Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes
Sheri Skerget, Daniel Peñaherrera, Ajai Chari, Sundar Jagannath, David S. Siegel, Ravi Vij, Gregory Orloff, Andrzej Jakubowiak, Rubén Niesvizky, Darla Liles, Jesús G. Berdeja, Moshe Levy, Jeffrey L. Wolf, Saad Z. Usmani, The MMRF CoMMpass Network, Robert M. Rifkin, Kenneth R. Meehan, Don Benson, Jeffrey A. Zonder, João L. Ascensão, Cristina Gasparetto, Miguel‐Teodoro Hernández, Suzanne Trudel, Shaker R. Dakhil, Nizar J. Bahlis, Juan Vazquez Paganini, Pablo Rios, Antònia Sampol, Siva Mannem, Rebecca Silbermann, Matthew A. Lunning, Michael P. Chu, Carter Milner, Allyson Harroff, Mark E. Graham, Spencer H. Shao, Jyothi Dodlapati, Carlos Fernández de Larrea, Leonard Klein, Charles Kuzma, Rafaël Fonseca, Gemma Azaceta, Miquel Granell, Carmen Martínez‐Chamorro, Rama Balaraman, Carlos Fernandes da Silva, Anabelle Chinea, Caitlin Costello, Suman Kambhampati, DeQuincy Andrew Lewis, Michael L. Grossbard, Kathleen J. Yost, Robert Robles, Michaël Sébag, Wayne Harris, Justinian R. Ngaiza, Michael Bär, Marie Shieh, Fredrick Min, Adedayo A. Onitilo, Fabio Volterra, William Wachsman, Madhuri Yalamachili, Eugènia Abella, Larry J. Anderson, Joan Bargay, Hani Hassoun, Gerald C Hsu, Hakan Kaya, Alex R. Menter, Dilip Patel, Donald Richards, William B. Solomon, Robert F. Anderson, Sumeet Chandra, Miguel Á. Conde, Saulias Girnius, May Matkiwsky, Isabel Krsnik, Shaji Kumar, Albert Oriol, Paula Rodríguez, Vivek Roy, Shanti Srinivas, Ronald G. Steis, Austin Christofferson, Sara Nasser, Jessica L. Aldrich, Christophe Legendre, Brooks A. Benard, C. S. Miller, Bryce Turner, Ahmet Kurdoglu, Megan Washington, Venkata D. Yellapantula, Jonathan Adkins, Lori Cuyugan, Martin Boateng, Adrienne Helland, Shari Kyman
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. 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.