Abstract
Abstract Objective: Severe immune dysregulation is a strong risk factor for multiple myeloma (MM), and experimental studies have implicated chemokines and pro-angiogenic cytokines in MM pathogenesis. We investigated whether circulating immune markers were prospectively associated with MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS), in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Methods: We characterized levels of 43 immune markers in banked sera from 243 MM cases, 506 subjects with MGUS (including those with light-chain disease) who did not progress to MM, and 258 MGUS-free controls using Luminex-based multiplex assay panels. Odds ratios (ORs) and 95% confidence intervals (CIs) for MM and MGUS were estimated using multivariate-adjusted polytomous logistic regression models. Results: Relative to MGUS-free controls, we observed statistically significant associations with MM risk for six markers using a false discovery rate of 10%, including several chemokines (MCP-2/CCL8, fourth quartile vs first: OR 2.1; 95% CI 1.2-3.7; Ptrend=0.017 and SDF-1/CXCL12, 2.6; 1.5-4.4; Ptrend=2.9x10-4), angiogenesis markers (ANG-2, 3.0; 1.7-5.3; Ptrend=1.3x10-4 and HGF, 3.0; 1.7-5.1; Ptrend=2.8x10-5), and growth factors (EGF, 3.2; 1.9-5.5; Ptrend=1.9x10-6 and BMP-9, 2.3; 1.4-4.0; Ptrend=3.3x10-4). Associations with these markers remained after restricting to MM cases diagnosed ≥8 years after blood collection although risk estimates were somewhat attenuated (Ptrend≤0.07). MCP-2/CCL8, SDF-1/CXCL12, and HGF were also significantly elevated among those with MGUS compared with MGUS-free controls (Ptrend≤0.04). Four markers were associated with progression from MGUS to MM after adjusting for clinical characteristics such as M-protein concentration, serum free light-chain ratio, and immunoglobulin type (ANG-2, fourth quartile vs first: OR 2.5, 95% CI 1.4-4.6; HGF, 2.6, 1.4-5.0; EGF, 3.3, 1.8-6.0; and BMP-9, 1.9, 1.0-3.4); dose-response trends were statistically significant for all four markers (Ptrend≤0.03). Conclusions: This is, to our knowledge, the first prospective study to investigate circulating immunologic markers in relation to MM risk and progression from MGUS to MM. Our findings provide insights into potential biological mechanisms associated with MM development and may have clinical utility for improving risk stratification models assessing the likelihood of progression from MGUS to clinically manifest MM. Citation Format: Jonathan N. Hofmann, Ola Landgren, Hormuzd Katki, Troy Kemp, Loredana Santo, Charlene McShane, Qing Lan, Nathaniel Rothman, Ligia Pinto, Ruth Pfeiffer, Allan Hildesheim, Mark Purdue. Circulating immunologic markers and risk of multiple myeloma and its precursor disease: A nested case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4943.
