Molecular profiling of immunoglobulin heavy-chain gene rearrangements unveils new potential prognostic markers for multiple myeloma patients
Medina A (1), Jiménez C (1), Sarasquete ME (2), González M (1), Chillón MC (1), Balanzategui A (1), Prieto-Conde I (1), García-Álvarez M (1), Puig N (1), González-Calle V (1), Alcoceba M (1), Cuenca I (3), Barrio S (3), Escalante F (4), Gutiérrez NC (1), Gironella M (5), Hernández MT (6), Sureda A (7), Oriol A (8), Bladé J (9), Lahuerta JJ (3), San Miguel JF (10), Mateos MV (1), Martínez-López J (3), Calasanz MJ (10), García-Sanz R (1).
(1) Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain.
(2) Hospital Universitario de Salamanca (HUSAL), IBSAL, IBMCC (USAL-CSIC), CIBERONC, Salamanca, Spain.
(3) Hospital 12 de Octubre, CIBERONC, Madrid, Spain.
(4) Complejo Hospitalario, León, Spain.
(5) Hospital Vall d'Hebrón, Barcelona, Spain.
(6) Hospital Universitario de Canarias, La Laguna, Spain.
(7) Hospital Duran i Reynals, Institut Català d'Oncología (ICO), L'Hospitalet de Llobregat, Barcelona, Spain.
(8) Hospital Germans Trias i Pujol, Institut Català d'Oncología (ICO), Institut Josep Carreras, Badalona, Spain.
(9) Hospital Clínic i Provincial, Institut de Investicacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
(10) Clínica Universidad de Navarra (CUN), Centro de Investigación Médica Aplicada, IDISNA, CIBERONC, Pamplona, Spain.
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.
CITA DEL ARTÍCULO Blood Cancer J. 2020 Feb 6;10(2):14. doi: 10.1038/s41408-020-0283-8