centro de Investigación del Cáncer (ES), Medical Research Associates (US), Rocky Mountain Cancer Centers (US), Holy Cross Hospital (US), Duke University Health System (US), Mayo Clinic in Florida (US), Atlanta VA Medical Center (US), Hospital Universitario Son Espases (ES), Nebraska Cancer Specialists (US), Kansas City VA Medical Center (US), Washington DC VA Medical Center (US), Center for Occupational Research and Development (US), Virginia Mason Memorial (US), Centro de Investigación Biomédica en Red de Cáncer (ES), Hospital Universitario Infanta Sofía (ES), Hospital Universitario Ramón y Cajal (ES), Weill Cornell Medicine (US), Moores Cancer Center, McGill University (CA), The Ohio State University (US), New York University (US), University of Nebraska Medical Center (US), University of Cincinnati (US), The University of Texas Southwestern Medical Center (US), Icahn School of Medicine at Mount Sinai (US), Billings Clinic (US)
Multiple Myeloma Research Foundation, Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, Sanofi, Gilead Sciences, Teva Pharmaceutical Industries, Array BioPharma, CSL Behring, Baxalta, Regeneron Pharmaceuticals, TG Therapeutics, Astex Pharmaceuticals, BeiGene, Incyte, SkylineDx, Moderna, Seagen, Novo Nordisk, Daewoong Pharmaceutical Company, Vifor Pharma, Swedish Orphan Biovitrum, MorphoSys, Genentech, EMD Serono, Kite Pharma, Pharmacyclics, Legend Biotech, Principia Biopharma
Openalex Percentile: Top 0%
Multiple Myeloma Research and Treatments
28.63
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