Evolution of myeloma bone disease over time: Comparison of selected biomarkers in MGUS, SMM and active MM

Abstract Background: Myeloma bone disease (MBD) is a hallmark of multiple myeloma (MM) and is present in up to 80% of newly diagnosed patients. The extent of lytic bone involvement varies and generally correlates with more advanced disease stages. MBD arises from an imbalance in bone homeostasis caused by increased bone resorption factors combined with suppression of bone formation factors. As MM progresses from its precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM)—we aimed to compare selected cytokines associated with MBD across these three conditions. Patients and Methods We assessed 121 patients with monoclonal gammopathies: 77 patients with active MM (at diagnosis or relapse), 14 individuals with SMM, and 30 individuals with MGUS. We measured the following serum cytokines and bone marrow microenvironment parameters known to be associated with MBD: procollagen type I propeptides (P1NP), Crosslaps (CTX-1), cross-linked telopeptide of type I collagen (ICTP), osteoprotegerin (OPG), nuclear factor kappa B (NF-kB), receptor activator of nuclear factor κB (RANK), receptor activator of nuclear factor-kB ligand (RANKL), MIP-1 alpha, Dickkopf-1 (DKK-1), osteopontin, hepatocyte growth factor (HGF), secreted Frizzled-related protein-1 (sFRP-1), and syndecan-1. Patients with MM who started therapy were re-assessed after 4 and 12 months of treatment. They were grouped based on therapeutic outcome into: those achieving very good partial response (VGPR) or complete response (CR) (n = 27), partial response (PR) (n = 23), and non-responders (n = 21). Changes in cytokine levels over time were compared within these cohorts. Results No statistically significant differences were found between MGUS and SMM in any analyzed parameter, although there was a trend toward increased osteoresorptive factors in SMM. Similarly, most parameters did not differ significantly between SMM and MM, except for CTX-1 (median 0.329 vs. 0.672 ng/ml, p = 0.02), RANK (median 0.4 vs. 0.65 ng/ml, p = 0.044), RANKL (median 30,472 vs. 7,354 pg/ml, p = 0.01), and syndecan-1 (median 33.1 vs. 77.7 ng/ml, p = 0.028). More significant differences were observed between MGUS and MM: P1NP (median 39.15 vs. 51.4 µg/l, p = 0.045), CTX-1 (median 0.323 vs. 0.672 ng/ml, p = 0.0004), MIP-1 alpha (median 22.1 vs. 26.1 pg/ml, p = 0.039), HGF (median 1,702 vs. 2,837 pg/ml, p < 0.001), DKK-1 (median 2,381 vs. 3,419 pg/ml, p = 0.002), syndecan-1 (median 21.2 vs. 77.7 ng/ml, p < 0.001), and NF-kB (median 0.078 vs. 0.6 ng/ml, p = 0.007). In MM patients undergoing therapy, there was a trend toward decreased osteoresorptive cytokines, more pronounced in patients achieving CR, VGPR, and PR compared to non-responders. Significant changes over time were found in syndecan-1 (p = 0.003), HGF (p = 0.03), Activin A (p = 0.02), and NF-kB (p = 0.001). Conclusions Our data suggest that MBD evolution is a continuous process, more pronounced in active myeloma but with potential origins and slow progression even in premalignant conditions, leading to an imbalance between osteoresorption and osteoprotection. Therapy administration prevents further bone destruction and decreases osteoresorptive cytokines in correlation with the depth of therapeutic response. With support of MH CZ – DRO (FNOl, 00098892) and IGA_LF_2025_005.