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Archive - Dec 11, 2017

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DNA Sequencing in Smoldering Multiple Myeloma Offers Clues to Risk of Progression to Full-Blown Multiple Myeloma

Researchers at the Dana-Farber Cancer Institute (DFCI) in Boston have carried out the largest genomic analysis of patients with smoldering multiple myeloma (SMM), a precursor to full-blown blood cancer that doesn't show outward symptoms. The next-generation sequencing project "will help to explain the biology of the disease and how it unfolds through time from asymptomatic stages to symptomatic ones," said Mark Bustoros, MD, a postdoctoral fellow in the lab of Irene Ghobrial, MD, at DFCI. "This research also will help us to understand which patients with SMM are at a high risk of progression, and eventually how we can target early stages of the disease, so that we don't wait to treat them until the cancer cells are spread everywhere in the body and cause major organ damage," said Dr. Bustoros, who presented results of the study at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta (December 9-12, 2017). The title of his presentation was “Next Generation Sequencing Identifies Smoldering Multiple Myeloma Patients with a High Risk of Disease Progression” (see link below). The scientists, led by Dr. Ghobrial, sequenced 186 bone marrow biopsies from patients with SMM, some of whom progressed to multiple myeloma and some of whom did not. The scientists then matched up the genomic data with standard analyses of risks of progression provided by current non-genetic clinical biomarkers. "We found that mutations were more frequent in the high-risk group of patients with SMM," Dr. Bustoros said. "We also found that certain mutations that are known to be drivers for cancer progression were more enriched in that group." Many of the mutations were among genes in the MAPK and NF-kB molecular pathways, while others were MYC gene aberrations that are known to be altered in multiple myeloma.

Tracking How Multiple Myeloma Evolves by Sequencing Cell-Free DNA (cfDNA) Found in Blood

Although people with multiple myeloma usually respond well to treatment, the blood cancer generally keeps coming back. Following genetic changes in how the disease evolves over time will help tscientists/physicians to understand the disease and, eventually, deliver more effective treatments. Researchers have now successfully demonstrated techniques to track these alterations over time by analyzing cell-free DNA (cfDNA) found in blood, according to Jens Lohr, MD, PhD, a hematologist and oncologist at the Dana-Farber Cancer Institute in Boston. Traditionally, multiple myeloma progress is monitored by painful and invasive bone marrow biopsies, but those biopsies are impractical to perform repeatedly, said Dr. Lohr, who presented study results at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta (December 9-12, 2017). The title of Dr. Lohr’s presentation was “Genomic Discovery and Clonal Tracking in Multiple Myeloma by Cell Free DNA Sequencing” (see link below). "We asked if you could get equivalent genetic information by monitoring cell-free DNA," he said. "The short answer is yes, in principle, all this information actually is in the blood." The scientists began by performing whole genome sequencing of 110 blood samples from 75 randomly selected multiple myeloma patients for cfDNA, and used the resulting data to predict the utility of deeper whole exome sequencing of the cfDNA. They also obtained cfDNA, matched normal blood cells, and bone marrow myeloma cells from ten myeloma patients at the same time point, and demonstrated that cfDNA whole exome sequencing robustly identified genetic mutations and these mutations matched up well with those found in sequencing bone marrow cells. The vast majority of clonal mutations and copy number variations in the bone marrow were also identified in cfDNA.