Type: Oral
Session: 652. MGUS, Amyloidosis, and Other Non-Myeloma Plasma Cell Dyscrasias: Clinical and Epidemiological: Genes, Cells and Algorithms: Novel Methods of Predicting Progression in MGUS and SMM
Hematology Disease Topics & Pathways:
Research, Translational Research, Clinical Research, Plasma Cell Disorders, Diseases, Lymphoid Malignancies
Cell turnover results in the release of cell-free DNA (cfDNA) fragments to blood. The tissue origins of such fragments can be determined using cell type-specific methylation patterns.
We hypothesized that plasma cell (PC)-specific DNA methylation markers and cancer-specific methylation alterations in cfDNA can serve as a minimally-invasive biomarker for diagnosis and surveillance of MGUS, SMM and MM, and may prospectively predict progression dynamics to MM.
Methods: We isolated PC from bone marrow samples of MM patients and healthy individuals, and determined their methylome using deep whole-genome bisulfite sequencing yielded genomic loci that are specifically demethylated in PCs (7 loci), or show disordered patterns of methylation in MM (10 loci). We developed a multiplex PCR-sequencing assay to determine the methylation status of these loci in cfDNA, and analyzed plasma samples from patients with MGUS (n=58), SMM (n=29) and MM (n=37). Results were also correlated with a prospective assessment for biochemical and clinical progression to MM.
Results: cfDNA methylation markers differentiated PC disease states. MM patients had increased PC-cfDNA levels and cancer-specific methylation alterations compared with SMM (AUC=0.81, P=0.0001) MGUS (AUC=0.9, P=0.0001) and healthy controls (AUC=0.94, P=0.0001). PC-cfDNA levels correlated (Pearson-R=0.68-0.86, p=0.0001) with BMPC %, and aberrant PC%. Furthermore, at a median follow up of 16.5 (5-32) months, the assay could significantly predict the progression of premalignant PCD. Patients with MGUS and SMM that had higher levels of PC-cfDNA methylation and cancer-specific methylation alterations had an overall faster biochemical and clinical progression. Utilizing these biomarkers alone had a negative predictive value of 80% for biochemical and 100% for clinical progression within 2 years. The positive predictive value increased upon the replacement of BMPC-20% counts with PC-cfDNA or cancer-specific methylation alterations combined with the 2gr/dL and FLC-Ratio>20 risk stratification model [HR 16-26.5 (CI 3.24-214.6) p<0.0001]. Finally, these results were cross validated with a machine learning approach, indicating that locally disordered methylation patterns in specific loci are the most significant among all laboratory and clinical markers for progression.
Conclusion: cfDNA methylation patterns are a promising biomarker for diagnosis and surveillance of plasma cell disorders, and for identifying patients at risk of progressing to MM. With further development, methylation-based liquid biopsies may offer a non-invasive, practical and essential tool to evaluate individual patient's risk for progression, on their initial MGUS or SMM diagnosis day.
Disclosures: Gatt: Hadassah Medical Center Jerusalem: Current Employment.