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Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2456-2464
Plasma Cell Disorders
Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated pre-diagnostic blood samples
Florentin Späth,1 Carl Wibom,1 Esmeralda J. M. Krop,2 Antonio Izarra Santamaria,1 Ann-Sofie Johansson,1 Ingvar A. Bergdahl,3 Johan Hultdin,4 Roel Vermeulen2* and Beatrice Melin1*
1Department of Radiation Sciences, Oncology, Umeå University, Sweden; 2Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, the Netherlands; 3Department of Biobank Research, Umeå University, Sweden and 4Department of Medical Biosciences, Clinical Chemistry, Umeå University, Sweden
*RV and BM contributed equally to this work.
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 inflamma- tory protein-1 alpha (MIP-1a), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor-alpha (TGF-a). 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 progres- sion. For this purpose, we identified 65 myeloma cases and 65 matched can- cer-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-a in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myelo- ma patients while remaining stable in controls. Decreasing trajectories were noted for TGF-a (P=2.5 x 10-4) indicating progression to MM. Investigating this, we found that low levels of TGF-a assessed at the time of the repeated sample were independently associated with risk of progression in a multi- variable model (hazard ratio = 3.5; P=0.003). TGF-a can potentially improve early detection of MM.
Introduction
Multiple myeloma (MM) is one of the most common but still incurable hemato- logic malignancies.1 MM is preceded by monoclonal gammopathy of undetermined significance (MGUS),2 a premalignant precursor, and smoldering multiple myeloma (SMM), characterized as an asymptomatic disease stage.3 The annual risk of pro- gression to MM is about 1% for MGUS4 and 10% for SMM,5 thus patients with either of these conditions require life-long follow-up.6 The most well established risk factors for progression to MM are the type and size of the monoclonal (M)-pro- tein, the free light chain (FLC) ratio, immunoparesis, and the number of plasma cells in the bone marrow.7,8 Nevertheless, there is a lack of reliable biomarkers pre- dicting which MGUS and SMM patients will progress to MM and which will not.9,10
Plasma proteome profiling has been suggested to be of potential value for risk stratification of MGUS and SMM.11 Low blood levels of six cytokines and growth factors have been associated with myeloma risk: monocyte chemotactic protein-3
Correspondence:
FLORENTIN SPÄTH
florentin.spaeth@umu.se
Received: January 20, 2019. Accepted: April 3, 2019. Pre-published: April 4, 2019.
doi:10.3324/haematol.2019.216895
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/12/2456
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