ASCO 2026 | cfDNA WGS versus plasma proteomics for minimally invasive MRD assessment in myeloma

So in multiple myeloma, we tend to have longer, more stable, durable remissions in patients. So minimal residual disease assessment is increasingly important to understand which patients are likely to maintain a stable, durable remission for many years and which patients are likely to have an earlier progression event that need closer monitoring or maybe earlier intervention. The way that we currently monitor MRD is very bone marrow centric, taking bone marrow aspirates for tests like adaptive clonoSEQ or multi-parameter flow cytometry. But those methods are highly invasive, and if patients are in remission for many years, we don’t want them to come in every six months and get another bone marrow aspirate. So we wanted to understand if we could monitor MRD less invasively. 

So previously in December, we talked about using cell-free DNA whole genome sequencing to get a personalized mutation catalog from bone marrow, which we then look for in the peripheral blood over time. We were able to get very high accuracy with the bone marrow-based methods using this technology. But another emerging technology is plasma proteomics, doing very sensitive mass spectrometry, looking for the peptides of a patient’s M protein. That’s using a technology called EasyM, which we use for that. But we wanted to compare these two methods head-to-head to decide if you’re doing minimally invasive MRD detection in myeloma, which one is better, and what are the pros and cons of each method. 

So what we found was that EasyM, looking at the mass spectrometry of the myeloma peptides in the peripheral blood, was very, very sensitive. We had 100% of patients were positive at post-transplant, and about 90% were positive at one-year maintenance. And the reason we think is because the M protein lingers for several weeks, whereas the cell-free DNA positivity was only around 30 to 50%, which is more in the range we’d expect from the bone marrow, because it lingers only for minutes to hours. So we defined clearance thresholds to see if we could then stratify the patients into high and low risk groups using the plasma proteomics, because 100% positivity was not prognostic. So we defined a clearance threshold of around 2% at post-transplant and then dropped to 1% at one-year maintenance. With these thresholds, it increased the concordance between the two peripheral blood methods around 90% and they were both prognostic. 

We then tried to understand how do the groups work together. Patients who were MRD positive by one or both methods like cfDNA or plasma proteomics tended to progress earlier whereas those who were negative by one or more methods tended to remain in durable remission for several years. Also, the burden of the amount of protein that we found or the amount of cell-free DNA were also correlated with each other across both methods. 

So overall, we think that both methods can be useful to identify patients that are likely MRD positive or negative using peripheral blood, which is much less invasive. This can help us do more frequent monitoring of patients, identify patients that may be at risk of early progression that need closer monitoring or early intervention, and then find patients that are at lower risk that can likely be left for quite some time without having to come in for bone marrow aspirates. Now, the limitation of the study is we had a small cohort. We only had 22 patients that received both methods. So this needs to be evaluated in larger centers of broader, more diverse patient cohorts to validate these thresholds and better understand the utility of these methods for stratifying patients in the future. But we hope that this kind of technology can help patients better understand their risk of progression in a less invasive way, identify those who need early intervention earlier, and overall reduce patient anxiety and invasiveness around bone marrow tests.

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