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, A, Vazquez, I, Cuenca, Isabel, Rosa-Rosa, J M, Ariceta, B, Jimenez, C, Fernandez-Mercado, M, Larrayoz, M J, Gutierrez, N C, Fernandez-Guijarro, M, Gonzalez-Calle, V, Rodriguez-Otero, Paula, Oriol, A, Rosiñol, Laura, Alegre, A, Escalante, Fernando, de la Rubia, Javier, Teruel, A I, de Arriba, Felipe, Hernández, Miguel-Teodoro, Lopez-Jimenez, J, Ocio, E M, Puig, N, Paiva, Bruno, Lahuerta, J J, Bladé, Joan, San Miguel, Jesus F., Mateos, Maria-Victoria, Martinez-Lopez, J, Calasanz, María-José, Garcia-Sanz, Ramon
Tipo de recurso: artículo
Fecha de publicación:2024
País:España
Institución:Conselleria de Salut i Consum del Govern de les Illes Balears
Repositorio:Docusalut
Idioma:inglés
OAI Identifier:oai:docusalut.com:20.500.13003/20746
Acceso en línea:https://hdl.handle.net/20.500.13003/20746
Access Level:acceso abierto
Palabra clave:Disease Progression
Male
Aged
Mutation
Biomarkers, Tumor
Female
High-Throughput Nucleotide Sequencing
Drug Resistance, Neoplasm
Humans
Antineoplastic Combined Chemotherapy Protocols
Smoldering Multiple Myeloma
Middle Aged
Resistencia a Antineoplásicos
Mieloma Múltiple Quiescente
Humanos
Persona de Mediana Edad
Protocolos de Quimioterapia Combinada Antineoplásica
Anciano
Progresión de la Enfermedad
Femenino
Secuenciación de Nucleótidos de Alto Rendimiento
Biomarcadores de Tumor
Mutación
Masculino
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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