Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes
Authors: Sheri Skerget, Daniel Penaherrera, Ajai Chari, Sundar Jagannath, David S. Siegel, Ravi Vij, Gregory Orloff, Andrzej Jakubowiak, Ruben Niesvizky, Darla Liles, Jesus Berdeja, Moshe Levy, Jeffrey Wolf, Saad Z. Usmani, Robert Rifkin, Kenneth Meehan, Don Benson, Jeffrey Zonder, Joao Ascensao, Cristina Gasparetto, Miguel Hernández, Suzanne Trudel, Shaker Dakhil, Nizar Bahlis, Juan Vazquez Paganini, Pablo Rios, Antonia Sampol, Siva Mannem, Rebecca Silbermann, Matthew Lunning, Michael Chu, Carter Milner, Allyson Harroff, Mark Graham, Spencer Shao, Jyothi Dodlapati, Carlos Fernández de Larrea, Leonard Klein, Charles Kuzma, Rafael Fonseca, Gemma Azaceta, Miquel Granell, Carmen Martinez-Chamorro, Rama Balaraman, Carlos Silva, Anabelle Chinea, Caitlin Costello, Suman Kambhampati, DeQuincy Lewis, Michael Grossbard, Kathleen Yost, Robert Robles, Michael Sebag, Wayne Harris, Justinian Ngaiza, Michael Bar, Marie Shieh, Fredrick Min, Adedayo Onitilo, Fabio Volterra, William Wachsman, Madhuri Yalamachili, Eugenia Abella, Larry Anderson, Joan Bargay, Hani Hassoun, Gerald Hsu, Hakan Kaya, Alex Menter, Dilip Patel, Donald Richards, William Solomon, Robert Anderson, Sumeet Chandra, Miguel Conde, Saulias Girnius, May Matkiwsky, Isabel Krsnik, Shaji Kumar, Albert Oriol, Paula Rodríguez, Vivek Roy, Shanti Srinivas, Ronald Steis, Austin W. Christofferson, Sara Nasser, Jessica L. Aldrich, Christophe Legendre, Brooks Benard, Chase Miller, Bryce Turner, Ahmet Kurdoglu, Megan Washington, Venkata Yellapantula, Jonathan R. Adkins, Lori Cuyugan, Martin Boateng, Adrienne Helland, Shari Kyman, Jackie McDonald, Rebecca Reiman, Kristi Stephenson, Erica Tassone, Alex Blanski, Brianne Livermore, Meghan Kirchhoff, Daniel C. Rohrer, Mattia D’Agostino, Manuela Gamella, Kimberly Collison, Jennifer Stumph, Pam Kidd, Andrea Donnelly, Barbara Zaugg, Maureen Toone, Kyle McBride, Mary DeRome, Jennifer Rogers, David Craig, Winnie S. Liang, Norma C. Gutierrez, Scott D. Jewell, John Carpten, Kenneth C. Anderson, Hearn Jay Cho, Daniel Auclair, Sagar Lonial, Jonathan J. Keats
Journal: Nature Genetics (2024)

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. Longitudinal genomic and transcriptomic profiling of 1,143 patients with multiple myeloma by the Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study yields an improved copy number and gene expression subtype scheme, most notably a high-risk proliferative subtype associated with complete loss of RB1 or MAX.