GLUT1 Expressing Circulating Normal and Malignant Plasma Cells Predict Multiple Myeloma Progression

Circulating tumor plasma cells (CTCs) serve as valuable biomarkers in multiple myeloma (MM). Studies highlight CTCs' prognostic potential and role in risk stratification and disease outcome prediction. Glucose transporter 1 (GLUT1) is the most common glucose transporter in humans, affects immune cell metabolism, and is also recognized as prognostic and diagnostic marker in various cancers. However, the surface expression of GLUT1 on normal and malignant plasma cells (PCs) and its prognostic implications in MM remain unclear. Therefore, we investigated GLUT1 expression on normal and tumor PCs, at different disease stages, and correlated GLUT1-expressing CTCs with clinical parameters.

Bone marrow (BM) and peripheral blood (PB) were collected from 112 patients, including 4 with monoclonal gammopathy of undetermined significance (MGUS), 15 with smoldering MM (SMM), 15 with newly diagnosed MM (NDMM), 59 in complete remission (CR), 19 with relapse refractory MM (RRMM) and 20 healthy controls (HCs). Samples were processed and analyzed using adapted Euroflow protocols and flow cytometry for the surface expression of GLUT1, utilizing receptor binding doming (RBD) reagents from Metafora Biosystems. Data were analyzed with Infinicyt and Metaflow software. The study adhered to Good Clinical Practice Guidelines (study n° 7411, prot. n° 0073322) with informed consent obtained from all patients.

GLUT1 expression on CTCs was evaluated in 49 patients: 3 MGUS, 13 SMM, 14 NDMM and 19 RRMM. Furthermore, GLUT1 was also evaluated in a cohort of BM matched samples: 3 MGUS, 8 SMM, 6 NDMM, 8 RRMM.Malignant PCs showed a heterogeneous GLUT1 expression in the bone marrow, while in PB, GLUT1 levels increased from MGUS to NDMM and decreased from NDMM to RRMM. NDMM patients exhibited significantly higher GLUT1 expression on CTCs compared to the SMM group (p=0.016). In the NDMM cohort, patients with high-risk cytogenetics defined as t(4;14), del(17p13), t(14;16) or 1qamp/gain had significantly higher GLUT1 levels than those with standard risk (p=0.0160), while no differences were observed in the bone marrow. Pearson's analysis revealed correlations between GLUT1 on CTCs and clinical parameters such as CTC count, BM infiltration, calcium, albumin and β2 microglobulin levels in the NDMM group. In the relapsed patients, GLUT1⁺ CTCs correlated with CTC bone marrow tumor PC values, hemoglobin, albumin and lactate dehydrogenase(LDH) levels.

We also evaluated GLUT1 expression on circulating PCs in 20 healthy controls and compared these results with those from patients at different MM stages. GLUT1 frequencies were significantly higher in HCs compared to any stage of myeloma disease (p=0.0177 for MGUS, p<0.0001 for SMM, p=0.0006 for NDMM, p=0.0004 for CR and p=0.029 for RRMM), supporting the predictive value of GLUT1. Overall, GLUT1 expression on CTCs increased from MGUS to NDMM, correlating with cytogenetic risk factors and clinical parameters such as BM infiltration, calcium, albumin and β2 microglobulin. Moreover, GLUT1 levels on circulating normal PCs in healthy controls significantly decreased in all MM stages, indicating GLUT1's potential as a predictor of MM disease progression.

Collectively, GLUT1 expression on circulating plasma cells in healthy controls and MM patients showed predictive value, correlating with MM risk factors and clinical parameters. These findings suggest GLUT1 as a powerful biomarker that, combined with disease stratification models, could predict active disease and patient outcomes in multiple myeloma.

Tabares:BD: Consultancy. Kortüm:Janssen: Honoraria; BMS: Honoraria; Skyline Dx: Research Funding; Pfizer: Honoraria; GSK: Honoraria; Amgen: Honoraria; Menarini Stemline: Honoraria. Rasche:Janssen: Honoraria; Skyline Dx: Research Funding; Pfizer: Honoraria; GSK: Honoraria; BMS: Honoraria; Amgen: Honoraria. Waldschmidt:Pfizer: Honoraria; GSK: Honoraria; Pharmamar: Honoraria; Stemline Menarini: Consultancy; Oncopeptides: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Beigene: Honoraria; Janssen: Consultancy. Rougé Dubroc:Sebia: Current Employment. Einsele:Sanofi: Honoraria; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beilhack:The University of Würzburg: Patents & Royalties: patent application filed for “Novel TNFR2 binding molecules.