Study Identifies Independent Predictors of Smoldering Multiple Myeloma Progression

A series of molecular abnormalities in smoldering multiple myeloma that are independent predictors of progression to multiple myeloma were accurately identified in a genomic test of bone marrow tissue, according to a study led by researchers at the Dana-Farber Cancer Institute and published in the Journal of Clinical Oncology.^1,2 Patients identified with these alterations can be closely monitored or put on a clinical trial intended to halt this progression when they are found to be at an increased risk.

“We found that the genomic alterations with smoldering multiple myeloma are essentially the same as full-fledged myeloma,” Romanos Sklavenitis-Pistofidis, MD, the study co-lead stated in a press release. “This suggests that by the time smoldering multiple myeloma is diagnosed, most of the molecular abnormalities found in myeloma have already occurred.”

A group of patients were followed for a median of 6.8 years to determine which patients developed myeloma, then investigators cross-linked the molecular and clinical data to evaluate the genetic abnormalities that increased the risk of progression. Patients with alterations in certain gene were predictive of progression, which included alterations in the MAPK pathway, such as KRAS and NRAS; mutations or deletions in the DNA repair pathway like deletion 17p, TP53, and ATM single nucleotide variants; and MYC gene amplifications or translocations.

In order to validate these findings, investigators evaluated an outside group of 72 patients with smoldering multiple myeloma who had their tumor DNA previously sequenced. This analysis confirmed that the presence of any of the 3 types of high-risk genomic alterations led to a higher risk of progression.

“This was a big collaborative effort between Dana-Farber and the Broad Institute to understand the genomic landscape of smoldering multiple myeloma and how this could help in a better management of patients and development of appropriate interventions,” said Gad Getz, PhD, co-senior author of the study and director of Cancer Genome Computational Analysis Group at the Broad Institute of MIT and Harvard and the Bioinformatics Department at the Massachusetts General Hospital Cancer Center, in a statement.

This was the largest genomic analysis of smoldering multiple myeloma tissue to date and included 214 patients with bone marrow samples at the time of diagnosis of smoldering multiple myeloma. The analysis included patients from multiple centers in the United States and Europe.

Investigators performed whole-exome sequencing on 166 tumors, which included 5 tumors with serial samples. Forty-eight tumors had deep targeted sequencing done.

Patients with smoldering multiple myeloma have blood or urine that contains a certain level of the M protein but do not have symptoms of multiple myeloma. Not all patients with smoldering multiple myeloma advance to multiple myeloma, so patients will not receive treatment until symptoms of myeloma appear, such as bone lesions or fractures, low blood counts, kidney problems, and increased calcium levels.

“As a group, patients with smoldering myeloma have a 10% annual risk of developing myeloma, but it’s difficult to determine which are at the greatest risk, so our goal was to understand the heterogeneity within smoldering multiple myeloma and explore which genetic alterations could predict the high-risk group,” said study lead author Mark Bustoros, MD, of Dana-Farber and the Broad Institute of MIT and Harvard.

The identification of these molecular abnormalities is important for use as biomarkers of future progression and can improve upon currently used methods for tracking disease progression. By determining which patients with smoldering multiple myeloma are more likely to progress to multiple myeloma, physicians can closely monitor the disease or recommend patients to clinical trials in which therapies could halt the progression of disease to multiple myeloma.

In conclusion, the study authors noted that their biological model could be combined with traditional clinical models to obtain the best indication of the risk of progression in patients with smoldering multiple myeloma. Taking appropriate action in patients at a higher risk of progressing to multiple myeloma could slow or stop the progression of disease.

_References

_{1. Genomic test accurately identifies patients with smoldering multiple myeloma at high risk of developing myeloma, study finds. News release. Dana-Farber Cancer Institute. June 9, 2020. Accessed June 9, 2020. https://bit.ly/3dOOjqK}

_{2. Bustoros M, Sklavenitis-Pistofidis R, Park J, et al. Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression. J Clin Oncol. Published online May 22, 2020. doi:10.1200/JCO.20.00437}