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Genomic Characteristics of Smoldering Multiple Myeloma and Risk of Progression


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In a study reported in the Journal of Clinical Oncology, Mark Bustoros, MD, and colleagues identified genomic features of smoldering multiple myeloma associated with a higher risk of progression to multiple myeloma and found that alterations that drive disease progression are already present at the time of smoldering multiple myeloma diagnosis.

Mark Bustoros, MD

Mark Bustoros, MD

As stated by the investigators, “Smoldering multiple myeloma is a precursor condition of multiple myeloma with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to multiple myeloma could improve current risk models.”

Study Details

Researchers performed next-generation sequencing on samples from 214 patients with smoldering multiple myeloma, with whole-exome sequencing performed on 166 tumors (including 5 with serial samples) and deep targeted sequencing performed on 48 tumors. Findings in this initial cohort were evaluated in an external cohort of 72 patients with smoldering multiple myeloma and previously sequenced tumor DNA.

Key Findings

Most of the genetic alterations associated with progression to multiple myeloma were already present by the time of diagnosis of smoldering multiple myeloma.

In analysis including clinical risk staging, independent risk factors for more rapid progression to multiple myeloma were:

  • Alterations of the MAPK pathway (KRAS and NRAS single-nucleotide variants; median time to progression for with vs without = 14.4 vs 60 months, P < .001)
  • The DNA repair pathway (deletion 17p, TP53, and ATM single-nucleotide variants; 15.5 vs 50.4 months, P = .004)
  • MYC translocations or copy number variations (8.4 vs 51.6 months, P < .001).

Patients with one or more vs none of these alterations had a significantly shorter median time to progression (1.2 vs 7.2 years, P < .001). Patients with none, one, or two or more of these alterations had significantly different median times to progression. Addition of these factors to the Mayo 2008 or 2018 clinical risk stratification model improved prediction of progression (C-statistic = 0.66 vs 0.75 and 0.72 vs 0.77; both P < .001). 

In the validation cohort, presence of any of the high-risk alterations was detected in 47 of 72 patients and was associated with a significantly shorter median time to progression (2.5 vs 10 years, P = .001). Patients with none, one, or two or more high-risk factors had different risks of progression. Addition of these factors to Mayo 2008 or 2018 clinical risk stratification improved prediction of progression (C-statistic = 0.57 vs 0.66 and 0.61 vs 0.67, P < .001 and P = .001).

“We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to multiple myeloma and, thus, improve on the precision of current clinical models.”
— Mark Bustoros, MD, and colleagues

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In addition, it was found that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like­–associated mutations were enriched in patients who progressed to multiple myeloma and were associated with shorter time to progression in the initial cohort.  

The investigators concluded: “Smoldering multiple myeloma is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to multiple myeloma. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to multiple myeloma and, thus, improve on the precision of current clinical models.”

Irene M. Ghobrial, MD, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Institutes of Health, Multiple Myeloma Research Foundation-Perelman Prevention Program, Leukemia and Lymphoma Society Specialized Center of Research, Stand Up To Cancer Dream Team, Adelson Medical Research Foundation, and, Cancer Research UK Early Detection Program. For full disclosures of the study authors, visit ascopubs.org.

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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