P-303: Prevalence of type I Gaucher disease in patients with smouldering or multiple myeloma: results from the prospective, observational CHAGAL study

Introduction: Type I Gaucher disease (GD1) is a lysosomal storage disease caused by genetic defect of the enzime beta-glucocerebrosidase (GBA), associated with increased cancer risk. Risk for multiple myeloma (MM) occurrence is 5.9 - 51.1 times greater in patients with GD1 compared to general population. No studies explored the concurrent GD1 in patients diagnosed with MM except a small retrospective study.

Methods: Type I Gaucher disease (GD1) is a lysosomal storage disease caused by genetic defect of the enzime beta-glucocerebrosidase (GBA), associated with increased cancer risk. Risk for multiple myeloma (MM) occurrence is 5.9 - 51.1 times greater in patients with GD1 compared to general population. No studies explored the concurrent GD1 in patients diagnosed with MM except a small retrospective study.

Results: A total of 1004 patients affected by Smouldering Myeloma (SMM) or MM were enrolled in 22 Italian haematology centres. Median age was 68 (range: 36-92) years, median haemoglobin value was 11.8 g/dl (range: 4.5-17.6), median platelet count was 195 x 10³/mmc (range: 10-772). Of 891 patients, 54% had newly diagnosed (NDMM), 32% relapsed refractory MM (RRMM) and 3% SMM. The monoclonal component was mainly IgG kappa (369, 37%), followed by IgG lambda (197, 20%). Forty percent of patients had anaemia, 15% renal failure, 6% hypercalcemia, 56% bone disease. As for high risk cytogenetic features, 1q21 was reported in 13% of patients, del17p in 4%, t(14;16) in 1% and t(4;14) in 8%. Twenty-three percent had International Staging System (ISS) III, 9% Revised-ISS (R-ISS) III. We found 14 patients (1.3%) with a positive DBS test, one with a compound heterozygous mutation of GBA gene (prevalence: 0.09%; 95%CI: 0.022-0.36), one with a double heterozygous mutation and 12 with a single heterozygous mutation (prevalence of double/single heterozygous status: 1.3%). The most frequently identified mutation was N370S (3 patients), followed by L444P (2 patients) and others; the compound heterozygous GBA mutated patient had L444P and R170C mutations.

In the 13 heterozygous patients, median value of GBA enzymatic activity was 2.8 nmol/h/ml (range: 2.4-3.9) and median LysoGb1 value was 2.8 ng/ml (range: 1.7-5.4); 30.7% had a lower range GBA enzymatic activity with no abnormal LysoGb1 value.

Conclusions: In our study the prevalence was 1 every 1004 MM/SMM patients - lower than hypothesized 0.5%- therefore the primary endpoint was not met. However, we found a 5.3 times higher prevalence in our study than that reported in Italy (0.09 vs 0.017/1000), closer to that in the Ashkenazi Jewish population (0,14/1000); as a similar study also found in MGUS. Therefore, it was demonstrated that GD1 should be considered an associated disease with plasma cell dyscrasias and patients with MGUS/SMM/MM and any signs of GD1 should be screened for the disease.