The Role of Next-Generation Sequencing in Predicting Early Relapse for Newly Diagnosed Multiple Myeloma Patients Treated with VRD Regimen

Background：Bortezomib, lenalidomide, and dexamethasone (VRD) is a standard therapy for newly diagnosed multiple myeloma (NDMM), which achieves over 90% response rate. However, some patients still relapsed in early stage. This study aims to demonstrate the predictive role of NGS in NDMM patients treated by front VRD regimen.Methods: Clinical characteristics of 106 NDMM patients receiving front-line VRD regimen were retrospectively analyzed from September 2019 to June 2023 at Peking Union Medical College Hospital. At baseline, interphase fluorescence in situ hybridization (FISH) was performed in CD138 sorted plasma cells. High-risk cytogenetic abnormalities (HRCA) were defined as 1q21+, del17p, t(4;14), t(14;16). A Next-generation sequencing (NGS) panel including 290 tumor-related genes was performed in plasma cells. Early relapse was defined as relapse within 12 months.Results：The median follow-up time of 106 NDMM patients was 32.6 months. 16 patients developed ER. The most frequently mutated gene in the whole cohort was KRAS (27.4%), followed by NRAS (13.2%), TP53 (7.5%), IGLL (5.7%) and BRAF (3.8%). The ER group, mutated genes including KRAS(4/29,13.8%)，NRAS(1/14,7 %), IGLL(2/6,33.3%) and BRAF(0/4,0%) were not significantly different from those in other patients, expect TP53 mutation(P=0.017). PFS in patients with TP53 or IGLL5 mutations and those with HRCA was worse. Whereas PFS in patients with KRAS, NRAS or BRAF mutations and those without HRCA was even longer. Univariate analysis indicated that the HRCAs and TP53 mutation were negatively associated with PFS and OS, however, KRAS mutation was a protective factor. Multivariate logistic regression analysis suggested that HRCA, KRAS and TP53 mutations were the independent influencing factors of PFS. Patients were further stratified into four groups according to these three conditions: Group I (only KRAS mutation), II (others), III (only TP53 mutation or only HRCA), and IV (TP53 mutation and HRCA). There were significant differences in PFS among the four groups. PFS in Group I was the longest, and Group IV represented the worst with majority relapsing within 12 months(4/5,80%).Conclusions: Although RAS mutation is considered as high-risk factors associated with poor prognosis, our findings suggest that VRD regimen may improve the response and survival in NDMM patients by overcoming KRAS mutation. TP53 mutation and HRCA are still unfavorable predictors. Therefore, NGS data could be a complementary method for risk stratification in MM.

No relevant conflicts of interest to declare.