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 × 10-4 (range 9.0 × 10-5 - 2.1 × 10-4). TF was prognostic, and tumors with high-risk genomics had higher baseline TF (P = 0.002) and eventual disease progression (n = 7, P < 0.001). Furthermore, dynamic changes in serially tracked TF portended outcome. In comparison to BM flow, cfDNA WGS was concordant in 33/45 (73.3%) MRD samples with consistent capture of BM-positive cases, but added resolution to apparent false-negative BM samples. Overall, despite the deeper LOD of localized BM flow, cfDNA WGS can detect MRD when BM flow did not, adding dynamic and systemic/spatial resolution to standard hyper-local MRD assessment.