Molecular profiling of immunoglobulin heavy-chain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients
Alejandro Medina, Cristina Jiménez, María Eugenia Sarasquete, Marcos González, Carmen Chillón, Ana Balanzategui, Isabel Prieto-Conde, María García‐Álvarez, Noemí Puig, Verónica González‐Calle, Miguel Alcoceba, Isabel Cuenca, Santiago Barrio, Fernando Escalante, Norma C. Gutiérrez, Mercedes Gironella, Miguel‐Teodoro Hernández, Anna Sureda, Albert Oriol, Joan Bladé, Juan José Lahuerta, Jesús F. San Miguel, María‐Victoria Mateos, Joaquín Martínez‐López, Marı́a José Calasanz, Ramón García‐Sánz
Abstract
Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation of IGHV3, IGHD2 and IGHD3, as well as IGHJ4 gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use of IGHD2 and IGHD3 groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progression-free survival rates for patients using IGHD2/IGHD3 groups (HR: 0.552, 95% CI: 0.361-0.845, p = 0.006), as well as prolonged overall survival rates for patients with hypermutation ≥7% (HR: 0.291, 95% CI: 0.137-0.618, p = 0.001). Our results provide new insights into the molecular characterization of multiple myeloma, highlighting the need to evaluate some of these clonal rearrangement characteristics as new potential prognostic markers.