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Role of Whole-Genome Sequencing in Identifying Patients With MGUS at Risk of Progression to Multiple Myeloma


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A study published by Oben et al in Nature Communications has shown that whole-genome sequencing can help determine which patients with a multiple myeloma precursor condition known as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma may be at risk for progression to cancer.

“Most patients with MGUS will never [have disease progression], but some will,” said co–corresponding author C. Ola Landgren, MD, PhD, Professor of Medicine, Chief of the Myeloma Service, and principal investigator of the Myeloma Genomic Laboratory at the University of Miami’s Sylvester Comprehensive Cancer Center. “In this study, for the first time, we were able to use a novel low-input whole-genome sequencing technology—partnered with our most advanced bioinformatics pipelines—to identify the progressors and the nonprogressors. Using modern genomic assays and analytical algorithms, we are able to split the older terminology of MGUS—monoclonal gammopathies of undetermined significance—and define progressors vs nonprogressors.”

C. Ola Landgren, MD, PhD

C. Ola Landgren, MD, PhD

Myeloma Precursor Conditions

Unlike most cancers, multiple myeloma has asymptomatic precursor conditions, which may or may not indicate a patient will develop the cancer. Clinicians use a variety of tests to detect an abnormal protein associated with the disease. Patients with high protein levels are at higher risk of developing multiple myeloma and are diagnosed with smoldering myeloma; those with lower levels have MGUS.

The key phrase in that description is “undetermined significance.” Many of the diagnostic technologies for multiple myeloma are from the 1980s and fail to delineate which patients with MGUS are at greatest risk. This can be a major issue, as people must undergo tests to track progression, such as bone marrow biopsies and imaging. Also, recurrent blood monitoring can have adverse impact on quality of life, often driven by uncertainty and anxiety.

Dr. Landgren and Francesco Maura, MD, Assistant Professor and co–principal investigator of the Myeloma Genomic Laboratory at Sylvester, together with their colleagues, felt whole-genome sequencing could provide more specific answers to help clarify each patient’s risk and potentially lead to better treatments.

Francesco Maura, MD

Francesco Maura, MD

Study Methods and Findings

In the study, the team used whole-genome sequencing to assess 18 patients with MGUS, as well as 14 with smoldering myeloma and 80 with multiple myeloma, following these cohorts for more than a year. The researchers looked at a variety of genetic variations, including insertions, deletions, driver gene mutations, and others. They found that patients with lighter mutational loads were less likely to develop multiple myeloma.

In addition to identifying a genomic signature that could delineate progressors from nonprogressors, the team also developed crucial methods to produce robust results with only a few cells, building on a technique developed at the Sanger Institute.

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

Prior to this study, scientists believed disease progression was linear from MGUS to smoldering myeloma to multiple myeloma. Now, it’s unclear whether smoldering myeloma is a distinct condition at all—or simply an earlier stage of multiple myeloma.

“The bigger picture is that there are several genomic defining events involved in the progression of multiple myeloma,” said Dr. Maura. “So far, whole-genome sequencing is the only technology that captures all these changes.”

Dr. Landgren noted that further study is needed to both validate and clarify these findings. The researchers are not entirely certain that patients classified as nonprogressors will definitely never have disease progression.

However, with further validation, this approach could have a tremendous impact on the field. Nonprogressors would no longer need to worry about their risk of developing multiple myeloma or wait anxiously for test results. In addition, better clarity on who will develop the disease could drive more efficient clinical trials.

“We are about to launch a large prospective study to take advantage of whole-genome sequencing and validate these findings,” said Dr. Landgren. “In 2021, we are planning on opening a new large study at the Myeloma Service in Sylvester Comprehensive Cancer Center. 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 whole-genome sequencing test. This study also creates new opportunities to develop early treatment studies, which we are about to start. If we could prevent multiple myeloma from happening, that would be a huge contribution.”

Disclosure: For full disclosures of the study authors, visit nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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