Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples

Biomarkers reliably predicting progression to multiple myeloma are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein 3, macrophage inflammatory protein 1 alpha, vascular endothelial growth factor, fibroblast growth factor 2, fractalkine, and transforming growth factor alpha. In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. Samples from myeloma cases were donated in median 13 and 4 years before myeloma diagnosis. Known risk factors of progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of monocyte chemotactic protein 3, vascular endothelial growth factor, fibroblast growth factor 2, fractalkine, and transforming growth factor alpha in myeloma patients than controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were marked for transforming growth factor alpha (P = 2.5 x 10 -4 ) indicating progression to multiple myeloma. Investigating this, we found that low levels of transforming growth factor alpha assessed at time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P = 0.003). Transforming growth factor alpha can potentially improve early detection of multiple myeloma.