Comparative Analysis of Bone Marrow, cfDNA and CTCs for NGS-Based Multiple Myeloma Detection: A Pilot Study Indicating the Potential of CTCs

Background/Objectives: Minimal residual disease (MRD) persists in most multiple myeloma (MM) patients, causing relapse despite deep remissions. Repeatability of MRD detection in MM bone marrow (BM) samples is limited, underscoring the need for blood-based monitoring approaches that can allow more thorough disease surveillance. Methods: This study compares tumor detection rates in BM-derived DNA with different blood-derived DNA sources, using next-generation sequencing of the immunoglobulin locus (NGS-IG). CD138-targeted immunomagnetic enrichment of circulating tumor cells (CTCs) followed by vacuum evaporation to concentrate DNA was used to optimize the tumor detection rate. Results: Tumor DNA was detected in 76%, 88% and 100% of cell-free DNA, peripheral blood-derived mononuclear cells, DNA and enriched CTC-DNA samples of patients with active myeloma, respectively. These data indicate that enriched CTC samples were the most informative for evaluation of disease detection with NGS-IG in patients with active myeloma. MRD detection was performed in paired BM and enriched CTC-DNA samples from 37 patients in remission. MRD positivity was found in the BM of 24 patients, with half of them (12/24) also showing the presence of MRD when enriched CTC-DNA was used. Interestingly, time to progression (TTP) of enriched CTC MRD-negative/BM MRD-positive patients was comparable to that of double MRD-negative (BM and CTC) patients. Moreover, double positive patients showed a trend to earlier relapses. Conclusions: Our data suggest that NGS-IG analysis with enriched CTC-DNA may offer improved predictive abilities for relapse in multiple myeloma compared to the currently used BM-DNA-based tumor detection method.