Introduction: Global prevalence of obesity has risen sharply in the last decade, raising the incidence and clinical progression of multiple myeloma (MM), a B-cell neoplasia resulting from the clonal proliferation of malignant plasma cells in the bone marrow, which accounts for 10-15% of all haematological malignancies. Obese patients exhibited a distinct serum profile characterized by low-grade inflammation, altered metabolic markers and elevated-derived hormones, which might influence MM progression. However, the molecular connection between obesity and MM is still not completely unraveled. The aim of this study was to evaluate the impact of the serum from healthy donors, stratified by body mass index (BMI), on modulating the MM cell phenotype.

Methods: RPMI-8226 and U-266 human MM cell lines were used as experimental models. Serum samples from healthy donors were pooled according to BMI into normal weight (n=20, NW; < 25.0 kg/m²) and overweight/obese (n=20, OW/Ob; ≥ 25.0 kg/m²) groups. In vitro assays were performed to assess cell viability, proliferation, migration, and invasiveness. Serum secretion profiles were analyzed using multiplex bead-based immunoassays. Protein–protein interaction was explored through STRING bioinformatic analysis.

Results: OW/Ob serum increased MM cell colony formation, migration and invasion compared to NW serum. In addition, OW/Ob serum exhibited elevated concentration of pro-inflammatory and pro-tumorigenic mediators and reduced amounts of immune-modulator factors. The differentially expressed molecules formed a protein network associated with cancer signalling and inflammatory pathways, with IL-8/CXCL8 acting as the central hub.

Conclusions: Our data demonstrated that serum from OW/Ob donors, characterized by an altered cytokine profile, promotes MM cell aggressiveness compared to NW serum. These findings suggest that the pro-inflammatory milieu fostered by high IL-8/CXCL8 provides a supportive environment for MM progression.