Adding precision to multiple myeloma treatments with DNA sequencing: ASH

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DNA sequencing of blood samples could provide valuable information about how multiple myeloma is progressing, reported researchers from Dana-Farber.

Multiple myeloma was in the spotlight at the annual American Society of Hematology (ASH) meeting in Atlanta, as positive clinical trial data generated excitement about the potential for both targeted and immunotherapy approaches to treating the disease. During the conference, oncologists at the Dana-Farber Cancer Institute tossed another idea for managing the complex blood cancer into the mix: DNA sequencing that may make it possible to use simple blood tests to track how multiple myeloma is progressing in individual patients—and whether they're becoming resistant to the therapies they’re given.

The Dana-Farber scientists presented results from two studies in which they analyzed cell-free DNA (cfDNA)—or circulating genetic information from cancer cells—in blood samples taken from multiple myeloma patients. They believe their findings could be used to develop a new form of “liquid biopsy” that would enhance the ability of oncologists to tailor therapies to individual patients.

Multiple myeloma is complicated to treat, because it mutates over time, causing patients to relapse and become resistant to treatments that used to work well for them. Tracking those changes in patients usually requires frequent, painful bone marrow biopsies. So the Dana-Farber team set out to prove that the same information could be gathered with simple blood tests.

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In one study, a Dana-Farber team sequenced blood samples from 75 multiple myeloma patients to look for cfDNA. In 10 of those patients, they also collected normal blood cells and bone marrow myeloma cells. They discovered that the mutations they found in the blood samples closely matched those in the bone marrow cells. They concluded that frequently tracking patients with simple blood tests could be a valuable way to stay on top of drug resistance.

"When we follow the patient in real time, we clearly see in the blood how the genetics actually changes when the patient relapses,” said Dana-Farber oncologist and hematologist Jens Lohr, M.D., Ph.D., in a statement. “That means that we get very good information about the changes that happen every time drug resistance develops, which is something that is simply not practical with bone marrow biopsies."

Liquid biopsies may also prove useful in monitoring patients with diseases that can progress to multiple myeloma, Dana-Farber oncologists discovered. In a separate study presented at ASH, they sequenced 186 bone marrow biopsies from patients with smoldering multiple myeloma (SMM), a precursor to multiple myeloma that rarely produces symptoms. Some of the patients did develop multiple myeloma, while others did not.

In patients who eventually developed multiple myeloma, they found an uptick in mutations in genes that are known to drive the cancer, including MAPK and MYC, according to a press release.

To determine whether liquid biopsies might be possible in patients with precursors to multiple myeloma, they also sequenced 20 cfDNA samples from patients with SMM. They found higher levels of tumor DNA in the blood of high-risk SMM patients than they did in those who were less likely to progress to multiple myeloma. They believe their findings point to the potential utility of developing liquid biopsy regimens for tracking patients with SMM and another precursor disorder called monoclonal gammopathy of undetermined significance.

The promise of liquid biopsies has already caught the attention of biotech startups and investors alike. Illumina spinout Grail has raised $1 billion from Jeff Bezos, Bill Gates and others to develop and commercialize liquid biopsies, and in the spring, it merged with Cirina in Hong Kong to gain a foothold in the Asian market. Google subsidiary Verily has also ventured into the liquid biopsy field, launching a startup called Freenome to develop tests for lung cancer, breast cancer and other solid tumors.

The Dana-Farber oncologists are planning more studies to further elucidate the potential role for liquid biopsies in enhancing the treatment of multiple myeloma. Mark Bustoros, M.D., a postdoctoral fellow at Dana-Farber who led the sequencing study on multiple myeloma precursors, has gone on to collect dozens more patient samples from cancer centers around the world. His idea is to sequence DNA from patients who are at different stages of myeloma progression.

"After finishing the study, we will integrate genomic and clinical data and try to construct a model that can be applied in the clinic,” Bustoros said, “to identify patients who are at high risk of progression, and potentially to offer them earlier treatment."

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