Abstract
Due to the high genetic complexity and heterogeneity, the treatment responses and prognosis of patients with multiple myeloma (MM) vary from person to person. Therefore, comprehensive risk assessment is a key to conduct precise treatment and improve prognosis, especially for newly diagnosed MM (NDMM) patients. Numerous studies have shown the key roles of genetic events in MM, but most of them focus on cytogenetic abnormalities. Right now, conclusions drawn from the analysis of mutated genes are mostly controversial and of limited value, and only the poor prognostic association of TP53 has reached a consensus. Based on this, guidelines only consider next-generation sequencing (NGS) as an optional method for prognosis assessment, but the potential values of NGS in risk stratification still need to be further evaluated. In this study, we conducted a systematic analysis of the gene mutations and their potential clinical values in Chinese NDMM patients.
The retrospective analysis was performed in 468 NDMM patients diagnosed from January 1998 to November 2024 (from Peking Union Medical College Hospital and Union Hospital, Tongji Medical College, Huazhong University of Science and Technology). Following the mutation filtration, we described the mutation landscape of patients via “maftools” package and further identified the genetic mutation patterns. Meanwhile, correlation analysis was conducted between genetic mutations and clinical pathological features. Categorical variables were analyzed via chi-square test/Fisher's exact test, while continuous variables were analyzed via t-test/Mann-Whitney U test. Moreover, Log-rank test and Cox regression analysis were performed for the identification of gene mutations with prognostic values.
Gene mutations were detected in 448 patients (95.72%), involving 343 genes. The mutation landscape revealed high-frequency (> 10%) mutations in KRAS, NRAS, ATXN1 and DIS3. Compared with prior reports from domestic and international cohorts, mutant genes detected were highly overlapping, but mutation frequencies differed. Correlation analysis between different gene mutations showed multiple co-occurring mutation pairs such as DIS3-IGLL5, DIS3-FGFR3 and TP53-DNAH9(all p < 0.01), as well as mutually exclusive mutation pairs including FGFR3-KRAS and FGFR3-NRAS(all p < 0.05). Meanwhile, the relationship of gene mutations with clinical pathological features was also analyzed. Patients with R-ISS stage Ⅲ (p = 0.0108) or immunoparesis (p < 0.0001) showed higher tumor mutational burden. In terms of the prognostic values, among 19 mutated genes associated with both overall survival (OS) and progression-free survival (PFS), only TP53met the threshold of mutation frequency ≥ 3%. Besides, patients with PRUNE2 mutation presented worse prognosis (p < 0.001), while those with ATN1 mutation showed favorable outcomes (p = 0.014) (all mutation frequency ≥ 3%). For the patients exclusively treated with bortezomib, lenalidomide and dexamethasone (VRD) regimen, TP53, PRUNE2, ATM, DNAH5and ZFHX4 mutation were identified as risk factors (all mutation frequency ≥ 3%, ATM PFS p = 0.012, DNAH5p = 0.039 and other p < 0.001). Additionally, among VRD-treated patients, PRUNE2 and CSMD1 mutation were only present in those with early relapse, but differences of mutation frequencies did not reach statistical significance.
Gene mutations are common events in NDMM patients, and present potential relationship with several clinica pathological features. Nevertheless, their prognostic values are somewhat limited, and only TP53 and some genes with low-frequency mutations affect survival. In this study, the prognostic value of PRUNE2 and DNAH5 in MM patients was confirmed for the first time. These findings highlight the advantages of targeted sequencing rather than whole-genome sequencing in MM. Taken together, although the conclusions are limited, it provides a new direction for the prognosis stratification and treatment strategy of Chinese MM patients to a certain extent.
