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Multiple Myeloma Study Suggests Circulating DNA Test Complements Bone Marrow Testing

NEW YORK (GenomeWeb) – There is new evidence that circulating tumor DNA can offer a window into mutations present in multiple myeloma (MM) tumors that could potentially offset the need for at least some of the bone marrow testing procedures patients need to endure.

In a study appearing online today in Nature Communications, a Canadian team outlined their method for detecting multiple myeloma (MM) mutations with the help of circulating tumor DNA sequencing. The approach, dubbed Liquid Biopsy Sequencing (LB-Seq), appeared to uncover the majority of MM mutations, suggesting it could serve as an avenue for detecting and characterizing MMs in a manner that is complementary to more invasive bone marrow aspiration-based testing.

The LB-Seq approach "can potentially replace medically unnecessary [bone marrow] sampling and provide an alternative non-invasive test for longitudinal genetic monitoring of MM patients receiving targeted therapy," co-corresponding authors Trevor Pugh and Suzanne Trudel, researchers affiliated with the Princess Margaret Cancer Centre and University of Toronto, and their colleagues wrote.

They explained that such a method is attractive because MM tumor testing typically involves a bone marrow aspiration process that "may be difficult, painful, and associated with significant patient anxiety as well as rare but significant complications including bleeding and infection."

The general LB-Seq strategy uses hybrid capture to grab sequences of interest out of a collection of circulating, cell-free DNA in the blood so that they can be profiled by deep Illumina sequencing. That sequence data is subsequently untangled using a variant filtering algorithm designed to find mutated sequences stemming from the MM tumor — even when these alterations represent a relatively small proportion of the cell-free DNA in the blood.

For their analysis, the researchers focused on protein-coding exon sequences for a handful of cancer-related genes: KRAS, NRAS, BRAF, EGFR, and PIK3CA. Using 64 ctDNA samples obtained from blood for 11 individuals with newly diagnosed MM and 42 individuals with a relapsed form of the disease, for example, they detected apparent actionable mutations in 34 individuals.

When the team compared the mutations detected with LB-Seq by those identified with bone marrow testing, meanwhile, they found that the circulating, cell-free DNA sequencing-based approach successfully picked up all but two somatic mutations present in four-dozen matched bone marrow samples, while pointing to four potential mutations not described from bone marrow-based sequences.

Based on their findings so far, the study's authors concluded that the LB-Seq strategy "can accurately detect 96 percent of mutations identified by genetic profiling of matched [bone marrow]-derived tumor DNA with more than 98 percent specificity, similar sub-clonal hierarchies, and good concordance between serial plasma samples."