Excess Risk of Monoclonal Gammopathy in Patients With Gaucher Disease

Gaucher disease (GD) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme glucocerebrosidase, resulting in accumulation of glucosylceramide within macrophages [1]. The disease is classically characterized by hepatosplenomegaly, hypersplenism, and skeletal involvement. However, GD is increasingly recognized as a multisystem disorder, with additional clinical manifestations arising from complex immunological, inflammatory, and metabolic dysregulation [2, 3]. The association between GD and malignancies, particularly hematologic cancers, has been one of the most debated and clinically concerning issues in the field for more than three decades [4]. This association causes considerable anxiety among diagnosed patients and during genetic counseling for affected families and carrier couples. Early registry-based analyses from the International Collaborative Gaucher Group (ICGG) Registry, which included 2742 patients, identified an association between GD and multiple myeloma (MM), although no overall increase in cancer incidence was observed. A subsequent ICGG analysis of 2123 adults with GD type 1 reported a higher prevalence of monoclonal gammopathies [5]. Interpretation of these findings has been complicated by inherent limitations of registry-based studies. Symptomatic patients are more likely to be referred, diagnosed, and enrolled, and may undergo more frequent laboratory and imaging surveillance. This may result in detection bias, lead-time bias, and overestimation of disease associations [6, 7]. Accordingly, reported links between GD and cancer may reflect increased diagnostic scrutiny or temporal proximity of diagnosis rather than true biological causality. Because MM is almost invariably preceded by monoclonal gammopathy of undetermined significance (MGUS), this asymptomatic precursor state has become a focus of increasing interest in GD research and clinical care. To date, however, estimates of MGUS prevalence in GD have relied largely on retrospective registry data or small, selected cohorts [5, 8-10]. Systematic screening studies using standardized assays and unbiased patient inclusion have been lacking. The current study aimed to define the prevalence of MGUS and light-chain MGUS (LC-MGUS) in a large, consecutive cohort of patients with GD using uniform, high-quality testing performed at an international myeloma reference laboratory. This design also enabled assessment of the potential influence of GD-specific therapies, including enzyme replacement therapy (ERT) and substrate reduction therapy (SRT), on the presence and evolution of monoclonal gammopathy. This cross-sectional study included consecutive patients with GD followed at the Gaucher Unit of Shaare Zedek Medical Center (SZMC) between January 2016 and June 2023. Inclusion criteria required availability of at least one stored serum sample in the institutional biobank and documented informed consent for biobanking, available in over 95% of patients. A longitudinal sub-analysis included adults with paired serum samples collected either during untreated follow-up or before and after initiation of ERT or SRT. The study protocol was approved by the SZMC Institutional Review Board (0350-19-SZMC). Clinical and demographic data were extracted from medical records. Genotyping was based on complete GBA1 sequencing and classified as mild (N370S (p.Asn409Ser) homozygotes or compound heterozygotes with N370S/R496H) or severe (all other GBA1 variant combinations). Treatment status at the time of serum collection was categorized as “treated” (ERT or SRT) or “untreated.” Laboratory data included complete blood count, serum creatinine, C-reactive protein, triglycerides, immunoglobulin profile, and glucosylsphingosine (Lyso-Gb1), a validated biomarker of GD disease burden. Elevated creatinine was defined as > 1.04 mg/dL for females and > 1.25 mg/dL for males. All serum samples were shipped on dry ice to the Sylvester Myeloma Institute at the University of Miami and analyzed in a blinded manner by trained laboratory personnel experienced in large population-based MGUS screening studies [11]. Screening consisted of serum protein electrophoresis (SPEP) (gel electrophoresis, Sebia Inc.), serum free light chain (FLC) quantitation using the Freelite assay on the Optilite analyzer, The Binding Site by Thermo Fisher, and confirmatory immunofixation (Sebia) for positive SPEP results. MGUS was defined by the presence of a monoclonal band on SPEP and confirmed by immunofixation. LC-MGUS was defined as an abnormal kappa/lambda ratio (reference range 0.26–1.65) in the absence of an intact monoclonal immunoglobulin on SPEP. Descriptive statistics are presented as frequencies and medians (with ranges). Group comparisons were performed using the Chi-square for categorical variables and Wilcoxon rank-sum test for non-normally distributed continuous variables. Associations between MGUS status and clinical variables were assessed using univariate and multivariate logistic regression models. Covariates included age, genotype severity, treatment status, and laboratory parameters. Variables with p < 0.1 in univariate analysis were considered for multivariate modeling using forward selection. Statistical significance was defined as two-sided p value < 0.05. Analyses were conducted using R (version 2025.05.0+496). A total of 510 patients with GD, including 411 adults, were included in the cross-sectional analysis (Table 1). Most participants carried mild genotypes and were receiving GD-specific therapy at the time of serum collection. Monoclonal gammopathy was identified in 126 adults (30.6%) and in 13 pediatric (13.1%) patients. Among affected adults, 43 (34%) had MGUS detected by SPEP and confirmed by immunofixation, and 63% of these also had an abnormal FLC ratio. The remaining 83 adults had LC-MGUS without detectable intact monoclonal immunoglobulin. One pediatric patient met criteria for MGUS. Compared with adults without monoclonal gammopathy, those with MGUS or LC-MGUS were significantly older, more likely to carry mild genotypes, had higher serum creatinine levels, and lower hemoglobin values (Table 2). Sex, treatment status, platelet count, Lyso-Gb1 levels, immunoglobulin levels, C-reactive protein, and triglyceride levels were not associated with MGUS or LC-MGUS. In multivariate logistic regression, age emerged as the only independent predictor of MGUS (odds ratio [OR] 1.07, 95% confidence interval [CI]: 1.05–1.10) and LC-MGUS (OR 1.02, 95% CI: 1.01–1.04). Age-stratified prevalence is shown in Table 3. The increase in combined monoclonal gammopathy with age was largely driven by MGUS, whereas LC-MGUS prevalence remained relatively stable across age groups. Sixty-eight adult patients had paired serum samples available for longitudinal analysis. Thirty-nine untreated patients, all with mild genotypes, were followed for a median of 1.4 years (range, 0.5–6 years). Two patients were MGUS-positive at both timepoints, while two converted from negative to positive MGUS at 1.2 and 6 years, respectively. Twenty-nine patients initiated ERT or SRT during a median follow-up of 1.0 year (range, 0.2–3 years). Four were MGUS-positive both before and after treatment. One female converted to MGUS-positive after 1 year despite improvement in GD clinical parameters, while another converted from MGUS-positive to negative within 2 months of treatment initiation. All but one patient in this group carried mild genotypes. This study provides the first large-scale, systematic screening for MGUS and LC-MGUS in a well-characterized cohort of patients with GD using centralized reference-laboratory testing. We found that over 30% of adults with GD harbored a monoclonal gammopathy, with prevalence rising from approximately 20% in those under age 40 to nearly 50% in individuals over age 60. MGUS prevalence increased steadily with age, while LC-MGUS remained relatively constant at around 20%. These findings demonstrate that myeloma precursor states are more than 10-fold more common in GD than in the general population. This observation has important clinical implications, as patients with GD, particularly those diagnosed at younger ages, may live many years with MGUS and a prolonged cumulative risk of progression to MM. Prior registry-based studies have reported highly variable MGUS prevalence in GD, reflecting differences in methodology, referral patterns, and diagnostic intensity [12]. Our systemic approach minimized these biases and supports a robust association between GD and monoclonal gammopathy across all adult age groups, including individuals younger than 40 years. The biological mechanisms underlying MGUS and LC-MGUS in GD remain incompletely understood. Chronic immune activation, cytokine dysregulation, and alterations in the bone marrow microenvironment may promote clonal plasma cell survival [9, 13]. Antigenic stimulation by lipids such as saposin C [14] or Lyso-Gb1 have been proposed [15]. Although we did not observe an association between Lyso-Gb1 levels and monoclonal gammopathy. A key objective of this study was to evaluate the influence of GD-specific therapy on MGUS and LC-MGUS. Both cross-sectional and longitudinal analyses showed no consistent association between treatment status and the presence or evolution of monoclonal gammopathy. MGUS and LC-MGUS appeared, persisted, or regressed regardless of treatment initiation or duration, consistent with prior reports [5, 8, 10]. Current consensus guidelines recommend routine screening and monitoring for monoclonal gammopathy in GD [16]. Our findings provide strong empirical support for these recommendations. If progression to MM occurs, standard anti-myeloma therapy should be administered in conjunction with ERT to optimize marrow reserve and treatment tolerance, emphasizing the importance of multidisciplinary management [17, 18]. Conversely, GD testing should be considered in patients with MGUS who present with cytopenias, organomegaly, bone pain, or unexplained bleeding [19, 20]. The strengths of this study include systematic, unbiased screening of consecutive patients using sensitive, uniform assays at a single reference laboratory. Limitations include limited longitudinal follow-up and the single-center design, which may affect the generalizability of findings to more diverse GD populations with different genetic or demographic characteristics. Classification of LC-MGUS relied on current FLC reference ranges; while these may evolve, such changes would affect GD and general populations similarly and do not alter our principal conclusions. In this systematically screened cohort of patients with GD, more than 30% of adults were found to have MGUS or LC-MGUS, independent of treatment status. These findings strongly support routine screening and longitudinal monitoring for monoclonal gammopathy in adult patients with GD. Further long-term studies are needed to better define progression rates to MM and to characterize clinical outcomes, treatment responses, and toxicity profiles in this high-risk population. Insights from the GD-MGUS association may also inform broader strategies for understanding and managing monoclonal gammopathies beyond GD. M.I., A.Z., S.R.-V., and O.L. contributed to the study conception and design and provided guidance for the study. M.I., D.F., T.D., and M.B.-C. enrolled patients. M.I., K.T., and D.K. contributed to the collection and/or assembly of data. All authors contributed to the data analysis and/or interpretation. M.I., K.T., S.R.-V., and O.L. drafted the manuscript. All authors critically revised the manuscript, approved the final version for publication, and agreed to be accountable for all aspects of the work. The authors thank the patients who participated in these studies and their families. Dr. Ola Landgren is supported by the Sylvester Comprehensive Cancer Center National Cancer Institute Core Grant (P30 CA 240139) and the Riney Family Multiple Myeloma Research Program Fund, Tow Foundation, Myeloma Solutions Fund, and Cannon Guzy Family Fund. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Shaare Zedek Medical Center Institutional Review Board (0350-19-SZMC). Written information consent was obtained from all participants, including consent for biobanking. M.I., D.K., D.F., T.D., and M.B.-C. declare no conflicts of interest. K.T. received research support from The Binding Site (Thermo Fisher) and Sebia. A.Z. received grant/research support, honoraria, and consulting fees from Takeda, Pfizer, and Sanofi. He is the Founder and CMO of Agyany Pharma LTD. S.R.-V. received grant/research support, honoraria, and consulting fees from Takeda, Pfizer, and Sanofi. The SZMC Gaucher Unit receives support from Sanofi for participation in the ICGG Registry and from Takeda for the GOS Registry. O.L. received funding from NCI/NIH, FDA, Leukemia & Lymphoma Society, Rising Tide Foundation, Multiple Myeloma Research Foundation, International Myeloma Foundation, Paula and Rodger Riney Foundation, Tow Foundation, Perelman Family Foundation, Myeloma Solutions Fund, Cannon Guzy Family Fund, Amgen, Janssen, and Pfizer; received honoraria from AbbVie, Adaptive, Amgen, Binding Site, Bristol Myers Squibb, GSK, Janssen, Sanofi, and Pfizer; participated in advisory boards for AbbVie, Adaptive, Amgen, Binding Site, Bristol Myers Squibb, GSK, Janssen, Sanofi, and Pfizer; and served on independent data monitoring committees for international randomized trials by Kite, Merck, Janssen, and Novartis—all outside the submitted work. The data supporting the findings of this study are available from the corresponding author upon reasonable request.