The genomic profiling of high-risk smoldering myeloma patients treated with an intensive strategy unveils potential markers of resistance and progression

Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined f...

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Detalles Bibliográficos
Autores: Medina-Herrera, Alejandro, Vázquez Urio, Iria, Cuenca, Isabel, Rosa-Rosa, Juan Manuel, Ariceta, Beñat, Jiménez, Cristina, Fernández-Mercado, Marta, Larráyoz, María José, Gutiérrez, Norma C., Fernández-Guijarro, M., González-Calle, Verónica, Rodríguez-Otero, Paula, Oriol, Albert, Rosiñol, Laura, Alegre, Adrián, Escalante, Fernando, Rubia, Javier de la, Teruel, A. I., Arriba, Felipe de, Hernández, Miguel-Teodoro, López-Jiménez, Javier, Ocio, Enrique María, Puig, Noemí, Paiva, Bruno David Lourenço, Lahuerta, Juan-José, Bladé, Joan, San-Miguel, Jesús F., Mateos, María-Victoria, Martínez-López, Joaquín, Calasanz, María José, García-Sanz, Ramón, GEM/PETHEMA (Grupo Español de Mieloma/Programa para el Estudio de la Terapéutica en Hemopatías Malignas) cooperative study group
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2024
País:España
Institución:Universidad Pública de Navarra
Repositorio:Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
OAI Identifier:oai:academica-e.unavarra.es:2454/52483
Acceso en línea:https://hdl.handle.net/2454/52483
Access Level:acceso abierto
Palabra clave:Smoldering multiple myeloma
Genomic predictors
Progression risk
Treatment resistance
Molecular characterization
Descripción
Sumario:Smoldering multiple myeloma (SMM) precedes multiple myeloma (MM). The risk of progression of SMM patients is not uniform, thus different progression-risk models have been developed, although they are mainly based on clinical parameters. Recently, genomic predictors of progression have been defined for untreated SMM. However, the usefulness of such markers in the context of clinical trials evaluating upfront treatment in high-risk SMM (HR SMM) has not been explored yet, precluding the identification of baseline genomic alterations leading to drug resistance. For this reason, we carried out next-generation sequencing and fluorescent in-situ hybridization studies on 57 HR and ultra-high risk (UHR) SMM patients treated in the phase II GEM-CESAR clinical trial (NCT02415413). DIS3, FAM46C, and FGFR3 mutations, as well as t(4;14) and 1q alterations, were enriched in HR SMM. TRAF3 mutations were specifically associated with UHR SMM but identified cases with improved outcomes. Importantly, novel potential predictors of treatment resistance were identified: NRAS mutations and the co-occurrence of t(4;14) plus FGFR3 mutations were associated with an increased risk of biological progression. In conclusion, we have carried out for the first time a molecular characterization of HR SMM patients treated with an intensive regimen, identifying genomic predictors of poor outcomes in this setting.

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