Cumulative Antigen Suppression Reduces Clonal Plasma Cell Evolution in Gaucher Disease

Chronic antigenic stimulation is implicated in the pathogenesis of monoclonal gammopathy and multiple myeloma, yet longitudinal human evidence linking sustained antigen exposure to modifiable clonal plasma cell evolution remains limited. Gaucher disease (GD), caused by biallelic GBA1 pathogenic variants, is characterized by accumulation of glucosylsphingosine (LysoGL1), the direct antigenic target of GD-associated clonal immunoglobulins and a pharmacologically suppressible stimulus. We conducted a longitudinal retrospective cohort study of 235 adults with GD (3628 person-years; 2662 clinical visits), with incident-only ascertainment from a confirmed gammopathy-free baseline. Thirty-one patients (13.2%) developed incident monoclonal gammopathy. GD conferred a ninefold excess risk relative to population expectations (SIR 9.04; 95% CI 5.79-13.45). Male sex independently increased hazard 3.3-fold (HR 3.30; 95% CI 1.55-7.03; p < 0.01), mirroring the established male predominance of plasma cell dyscrasias. GD-specific therapy, initiated solely for systemic disease indications, was associated with a dose-dependent reduction in incident risk. In univariate Cox regression with age as the time scale, each additional therapy year conferred a 9% lower hazard (HR 0.91; 95% CI 0.88-0.94; p < 0.001), extending mean MGUS-free time by 8.4 years between untreated and most-treated quartiles. Cumulative therapy progressively suppressed circulating LysoGL1, with eliglustat achieving substantially deeper reduction than enzyme replacement therapy alone. Propensity score-weighted analyses were directionally concordant (IPTW HR 0.19; 95% CI 0.11-0.30; p < 0.001). These findings establish GD as a tractable model of antigen-driven oncogenesis-and provide a precedent for investigating whether therapeutic reduction of a defined antigenic stimulus can modify oncogenic trajectory in other chronic inflammatory states.