Circulating Tumor DNA: Less Invasive, More Representative Method to Unveil the Genomic Landscape of Newly Diagnosed Multiple Myeloma Than Bone Marrow Aspirates

Abstract

Multiple myeloma (MM) is highly heterogenous and dynamic in its genomic abnormalities. Capturing a representative image of these alterations is essential in understanding the molecular pathogenesis and progression of the disease but was limited by single-site invasive bone marrow (BM) biopsy-based genomics studies. We compared the mutational landscapes of circulating tumor DNA (ctDNA) and BM in 82 patients with newly diagnosed MM. A 413-gene panel was used in the sequencing. Our results showed that more than 70% of MM patients showed one or more genes with somatic mutations and at least half of the mutated genes were shared between ctDNA and BM samples. Compared to the BM samples, ctDNA exhibited more types of driver mutations in the shared driver genes, higher numbers of uniquely mutated genes and subclonal clusters, more translocation-associated mutations, and higher frequencies of mutated genes enriched in the transcriptional regulation pathway. Multivariate Cox analysis showed that age, ctDNA mutations in the transcriptional regulation pathway and DNA repair pathway were independent predictors of progression-free survival (PFS). Our results demonstrated sequencing of ctDNA provides more thorough information on the genomic instability and is a potential representative biomarker for risk stratification and in newly diagnosed MM than bone marrow.

Liquid biopsy by analysis of circulating myeloma cells and cell-free nucleic acids: a novel noninvasive approach of disease evaluation in multiple myeloma

“…There have been few studies that directly compare the disease burden mirrored by CMMCs and cfDNA. Patients with higher molecular tumor burden index levels in ctDNA had higher percentages of CPCs [73]. A comparison of the frequency of MM clones by IGK or IGL rearrangement in cfDNA by NGS and CMMC levels by MFC revealed 80% concordance, and the cell-based approach achieved greater patient coverage than the NGS assay [36].…”

“…However, the ctDNA level only showed a conditional correlation with myeloma cell infiltration in the BM. Although some studies found that patients with a high ctDNA level had more BM infiltrations [47,48,57,73], no quantificational correlation was found between the VAF of tumor-related mutations in cfDNA and BM MM cell infiltration [10], which could be explained by BM heterogeneity and the presence of EM lesions. According to a previous report, patients with short progression-free survival (PFS) and high tumor burden by cfDNA were observed to have inconsistently low BM infiltration.…”

“…Overall, an average of approximately 83%-93% of clonal mutations discovered in BM clonal PCs were confirmed in cfDNA, and approximately 88%-91% of clonal mutations discovered in cfDNA were confirmed in BM clonal PCs [46,49]. Most recurrently mutated genes in MM and pan-cancer mutations were shared by matched cfDNA and BM samples [3,10,46,49,57,73,75,76,79,80]. Furthermore, identical subclonal hierarchies were observed in paired BM and plasma samples from patients with MM with ≥ 3 mutations or several mutations in the same gene [3].…”

“…The cfDNA levels were observed to be significant predictors of clinical scores or markers of high disease burden, including advanced ISS stage [9,57,73] and R-ISS stage [46,73], elevated levels of LDH [3,9,47,73] and β2-MG in serum [9], more EM disease in positron emission tomography-computed tomography (PET-CT) [47,74], or osteolytic lesions [48,74]. Most patients showed a positive correlation between the frequencies and VAF of mutations [57,73,75,76], the TF based on CNAs [3,49,74,76], and the frequencies of MM clones (Ig rearrangements) [36] in paired myeloma cells in the BM and cfDNA. However, the ctDNA level only showed a conditional correlation with myeloma cell infiltration in the BM.…”

“…Furthermore, to predict prognosis independent of the R-ISS stage, age, and high-risk cytogenetics and improve the risk-stratifying ability of the R-ISS stage or cytogenetics, Abe et al developed a PET-CMMC staging system that combined CMMC and imaging characteristics from PET-CT (presence of more than three focal lesions with or without EM disease) [32]. Based on the genetic profile of ctDNA in MM, a three-factor nomogram (age ≥ 65 years, DNA repair pathway mutation, and/or transcriptional regulation pathway mutation in ctDNA) was constructed to predict the PFS of patients with NDMM [73].…”