Monoclonal gammopathy in patients with type I gaucher disease: Data from the Russian gaucher registry

Abstract

Abstract Background Gaucher disease (GD), a lysosomal storage disorder caused by deficient glucocerebrosidase activity, is associated with polyclonal and monoclonal gammopathies. This results from chronic B-lymphocyte stimulation by macrophage-derived cytokines and chemokines (IL-6, IL-10, CCL18). Materialsandmethods Using data from the Russian Gaucher Disease Registry (cutoff: November 17, 2023), we analyzed 1,171 serum protein immunochemical studies from 336 GD patients (93% of registry participants) at the National Medical Research Center of Hematology. Assessments were performed pre-treatment and during disease-specific therapy (enzyme replacement/substrate reduction). Patients with monoclonal gammopathy were monitored for 24–228 months (median 54). Turnbull interval estimates (right-left censored) assessed gammopathy probability, while repeated-measures regression analyzed paraprotein dynamics. Results Monoclonal gammopathy was detected in 24 patients (7%), with IgG:IgA:IgM paraprotein ratios of 15:7:2. One patient had symptomatic multiple myeloma at GD diagnosis. Median age at gammopathy detection was 47 years (range: 30–71), with slight male predominance (54%); 17% were splenectomized. Gammopathy first appeared: pre-treatment (46%), during enzyme replacement (37%), or substrate-reduction therapy (17%). Paraprotein concentrations increased progressively (mean rate: 0.5 g/L/year). The 15-year probability of monoclonal gammopathy was 18%, significantly higher in patients >40 years (20%; *p*=0.001) and with splenomegaly >200 mm (36%; *p*=0.0007). Conclusion Chronic antigenic stimulation and sphingolipid-driven macrophage dysfunction underlie B-cell dysregulation in GD, explaining its high frequency of monoclonal gammopathies and associated multiple myeloma risk.