High neutrophil-to-lymphocyte ratio does not predict MGUS to myeloma progression but is associated with worse survival as a marker of global inflammation

Abstract BACKGROUND Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder affecting approximately 4% of the general population. It is typically identified incidentally during evaluation for unrelated clinical concerns. Although asymptomatic, MGUS carries an annual progression risk of approximately 1% to multiple myeloma (MM). Prior studies have demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a marker of immune dysregulation and is associated with worse survival in MM. However, the prognostic significance of NLR in the MGUS population remains underexplored. METHODS Patients diagnosed with MGUS between 2011 and 2021 who had both a documented last follow-up date and a baseline neutrophil-to-lymphocyte ratio (NLR) measured within six months before or after MGUS diagnosis were included. Patients missing either data point were excluded. Additional exclusion criteria included: (1) a co-occurring malignancy at MGUS diagnosis or within six months of MGUS, and (2) a NLR/MLR during documented infectious process were replaced with the NLR following infection resolution.Patient co-morbidites, MM dg and survival status were extracted from medical records. Median was utilized to optimize survival stratification. Given that the median was close to this value, patients were stratified into NLR categories based on the median: low (<2.75) vs high (≥2.75). Patient characteristics were compared by NLR and also by progression to MM. MM -free survival (MFS) and OS by NLR was estimated using Kaplan-Meier methods and compared using the log-rank test. Cumulative incidence of MM progression was analyzed using Fine and Gray's competing risks model. Categorical variables were compared using Chi-square tests, and continuous variables were assessed using the Wilcoxon rank-sum test. Cause-of-death data were collected from available clinical documentation and classified into major categories. RESULTS We evaluated 1,669 patients with median age of 68 years; 53% were male and 86% identified as white. Of the included cohort, 76 progressed to MM.There were no significant differences in demographics between MM progressors and non-progressors. Group with high NLR (n=842) had higher proportion of patients with diabetes (36% vs 26% in low NLR group) and CAD (24% vs 15%), higher age (68 vs 65yr), male gender (56% vs 50%) and white race (88% vs 84%). High NLR group (n=842) experienced a similar 5 year cumulative incidence of MM progression (6%; 95%CI 4-8%) compared to low NLR group (n=827) (9%; 95% CI 7-11%; 0.10). Notably, MGUS patients with high NLR had higher overall mortality resulting in a significantly inferior 5 year OS (71%; 95%CI 68-75) compared to 87% (95%CI 84-89%; p<0.01) in low NLR patients. Among 579 deceased patients with available data, the most common causes of death were cardiovascular disease (25.3%), malignancy (21.7%), and infection (20.9%). Other causes included trauma, gastrointestinal, pulmonary, and neurodegenerative conditions. CONCLUSION Elevated baseline NLR in patients with MGUS was associated with comorbidities particularly DM and CAD. While NLR as a marker of inflammation was not associated with increased risk of progression to MM. Patients with elevated NLR had significantly lower overall survival particularly due to non-malignant comorbidities but also other (non MM) malignancies. These findings suggest that NLR, a readily available biomarker, is not prognostic to predict progression to MM but serves to identify patients with global inflammation and should be further studied to identify patients at risk of increased mortality.