Whole-Genome Sequencing Shows Ability to Identify Progressive Myeloma Precursor

A higher mutational load detected by whole-genome sequencing in patients with multiple myeloma precursor conditions was likely predictive of subsequent disease progression.

In a cohort of patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma, whole-genome sequencing (WGS) identified disease-defining genomic events that successfully identified 2 distinct precursors of multiple myeloma that may be able to stratify individuals as having either progressive or stable disease entities.1

Patients with a lighter mutational load—which was determined by looking at genetic variations such as insertions, deletions, and oncogenic driver mutations—were less likely to progress to multiple myeloma.

“Most patients with MGUS will never progress, but some will,” study author Ola Landgren, MD, professor of medicine, chief of the Myeloma Service, and principal investigators of the Myeloma Genomic Laboratory, said in a press release.2 “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 non-progressors. 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 versus non-progressors.”

The study looked at 18 patients with MGUS, 14 with smoldering myeloma, and 80 with multiple myeloma, following them for over a year. Only 1 of the patients with smoldering myeloma were defined as having high-risk disease by the clinical prognostic model and none of the patients exhibited signs of progression when samples were collected.

After a median follow-up of 24 months from the time of sampling, 53% of patients with precursor conditions (smoldering myeloma, n = 13; MGUS n = 4), had progressed to multiple myeloma and had started therapy. The median time to progression was 14.5 months.

Patients with stable disease had lower clonal bone marrow plasma (BMPC) versus progressive disease (Wilcoxon rank-sum test, P = .0005). The median mutational burden in those with stable disease was 3406 (range, 1130-8244) single-nucleotide variants (SNVs) versus 5518 (range, 2385-7257) in progressive disease (Wilcoxon rank-sum test, P = .034).

Although the authors acknowledged that the small sample size and retrospective nature of the data as a limitation, they proposed 2 biologically and clinically distinct entities of myeloma precursor events. The first is characterized by a number of genomic events significant enough to be predictive of malignant potential; whereas, the second with a lower burden of events carries a higher likelihood of a prolonged, indolent condition.

“We are about to launch a large prospective study to take advantage of WGS and validate these findings,” Landgren said. “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 WGS 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.”


1. Oben B, Froyen G, Maclachlan KH, et al. Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities. Nat Commun. 2021;12(1):1861. doi: 10.1038/s41467-021-22140-0

2. Baxt J. Whole genome sequencing offers new diagnostic insights for multiple myeloma precursor conditions. University of Miami website. March 25, 2021. Accessed April 2, 2021. https://bit.ly/3cJ1Ku0