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

Abstract

Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor-alpha (TGF-α). 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. The first and repeated samples from myeloma cases were donated at a median 13 and 4 years, respectively, before the myeloma was diagnosed. Known risk factors for progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, and TGF-α in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were noted for TGF-α (P=2.5 × 10^-4) indicating progression to MM. Investigating this, we found that low levels of TGF-α assessed at the time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P=0.003). TGF-α can potentially improve early detection of MM.

Figure 1.

Overview of the pre-diagnostic samples for each included case (1-65) with respect to disease status during the study period. The x-axis is scaled around the myeloma diagnosis for a clearer overview. Pre-diagnostic disease status was determined for 61 individuals. MGUS: monoclonal gammopathy of undetermined significance; SMM: smoldering multiple myeloma; MM: multiple myeloma; NA: not available.

Figure 2.

Trajectories of biomarker levels among 65 future myeloma patients and 65 matched cancer-free controls. (A) Mean plasma levels (pg/mL) for cases (orange) and controls (blue), grouped by pre-diagnostic baseline (S1) and repeated (S2) samples. Error bars represent the standard error of mean. (B) Fold change between the case and control for matched case-control pairs. S1 and S2 are connected with a line representing increasing (green) or decreasing (red) fold change over time. Bold lines represent linear regression over all data points. MCP-3: monocyte chemotactic protein-3; MIP: macrophage inflammatory protein; VEGF: vascular endothelial growth factor; FGF-2: fibroblast growth factor-2; TGF-α: transforming growth factor-alpha; IL: interleukin, TNF-α: tumor necrosis factor-alpha.

Figure 3.

Probability of progression to multiple myeloma from the time of the pre-diagnostic repeated blood sampling until latest follow-up. Immune marker levels are dichotomized according to receiver operating characteristic optimized cut-off values between individuals who progressed to multiple myeloma (n=58) and individuals who did not (n=7). (A-D) Patients with low levels of an immune marker are represented in green, those with high levels in blue.

Figure 4.

Probability of progression of monoclonal gammopathy of undetermined significance to multiple myeloma depending on transforming growth factor-alpha level at pre-diagnostic repeated sampling. Patients with low transforming growth factor-alpha (TGF-α) levels are represented in green, those with high levels in blue. Probability of progression of monoclonal gammopathy of undetermined significance (MGUS) according to TGF-α levels in patients with (A) low- (no risk factor) or low-intermediate-risk (one risk factor) MGUS (n=28) or (B) high-intermediate- (two risk factors) or high-risk (three risk factors) MGUS (n=22). Risk factors considered were: M-protein ≥15 g/L, non-IgG MGUS, and abnormal free light chain (FLC) ratio. Risk of progression of MGUS according to TGF-α levels in patients with (C) stable (n=16) or (D) increasing M-protein levels or involved FLC ratios (n=25) between baseline and repeated samples. Increasing M-protein levels and involved FLC ratios were defined by an increase ≥25% with either an absolute rise ≥5 g/L for M-protein levels or ≥100 mg/L for involved light chains.