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Genome Sequencing Identifies Myeloma Precursor Disease With High Progression Risk

NEW YORK – A team from the US, Belgium, the UK, and Italy has narrowed in on genomic features that distinguish myeloma precursor conditions — monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma SMM — that do or do not progress to multiple myeloma. 

"Overall, our temporal estimates suggest that stable myeloma precursor condition represents a different biological entity; one that is acquired at a later age in life, without myeloma-defining genomic events, and with a much lower tendency to progress compared to progressive myeloma precursor condition," co-senior and co-corresponding author Francesco Maura, an assistant professor at the University of Miami Millers School of Medicine's Sylvester Comprehensive Cancer Center, and his colleagues wrote in a study published in Nature Communications on Friday.

Using flow cytometry-based bone marrow plasma cell sorting, a low-input whole-genome sequencing strategy, and bioinformatics analysis, the researchers characterized bone marrow plasma cell infiltrates in more than two dozen samples from individuals with MGUS, SMM, or multiple myeloma.

"We successfully applied this technology in cancer for patients with a myeloma precursor where the disease burden is extremely low," Maura said in a statement, noting that the "quality was incredibly good, allowing us to be the first to characterize the whole-genome sequencing landscape in MGUS."

In total, they interrogated genome sequence data for 80 multiple myeloma, 18 MGUS, and 14 SMM cases, including a single SMM case classified as high risk based on an available prognostic model.

From there, the team compared genome features in 17 precursor cases that progressed to multiple myeloma within two years and 15 stable precursor cases, uncovering a set of "myeloma-defining genomic events" that included chromothripsis, aneuploidy, driver gene mutations, APOBEC mutational profiles, and templated insertions.

"Given the ability of WGS to characterize [single-nucleotide variants], [structural variants], [copy number variants], and mutational signatures, we have shown that clinically stable cases of MGUS and SMM are characterized by a different genomic landscape and by differences in the temporal acquisition of myeloma-defining genomic events in comparison to progressive entities," the authors wrote.

In contrast, the investigators reported, the more clinically stable set of precursor gammopathies were missing such alterations. They also tended to turn up in individuals diagnosed with MGUS or SMM somewhat later in life (between around 28 and 65 years old), compared to precursor conditions in those with progressive disease, who were diagnosed between the ages of five and 46 years.

"Despite its limited sample size, this study provides proof of principle that WGS has the potential to accurately differentiate stable and progressive precursor conditions in low disease burden clinical states," the authors suggested, arguing that the "application of this technology in the clinic has the potential to significantly alter the management of individual patients, but will require confirmation in larger studies."

In a statement, co-senior author Ola Landgren, University of Miami myeloma service chief and co-principal investigator at the center's Myeloma Genomic Laboratory, noted that the team plans to launch a prospective follow-up study to validate and expand on the genomic findings documented in the current analysis.

"The plan is to offer individuals diagnosed with MGUS or smoldering myeloma to come to us here in Miami for a bone marrow biopsy which will include our new WGS test," Landgren explained. "This study also creates new opportunities to develop early treatment studies, which we are about to start."