Abstract 4807: Gaucher disease treatment reduces the progression of smoldering myeloma
Authors: Shukla Ravi Prakash , Parekh Anshuman , Leshchenko Violetta V , Barley Kevin , Vatti Deepa , Verina Daniel , Balwani Manisha , Parekh Samir 
Published: March 2024

Abstract
Background: Gaucher disease (GD), a hereditary condition characterized by glucocerebrosidase deficiency, results in the impaired degradation of glucocerebroside (GL1) and its deacetylated form, lyso-GL1 (LGL1). This leads to the accumulation of these substrates primarily in the bone marrow (BM), liver, and spleen. Notably, individuals with GD face an increased risk of plasma cell dyscrasias (PCD) by approximately nine-fold. We present two compelling cases of the regression of smoldering multiple myeloma (SMM) following GD treatment, substantiated by biochemical evidence of lipid-reactive clonal paraproteins (PP) in both patients.
Methods: Peripheral blood samples were obtained with IRB approval from patients with concurrent SMM and GD at the Icahn School of Medicine at Mount Sinai. Utilizing C-18 beads coupled with gly-sphingosine-coated liposomes and Sphingosine-1 phosphate bead liposome-based pulldown, we established the binding of glycolipids to serum PP.
Results: In a 66-year-old male, hepatosplenomegaly and pancytopenia revealed compound heterozygous N370S/V394L mutations and reduced β-glucosidase activity, confirming Type 1 GD. Laboratory findings included substantial pancytopenia (WBC 2.5 k/µL, Hgb 12.1 g/dL, platelet 44 k/µL) and myeloma markers (M spike 1.58 g/dL, monoclonal IgA λ). A BM biopsy indicated 30% λ-restricted plasma cells. PET-CT showed hepatosplenomegaly without FDG avid lytic lesions, consistent with SMM. Imiglucerase enzyme therapy improved GD biomarkers, decreased hepatosplenomegaly, and blood count improvement (WBC 4.7 k/µL, Hgb 13.6 g/dL, platelet 66 k/µL). Notably, myeloma burden significantly reduced (M-spike 0.94 g/dL, IgA 1373 g/dL and free lambda 26.1 mg/L). Similarly, a 41-year-old female with mild fatigue, Hgb levels of 10.9 g/dL, a platelet count of 169 k/µL, M spike of 0.9 g/dL, IgG κappa on immunofixation, and IgG levels at 1730 mg/dL, indicating SMM. GBA analysis showed homozygous N370S mutation and reduced beta-glucosidase activity consistent with Type 1 GD. Substrate reduction therapy with eliglustat alleviated fatigue, reduced GD biomarkers, normalized cytopenias, and gradually decreased myeloma markers. Laboratory results indicated an M spike of 0.5 g/dL, IgG levels at 1295 mg/dL, and free kappa at 31.3 mg/L. To explore the interaction between clonal immunoglobulins (Ig) and lyso-lipids, we utilized Gly-sphingolipids (see methods) and demonstrated a robust interaction with IgA (patient 1) and IgG (patient 2) paraprotein by western blotting.
Conclusion: Our experimental findings confirm specific clonal Ig binding in SMM and GD patients and demonstrate potent and timely benefits from addressing GD in managing SMM patients. This holds significance amid ongoing clinical trials exploring aggressive interventions for SMM, including bispecific and CAR-T therapies.
Citation Format: Ravi Prakash Shukla, Anshuman Parekh, Violetta V Leshchenko, Kevin Barley, Deepa Vatti, Daniel Verina, Manisha Balwani, Samir Parekh. Gaucher disease treatment reduces the progression of smoldering myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4807.