Circulating Cell-Free DNA Could Be Marker of Progression in Multiple Myeloma

A new study suggests a potential new marker that could be used to track response to therapy and disease progression in patients with multiple myeloma.

Circulating cell-free DNA (cfDNA) levels appear to be a viable tool for risk stratification and progression detection in patients with multiple myeloma (MM), according to a new study.

The findings were published in the European Journal of Hematology.

Corresponding author Brian A. Walker, PhD, of the University of Indiana School of Medicine, and colleagues wrote that 70 gene expression profile (GEP70) can be a meaningful outcome-prediction tool in patients with MM, but they said that cfDNA has gained attention as a potential biomarker for tumor burden in cancers such as myeloma.

“Although cfDNA is an admixture of normal and tumor-derived DNA [ctDNA], increased concentration of cfDNA is indicative of higher tumor burden and is a prognostic biomarker of survival in many cancers,” they wrote.

Specifically, they said that heightened ctDNA levels indicate disease progression, and genomic variations in cfDNA can be used to monitor response to therapy.

The investigators sought to find out whether cfDNA levels might correlate with GEP70 levels in MM. They identified 77 patients with MM, and stratified them into high- and low-risk groups based upon their GEP70 scores. Using a cutoff of higher than 0.65, they identified 39 patients as high risk and 38 patients as low risk. They then correlated those risk scores with a number of markers, including lactate dehydrogenase (LDH), β2-microglobulin, and International Staging System (ISS) score.

The authors found that patients with high levels of cfDNA tended to have worse progression-free survival (PFS) and overall survival (OS), with hazard ratios of 6.4 and 4.4, respectively. The high-risk group also had higher levels of ctDNA, which showed a strong correlation to GEP70 risk scores.

Serial peripheral blood samples were available from 8 patients during and after chemotherapy. Those samples showed an increase in cfDNA levels 3 to 5 days following chemotherapy. That spike made sense, the authors wrote, given that the main mechanism for cfDNA release from tumor cells is cell death. However, the authors also hypothesized that there would be a similar increase in ctDNA, but that outcome only occurred in 2 of the 8 patients.

“The lack of increased ctDNA in the 6 patients could be due to dilution of ctDNA as a result of cell death of normal cells or individual variation in cfDNA clearance kinetics,” they suggested.

Patients’ ctDNA levels in all 8 cases were reduced by 8 to 13 days following chemotherapy.

Meanwhile, a subset of 15 patients showed increased ctDNA levels 5 days after chemotherapy; those patients were found to be at higher risk of early disease relapse.

The study also included 25 patients with smoldering MM (SMM), a precursor to MM. Samples from those patients indicated increased allele fraction of mutated KRAS at progression in cfDNA. Walker and colleagues said allele fraction of mutations in ctDNA might be a meaningful metric to track disease progression.

The authors acknowledged the limitation that they had few patients with SMM who progressed to MM, and they were only able to sequence a small number of their patients with MM.

Still, they said their data provide compelling evidence that cfDNA is a valuable data point that could be used for further larger studies.


Deshpande S, Tytarenko RG, Wang Y, et al. Monitoring treatment response and disease progression in myeloma with circulating cell-free DNA. Eur J Haematol. Published online October 26, 2020. doi:10.1111/ejh.13541