Whole-genome sequencing of cell-free DNA for assessment of minimal residual disease in high-risk smoldering multiple myeloma.

In multiple myeloma (MM), minimal residual disease (MRD) is an established endpoint for accelerated drug approval but is limited by a need for serial invasive bone marrow (BM) biopsies, which may under-sample spatial heterogeneity and result in false negativity. Furthermore, longitudinal (i.e., sustained) MRD negativity is emerging as a powerful tool for clinical decision-making. To these ends, reliable systemic MRD assessment is a growing need. Next-generation sequencing approaches for plasma cell-free (cf) DNA generally fail to achieve adequate detection limits in low tumor fraction (TF) settings (i.e., MRD), but tumor-informed approaches leveraging whole-genome sequencing (WGS) have thus far achieved the lowest limits of detection (LODs). We therefore performed a longitudinal analysis of MRD assessed by serial WGS of plasma cfDNA as compared to clinical standard flow-cytometric BM MRD in high-risk smoldering MM. 25 baseline tumor WGS served to inform detection of disease in 87 sequential plasma samples. The median LOD across patients was 1.2 × 10