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.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
This work is licensed under a Creative Commons Attribution 4.0 International License .
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First page of Prediagnostic Serum Immune Marker Levels and Multiple Myeloma: A Prospective Longitudinal Study Using Samples from the Janus Serum Bank in Norway<alt-title alt-title-type="short">Prediagnostic Immune Markers and Multiple Myeloma Risk</alt-title>

Supplementary data

Supplementary Table S1

Supplementary Table S1 shows categorization and handling of serum marker levels.

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Supplementary Figure S1

Supplementary Figure S1 illustrates the timing of the pre-diagnostic blood sampling in relation to myeloma diagnosis among cases.

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Supplementary Figure S2

Supplementary Figure S2 illustrates immune marker trajectories in myeloma cases (based on repeated samples) and matched cancer-free controls (based on a single sample per control). Panels display trajectories of (a) MIP-1α, (b) TGF-α, and (c) VEGF. To minimize the influence of extreme immune marker concentrations, analyses were conducted using winsorized data.

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Supplementary Figure S3

Supplementary Figure S3 illustrates immune marker trajectories in myeloma cases (based on repeated samples) and matched cancer-free controls (based on a single sample per control). Panels display trajectories of (a) MIP-1α, (b) TGF-α, and (c) VEGF. To avoid potential effects of multiple imputation on observed marker trajectories, analyses were conducted using complete data only.

- pdf file