Prediagnostic Serum Immune Marker Levels and Multiple Myeloma: A Prospective Longitudinal Study Using Samples from the Janus Serum Bank in Norway

Abstract

Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Only a minority of patients with MGUS will develop multiple myeloma, but precise prediction of progression is impossible using routine clinical biomarkers. Changes in the levels of blood immune markers can help predict disease progression. Data remain inconsistent for some markers of interest such as monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), fractalkine, and transforming growth factor-alpha (TGF-α). We aimed to investigate the associations between the prediagnostic serum levels of these candidate biomarkers and future multiple myeloma risk, as well as to assess marker changes over time. We performed a nested case-control study using prospective samples from the Janus Serum Bank in Norway to investigate associations between multiple myeloma risk and prediagnostic serum levels of MCP-3, MIP-1α, FGF-2, VEGF, fractalkine, and TGF-α. The study included 293 future multiple myeloma cases with serum samples collected 20 years (median) before multiple myeloma diagnosis and 293 matched cancer-free controls. Patients with multiple myeloma had an additional prediagnostic sample collected up to 42 years before diagnosis to identify marker changes over time. Markers with >60% detection rate (MIP-1α, VEGF, and TGF-α) were included in the statistical analysis. We observed no statistically significant associations between multiple myeloma risk and serum levels of MIP-1α, VEGF, or TGF-α in samples collected 20 years before diagnosis. However, TGF-α levels decreased significantly closer to the diagnosis in patients with multiple myeloma (P < 0.001). The decrease in TGF-α levels may reflect subtle microenvironmental changes related to multiple myeloma progression.

Prevention relevance: This study observed a decline in TGF-α serum levels closer to multiple myeloma diagnosis, which may aid in predicting multiple myeloma progression and early detection, although validation in other longitudinal cohorts is needed.

Figure 1.

Immune marker concentrations in controls and cases. Panels display concentrations of (A) MIP-1α, (B) TGF-α, and (C) VEGF. Controls are shown in blue, whereas cases, including first and additional samples, are shown in orange. Statistical comparisons were performed using the Wilcoxon signed-rank test.

Figure 2.

Immune marker levels over time in 293 patients with future myeloma and 293 matched cancer-free controls. Panels display levels of (A) MIP-1α, (B) TGF-α, and (C) VEGF. Patients with future myeloma, each with a first and an additional sample, are shown in orange, whereas matched cancer-free controls, each with a single sample per participant, are shown in blue. Lines represent linear regression across all data points.