The use of liquid biopsies for MRD detection in Multiple Myeloma

Multiple myeloma (MM) is a hematological malignancy affecting 700-1000 Belgian patients every year. Despite new therapies the disease remains incurable with a significant morbidity and mortality. New therapies result in deeper responses that are not detectable with conventional methods. However (persistent) absence of measurable residual disease (MRD) has recently been shown to be associated with improved survival. Detection of MRD is based on bone marrow (BM) sampling which is an invasive and often painful procedure with risks of false negative results due to risk of hemodilution and/or patchy distribution of the myeloma cells. Sample collection by venepuncture is much less invasive and overcomes some drawbacks inherent to BM sampling. With this project we aim to determine whether immunoglobulin (lg)-targeted molecular tumor detection and MRD analysis in MM is feasable by using liquid biopsies, with particular focus on circulating tumor cells (CTC), cell-free DNA and exosomal DNA. In first instance we demonstrated that lg-targeted next generation sequencing (NGS) is superior to ASO-PCR for tumor detection in MM (accepted manuscript). Meanwhile we developed and validated a dual platform method, combining CTC enrichment with lg-targeted NGS for MM. Currently we are completing a study comparing the tumor detection sensivity of lg-NGS between CTC derived DNA, cell-free DNA, exosomal DNA and "standard" BM-MM cell derived DNA, using samples of patients with active disease (second manuscript to prepare). Throughout this project we could extend our biobank up to 600 study samples from 130 different patients. Our series include 30 patients in (conventional) remission with different follow-up samples (3-month interval) to allow for MRD detection on multiple time points and to verify at which level one of the circulating biomarkers, mentioned earlier, could serve as a valuable prognostic marker. This last study (third manuscript to prepare) has been initiated this year and will be completed within the time frame of the grant requested in this application. Finally our laboratory also started to explore the use of liquid biopsies for mutation profiling in MM, using the same circulating biomarkers and patient samples as tested for MRD. This last part, however, will not be included in the final scope of the PhD thesis.