High-dose melphalan was associated with “increased genomic changes” in patients with multiple myeloma, according to a recent study.
Mehmet Samur, PhD, of the Dana-Farber Cancer Institute and the Harvard T.H. Chan School of Public Health at Harvard University, and colleagues conducted the study and published their findings in Blood.
Dr. Samur and colleagues performed deep whole-genome sequencing on samples from 68 patients. They obtained the samples from 43 patients who received lenalidomide, bortezomib, and dexamethasone; and 25 patients who received lenalidomide, bortezomib, and dexamethasone plus high-dose melphalan.
Researchers Find More Post-Relapse Mutations in Patients Receiving High-Dose Melphalan
There was no significant difference in the number of mutations present at diagnosis between the two groups of patients (7,137 vs 7,230; P=.67). However, the group of patients who received lenalidomide, bortezomib, and dexamethasone plus high-dose melphalan had significantly more mutations at relapse (9,242 vs 13,383; P=.005). The researchers did not report any change in the number of copy number alterations or structural variants.
“The newly acquired mutations were typically associated with DNA damage and double-stranded breaks and were predominantly on the transcribed strand,” Dr. Samur and colleagues wrote. “A machine-learning model, using this unique pattern, predicted patients who would receive [high-dose melphalan] with high sensitivity, specificity, and positive prediction value.”
Dr. Samur and colleagues conducted a clonal evolution analysis, finding that all patients who received lenalidomide, bortezomib, and dexamethasone plus high-dose melphalan had clonal selection. Patients who received lenalidomide, bortezomib, and dexamethasone alone had “static progression,” according to the study’s authors. There was a significantly higher percentage of subclonal mutations in patients who received lenalidomide, bortezomib, and dexamethasone plus high-dose melphalan.
“Intriguingly, patients treated with [high-dose melphalan] who achieved complete remission (CR) had significantly more mutations at relapse yet had similar survival rates as those treated with [lenalidomide, bortezomib, and dexamethasone] who achieved CR,” the study’s authors noted.
They suggested that this could be explained by the presence of a significantly higher amount of neoantigens in relapse samples from patients receiving lenalidomide, bortezomib, and dexamethasone plus high-dose melphalan.
“Overall, our study identifies increased genomic changes associated with [high-dose melphalan] and provides rationale to further understand clonal complexity,” Dr. Samur and colleagues concluded.
Reference
Samur MK, Roncador M, Aktas Samur A, et al. High-dose melphalan treatment significantly increases mutational burden at relapse in multiple myeloma. Blood. 2023;141(14):1724-1736. doi:10.1182/blood.2022017094