Prevalence of Type 1 Gaucher Disease in Patients with Multiple Myeloma: Updated Interim Analysis of a Prospective, Multicentre, Observational Study

Introduction. Type I Gaucher disease (GD1) is an autosomal recessive lysosomal storage disease, caused by deficiency of the enzyme glucocerebrosidase, that degrades glycosphingolipids, resulting in a storage of them with/without enlargement of vital organs and complex bone involvement. GD1 is characterized by its extreme heterogeneity including asymptomatic or more severe presentations. In GD1, aberrant macrophage activation and immune dysregulation are associated with increased cancer risk, particularly Multiple Myeloma (MM), whose risk was estimated at almost 37-fold compared to the general population [Mistry, Crit Rev Oncog 2013]. Recent studies even described biological implications of sphingolipid metabolism alterations in the regulation of MM development and its progression from the pre-malignant stage, discussed the roles of sphingolipids in MM migration and adhesion, survival, proliferation, angiogenesis and invasion [Petrusca, Front Oncol. 2022]. The International Collaborative Gaucher Group (ICGG) Registry comprising 2742 eligible patients [Rosenbloom BE et al, 2005] found there was a 5.9-fold (95% CI 2.8-10.8) increased risk of Multiple Myeloma (MM) in patients with GD1. However, this risk was likely underestimated in this study because the younger age distribution of the study population and incomplete ascertainment because the ICGG is an observational registry to track responses to treatment. Despite the association between GD1 and cancer, specifically MM, is well-documented there's not enough data on the association of cancer with GBA mutation carriers. Moreover, data describing the prevalence of GD1 in MM patients are lacking. So, we prospectively investigated the prevalence of GD1 in a large population of patients affected by MM, also collecting the prevalence of GBA mutation carriers in the same population.

Methods. This is an observational, prospective, cross-sectional, multicentre study. The primary objective was to determine the prevalence of Dried Blood Spots (DBS) test positivity in a large prospective MM population. Patients with DBS test positivity were then purposed for genetic test to confirm the diagnosis GD1. The DBS test will be centralized at the Istituto per la Ricerca e l'Innovazione Biomedica CNR-Palermo. Considering that no effective prevalence data of GD1 in patients with MM are available, the sample size has been determined considering clinically relevant a prevalence > 0.5% for defining as "high risk” the selected population. To test this hypothesis (alpha 5%, beta 5% errors), we will enrol approximately 1000 patients.

Results. At the present data cut-off, 454 patients have been enrolled, so far. Median age was 67 years (range 37-90 years) and 56% of patients were male. No patients was of Jew ethnicity, one was Asian and one was black, Caucasian the remaining. Fifty-five percent had newly diagnosed MM while 45% had relapsed-refractory MM. Ten percent of patients had smouldering MM and 60% of all patients enrolled had prior diagnosis of MGUS. Monoclonal component was IgG in 56%, IgA in 24%, light chain in 10%. Median Ferritin was 325 ng/ml (range 17-1236 ng/ml) and median Alkaline Phosphatase was 83 U/L (range 29-355 U/L). At July data cut-off, we identified 6 patients with low glucocerebrosidase enzyme activity by DBS screening (< 4 nM/h/ml). Among them, 5 had heterozygous mutation in GBA gene (enzymatic activity 2.7, 3.4, 3.9, 2.5 and 3.5 nM/h/ml) whereas one was double heterozygous (enzymatic activity 2.0 nM/h/ml). This patient had Lyso Gb1 high level (14.6 ng/ml) and than he started eliglustat for GD1 in conjunction with therapy for MM. Considering only this patient as DBS positive the prevalence was 1/454 (0.22%), so far.

Conclusions. Despite the trial enrolment is just in the first third of the whole planned sample size, our preliminary data showed an interesting prevalence of DBS test positivity. Data updates are needed to define the real incidence of DBS test positivity in MM and the relationship of GD1 and plasma cell disorders.

Acknowledgment. This study is supported by Sanofi Genzyme

Morè:GSK: Honoraria; Janseen: Honoraria. Petrucci:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Celgene/Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Roche: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Fazio:BMS CELGENE: Honoraria; Janseen: Honoraria; gsk: Honoraria. Corvatta:Bristol: Honoraria; Janssen: Honoraria; Amgen: Honoraria.