Reduction of paraprotein levels in type 1 Gaucher disease with enzyme therapy

Individuals with type I Gaucher disease (GD) have a 25-50-fold increased risk of developing monoclonal gammopathy of undetermined significance (MGUS), and its post-cursor, multiple myeloma, compared with the general population. Multiple myeloma is a major contributor to morbidity and mortality in patients with GD with up to 8.0% of patients progressing to a malignant gammopathy. Chronic immune activation and the pathogenic accumulation of lysolipids in GD are hypothesized to contribute to this increased risk. However, the response of MGUS to enzyme replacement therapy and/or an alteration in the risk of progression to multiple myeloma on treatment is not clear. Retrospective chart review of 85 patients with Type 1 GD revealed 12 patients with MGUS (incidence: 14%), including 4 who received enzyme replacement therapy (ERT). ERT resulted in an improvement in markers of disease activity (including chitotriosidase, ferritin, lysoGb1) and in reduction of the monoclonal protein. In the majority of patients, the response was sustained. One patient demonstrated a transient reduction in paraprotein with ERT but progressed to smoldering myeloma with an IgG-κ monoclonal component. These data suggest that MGUS may respond to ERT and provide further evidence that altering the levels of lysolipid accumulation in GD individuals with MGUS may attenuate the risk of progression to malignancy.