Methylated Circulating Tumour DNA in Myeloma

Abstract

Myeloma is an incurable malignancy of plasma cells in the bone marrow. Improvements in myeloma treatment have highlighted the need for more sensitive non-invasive measures of residual disease. Circulating tumour DNA in the plasma fulfils this need, but the use of mutation-based monitoring is limited by the vast genetic heterogeneity of myeloma, by the known clonal evolution of myeloma and the cost. To avoid these limitations, a novel approach using methylation differences to distinguish circulating myeloma DNA from healthy cell-free DNA was designed.

A final biomarker panel consisting of two differentially methylated genes (PPFIA1 and SLC9A3) was identified. This panel was measurable in more patients (84.4%) compared to conventional protein biomarkers (55%) or a targeted sequencing panel of the commonest genetic mutations (63-68%). Additional advantages of this novel circulating tumour DNA biomarker panel include a “real-time” representation of disease burden and being able to track clonal evolution. Based on a small number of cases, these methylation biomarkers reflect response to treatment, predict relapse earlier and potentially guide therapeutic choices. Follow up studies to validate these results are required.