METTL14 overexpression identifies a biologically aggressive subgroup and correlates with adverse clinical outcomes in multiple myeloma

Abstract Background N⁶-methyladenosine (m⁶A) is the most prevalent internal modification of eukaryotic mRNA and plays a central role in post-transcriptional gene regulation. METTL14, a key component of the m⁶A methyltransferase complex, has been implicated in cancer progression and prognosis. However, its expression profile and clinical significance in multiple myeloma (MM) remain poorly understood. In this study, we examined METTL14 expression in MM patients and evaluate its prognostic value. Methods METTL14 expression was quantified in bone marrow plasma cells from 146 newly diagnosed MM patients and 11 healthy donors using RT-qPCR. Circulating plasma cells (CPCs) and minimal residual disease (MRD) were evaluated via multiparameter flow cytometry. Associations between METTL14 expression and clinical characteristics, therapeutic response, and survival outcomes were assessed. External validation was conducted using public datasets (GSE193531, GSE99636, and MMRF CoMMpass). Kaplan-Meier survival analysis and multivariate Cox regression were employed to determine prognostic significance. Furthermore, a composite prognostic model integrating METTL14 expression with R-ISS parameters was developed. Results METTL14 expression was significantly elevated in MM plasma cells compared to healthy controls. Patients were stratified into high and low METTL14 expression groups using the median RT-qPCR value (2^−ΔCt = 0.01253) as the cutoff. High METTL14 expression was significantly associated with features indicative of greater tumor burden, including advanced ISS (P = 0.005), R-ISS (P = 0.001), and R2-ISS (P = 0.001) stages; elevated serum β2-microglobulin levels (≥3.5 mg/L: 89.0% vs. 68.5%, P = 0.002); increased serum lactate dehydrogenase levels (>250 U/L: 28.8% vs. 13.7%, P = 0.026); higher bone marrow plasma cell proportions (≥60%: 16.4% vs. 5.6%, P = 0.037); greater CPC levels (≥0.038%: 54.8% vs. 37.0%, P = 0.031); and renal impairment (estimated glomerular filtration rate <60 mL/min/1.73 m²: 60.3% vs. 39.7%, P = 0.013). In parallel, high METTL14 expression correlated with aggressive disease features, including ≥3 osteolytic lesions (61.6% vs. 35.6%,P = 0.007); high-risk cytogenetic abnormalities such as t(4;14) (30.1% vs. 15.1%, P = 0.030), t(14;16) (13.7% vs. 4.1%, P = 0.042), and del(17p) (20.5% vs. 6.8%, P = 0.016); and adverse immunophenotypes, including CD56 negativity (54.8% vs. 75.3%, P = 0.009), CD27 negativity (13.7% vs. 28.8%, P = 0.026), and CD117 negativity (8.2% vs. 19.2%, P = 0.054). Additionally, the incidence of extraosseous extramedullary disease was higher in the high-expression group (11.0% vs. 1.4%, P = 0.033). Patients with high METTL14 expression exhibited poorer treatment responses, including lower rates of ≥VGPR (38.2% vs. 55.6%, P = 0.040) and MRD negativity (7.4% vs. 20.8%, P = 0.023). High METTL14 expression was an independent predictor of shorter progression-free survival (PFS) (hazard ratio [HR] = 2.88, P = 0.001) and overall survival (OS) (HR = 3.43, P = 0.001). These findings were validated in an external cohort (n = 785). Among R-ISS stage II patients, METTL14 expression further stratified outcomes: patients with low expression had survival rates comparable to those with R-ISS stage I, whereas patients with high expression resembled those with R-ISS stage III. The METTL14-integrated model improved predictive accuracy for 3-year PFS (AUC 0.767 vs. 0.694) and OS (AUC 0.770 vs. 0.690) compared to R-ISS alone. Conclusion METTL14 overexpression identifies a biologically aggressive subset of MM and serves as a robust, independent predictor of poor outcomes. Incorporating METTL14 into existing risk stratification systems significantly enhances prognostic accuracy, particularly for patients classified as intermediate risk. These findings suggest that METTL14 may serve as a clinically relevant biomarker with potential utility in refining prognostic assessments and guiding future risk-adapted treatment strategies in MM.