IMS 2025 | Ultra-deep, cost-efficient whole-genome sequencing of cell-free DNA in NDMM

So in our lab we’ve been exploring using whole genome sequencing of bone marrow cells and cell-free DNA to try better understand what myeloma looks like. Previously we’ve discussed here about getting mutation lists from bone marrow cells and then using them to track minimal residual disease over time in cell-free DNA. But for a long time we were limited by costs because whole genome sequencing with 3 billion base pairs in the genome, it’s a lot of coverage that we need, a lot of reads that we have to actually sequence. Now Ultima Genomics, which is a new company out of San Francisco, has come up with a new machine which is about 3 to 4 times less expensive than the standard Illumina machines which we were using before. So what we experimented is taking the standard Illumina 30 to 40x whole genome sequencing, which we’ve done, and the Ultima Genomics 150x, because now it’s about the same price as the 30 to 40x Illumina, and comparing them head to head. So what we found was that on average, we find about 20% more of the bone marrow mutations in the peripheral blood cell-free DNA when we go up to 150x whole genome sequencing with the Ultima compared to the standard 30 to 40x with Illumina. Now, that’s really exciting because we can basically recapitulate the bone marrow tumor genome in the cell-free DNA. We’re finding on average 88% of the bone marrow-specific SNV mutations in the peripheral blood cell-free DNA, which we hope can help reduce reliance on repeated bone marrow sampling to get a mutation catalogue. Now the biggest gain that we were able to find when we used the deeper sequencing was in patients with predominantly lower tumor fraction. So in our cohort, about half of the patients have 5% or less circulating tumor DNA content in their peripheral blood. So out of all the DNA fragments that are circulating, about 1 in 20 of them or less come from the tumor. Now in those patients, we found double the actionable mutations like the NRAS, KRAS, TP53, and the biggest gains when we went up to 150x sequencing, which is as expected because when we have so few DNA fragments in the blood, when we sample a lot more of them through deeper sequencing, that’s where we see really the biggest gains in mutation recovery. So we’re really excited about this because now we can offer whole genome cell-free DNA sequencing to nearly all of our patients, because even the low tumor fraction patients, we can find the majority of the bone marrow mutations. And we’re hoping to further use this technology to generate baseline mutation lists for MRD tracking in the future.

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