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Biomarkers of progression to multiple myeloma
statistical significance (P=0.334 and P=0.169, respectively).35 Future studies, including in vitro experi- ments, could help to understand the role of these markers in MM development.
One drawback of this study was the small number of participants with repeated pre-diagnostic samples avail- able, limiting the study’s power, particularly for subgroup analyses. Nevertheless, longitudinal studies might be sta- tistically more powerful than their counterparts based on single biological samples.36 Another drawback is the lack of bone marrow samples both at the time of pre-diagnos- tic sample collection and at the time of myeloma diagnosis (collected and stored for later research purpose). Such samples were not available in this cohort recruited from the general population but would have been of particular interest for investigating the trajectories of the markers in the bone marrow microenvironment. Inclusion of matched MGUS cases not progressing to MM would also have improved the study design. Limitations in study design and size might have affected the validity of the applied Cox model and may have contributed to the observation that known risk factors of progression did not reach formal significance within this analysis. Nevertheless, the study design has unique features, with its origin in repeated samples obtained prospectively from the general population.
The median survival of patients in the present cohort seemed to be longer than that of other series,37,38 which might be explained by the small and slightly younger study population, as well as a higher proportion of SMM among our cases (33.8%) than that reported by the Swedish Myeloma Registry (14.4%).39 All cases were diag-
nosed before 2013 and the classification into SMM or MM was therefore based on IMWG criteria from 2003,19 as the more recent IMWG criteria from 201440 were not applica- ble. Interestingly, the number of individuals displaying high-risk SMM (as defined by a M-protein level ≥30 g/L and plasma-cell infiltration of ≥10%) at diagnosis (n=6, 9.2%) was higher than expected from other data (4.2%).39 Thus, the median time of progression to MM among SMM patients (n=15) was 2.4 years, which is shorter than that reported by other investigators.41,42
In conclusion, we observed changes in immune markers among future myeloma patients which might be indica- tive of progression to MM. We found that low plasma lev- els of TGF-a, measured a median of 3.9 years before the diagnosis of myeloma, were associated with a 3-fold increase in risk of progression to MM. This seemed to be independent from known risk factors of progression in a multivariable model and might therefore add useful infor- mation for early prediction of MM. The results of this study warrant further investigation, ideally in a large prospective cohort following both MGUS and SMM patients to evaluate the role of TGF-a as a predictor of progression to MM.
Acknowledgments
All authors would like to thank to Betty Jongerius-Gortemaker for performing excellent laboratory work (Institute for Risk Assessment Sciences, Utrecht University). The authors also thank the participants of the study, VIP and Västerbotten County Council for providing data and samples, and staff of NSHDS (Department of Biobank Research, Umeå University) for their fundamental contributions to this study.
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