Excess Risk of Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Screened Cohort of Patients with Gaucher Disease (GD)

BACKGROUND

Prior retrospective studies and smaller case series have proposed that patients with Gaucher Disease are more likely to of be diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). To our knowledge, we have performed the first systematic screening study to define the prevalence of MGUS in a large cohort of patients with Gaucher Disease.

METHODS

We included consecutive adult (>20 years) Gaucher Disease patients who have been followed at the Gaucher Unit, Shaare Zedek Medical Center, Israel since 2016 and who signed consent for biomarker testing. All assays were performed at the Sylvester Myeloma Institute at the University of Miami. Similar to prior large screening studies, all samples were tested with serum protein electrophoresis (SPEP) and free light-chain (FLC) assays, with reflex immunofixation for positive cases. All analyses were conducted in a blind manner, and results were independently evaluated by two experts. Demographics data, Gaucher Disease genotype, treatment status, and laboratory data, including platelet count, hemoglobin, creatinine, C-reactive protein, immunoglobulin, triglyceride, and glucosylsphingosine (Lyso-Gb1), a downstream metabolic product of glucosylceramide, levels were extracted for the Gaucher Unit database. Variables were evaluated across MGUS subtypes (M-spike MGUS and light-chain MGUS).

RESULTS

The cohort included a total of 411 patients;182 (44%) were males and the median age was 46.5 years (range:20-92). The majority of patients (n=258, 62%) had mild GD genotype and 282 (68.2%) patients had received Gaucher Disease-specific treatment. M-spike MGUS and light-chain MGUS were found in 43 (10.5%) and 83 (20.2%) patients, respectively. In univariate analysis, factors associated with M-spike MGUS were increasing age (OR=1.08, 95% CI: 1.05-1.10), mild genotypes (OR=3.48, 1.49-8.08), and elevated creatinine levels (OR=9.36, 2.2-39.4). Hemoglobin and lyso-Gb1 levels were lower in patients with M-spike MGUS, but this did not reach statistical significance. In multivariate analysis, only older age was associated with excess risk of M-spike MGUS. Similarly, older age was associated with increased risk (OR=1.02, 1.01-1.04) of light-chain MGUS. Gaucher Disease-specific treatment status did not significantly alter the risk of having M-spike or light-chain MGUS.

CONCLUSIONS

In this first systematic screening study of 411 Gaucher Disease patients and with a median age of less than 50 years, the prevalence of M-spike MGUS and light-chain MGUS were 10.5% and 20.2%, respectively, which is significantly higher than rates in the general population. These novel findings are expected to shape future therapeutic strategies and improve patient care, potentially influencing genetic counseling practices in the management of Gaucher Disease.

Thoren:the Binding Site and Sebia: Research Funding, Speakers Bureau. Revel-Vilk:Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Zimran:Agyany Pharma Ltd: Current equity holder in private company; Bio-Events: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria. Landgren:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees..