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ASH 2025 | WGS of cfDNA for assessment of MRD in high-risk smoldering multiple myeloma
Chrissy Baker, MSc, PhD(c), University of Miami Miller School of Medicine, Miami, FL, discusses the potential of plasma-based cell-free DNA (cfDNA) analysis to assess measurable residual disease (MRD) in high-risk smoldering multiple myeloma (SMM). She explains how whole genome sequencing (WGS) of blood samples can capture disease heterogeneity, predict clinical outcomes, identify genomic drivers, and track disease progression, offering a less invasive alternative to bone marrow biopsies. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
So an important endpoint in multiple myeloma is minimal residual disease or MRD negativity. And typically this is assessed using a single-site bone marrow biopsy. However, this is really invasive and it often fails to capture the spatial heterogeneity of the disease. So to address that, we investigated whether we could use plasma samples or blood samples to assess disease status...
So an important endpoint in multiple myeloma is minimal residual disease or MRD negativity. And typically this is assessed using a single-site bone marrow biopsy. However, this is really invasive and it often fails to capture the spatial heterogeneity of the disease. So to address that, we investigated whether we could use plasma samples or blood samples to assess disease status. Specifically, we used whole-genome sequencing of cell-free DNA found in the plasma sample. And we really just asked, what can we find from this? And we found some really exciting results.
So in our high-risk smoldering multiple myeloma cohort, we found that patients that had a higher tumor fraction also had worse clinical outcomes, such as not being able to sustain MRD negativity and also having worse progression-free survival. Additionally, we found that patients that had a high tumor fraction were also more likely to have known genomic drivers of multiple myeloma. And so this was really exciting because this is telling us that from a blood sample, we could inform on both clinical outcomes and disease biology. After that, we queried whether we could use that plasma sample to also assess MRD status. So to investigate that, we took both bone marrow biopsies and plasma samples at the same time, and we analyzed both for MRD status. And what we found was that out of the bone marrow biopsies that were MRD positive, we were able to recapitulate those results in all but one of the plasma samples. We found higher discordance in the bone marrow samples that were MRD negative and we’re wondering whether that could be that the plasma samples might be more sensitive or they’re detecting disease that is actually there. And so to investigate that further we used orthogonal validation methods and from that we found that the plasma samples were likely detecting real disease but we want to build on this method to make sure that we’re as accurate as we can be in this MRD assessment. Lastly, we tracked tumor fraction over time, and we found that as the disease progressed, tumor fraction increased. So all of this together is telling us that from just a blood sample, we’re able to inform on clinical outcomes, disease biology, MRD status, and progression of disease just using cell-free DNA.
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