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High-dose melphalantreatmentsignificantlyincreases mutationalburden at relapse inmultiple myeloma Mehmet SamurMarco RoncadorAnıl Aktaş Samur2023 год

High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma
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Аннотация: High-dose melphalan (HDM) improves progression-free survival in multiple myeloma (MM), yet melphalan is a DNA-damaging alkylating agent; therefore, we assessed its mutational effect on surviving myeloma cells by analyzing paired MM samples collected at diagnosis and relapse in the IFM 2009 study. We performed deep whole-genome sequencing on samples from 68 patients, 43 of whom were treated with RVD (lenalidomide, bortezomib, and dexamethasone) and 25 with RVD + HDM. Although the number of mutations was similar at diagnosis in both groups (7137 vs 7230; P = .67), the HDM group had significantly more mutations at relapse (9242 vs 13 383, P = .005). No change in the frequency of copy number alterations or structural variants was observed. The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand. A machine learning model, using this unique pattern, predicted patients who would receive HDM with high sensitivity, specificity, and positive prediction value. Clonal evolution analysis showed that all patients treated with HDM had clonal selection, whereas a static progression was observed with RVD. A significantly higher percentage of mutations were subclonal in the HDM cohort. Intriguingly, patients treated with HDM who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with RVD who achieved CR. This similarity could have been due to HDM relapse samples having significantly more neoantigens. Overall, our study identifies increased genomic changes associated with HDM and provides rationale to further understand clonal complexity.
Год издания: 2023
Авторы: Mehmet Samur, Marco Roncador, Anıl Aktaş Samur, Mariateresa Fulciniti, Abdul Hamid Bazarbachi, Raphaël Szalat, Masood A. Shammas, Adam S. Sperling, Paul G. Richardson, Florence Magrangeas, Stéphane Minvielle, Aurore Perrot, Jill Corre, Philippe Moreau, Anjan Thakurta, Giovanni Parmigiani, Kenneth C. Anderson, Hervé Avet‐Loiseau, Nikhil C. Munshi
Издательство: Elsevier BV
Источник: Blood
Ключевые слова: Multiple Myeloma Research and Treatments, Phytochemical compounds biological activities, Glycosylation and Glycoproteins Research
Другие ссылки: Blood (HTML)
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