Summary
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Original Article
Molecular Abnormalities & Biomarkers of Progression in Smoldering Multiple Myeloma
Oncology Times
By Amy Gallagher
A study conducted by researchers with the Dana-Farber Cancer Institute, performed a genomic test of bone marrow tissue identifying specific biomarkers in patients with smoldering multiple myeloma (SMM) who may be at a high risk of developing the symptomatic form of the disease with end organ damage. The results from the multicenter cohort encompassing global organizations from the United States and Europe showed that individuals with an increased risk of MM could be better identified through these biomarkers and benefit from close monitoring or from clinical trials of therapies intended to halt the progression toward myeloma.
Co-lead and first author, Mark Bustoros, MD, of Dana-Farber Cancer Institute and The Eli and Edythe L. Broad Institute of MIT and Harvard, said researchers identified a series of molecular abnormalities associated with a greater risk of smoldering myeloma progression.
“These abnormalities are important biomarkers for the risk stratification of SMM and a significant improvement to the currently used methods.” he explained. “The traditional risk models are not as accurate and do not reflect the molecular abnormalities behind the disease.”
According to the National Organization for Rare Disorders, myeloma is a cancer of a type of white blood cells known as plasma cells which occur in bone marrow. SMM is diagnosed when blood or urine is found to contain a certain level of the M protein, which is a fragment of an antibody produced in excessive amounts by myeloma cells.
Next-Generation Sequencing
“We used next-generation sequencing to study 214 patients with SMM,” said Bustoros. “We performed whole exome sequencing on 166 tumors, including five with serial samples, and deep targeted sequencing on 48 tumors.”
Bustoros, with co-lead and first author Romanos Sklavenitis Pistofidis, MD, from Dana-Farber, compiled the data of 214 SMM patients into three categories: 1) whole exome sequencing from 72 patients with matched normal and tumor tissues; 2) an additional 94 patients with tumor-only sequencing; and 3) 48 patient samples with deep-targeted sequencing.
The new study involved a genomic analysis of the largest number of SMM tissue to date. Investigators collected bone marrow samples from 214 patients at the time of diagnosis with SMM and sequenced the DNA within the tumor cells. The group of the patients were monitored for a median of 6.2 years to identify the development of overt (symptomatic) myeloma, then cross-linked the molecular and clinical data to explore whether certain genomic abnormalities increased the risk of progression toward myeloma.
“Discovery of these abnormalities as independent risk factors, biomarkers of disease progression, would improve on the traditional risk models,” Bustoros explained. “We validated these findings in an external SMM cohort where patients who harbored any of the three biomarkers had a higher risk of progressing to MM.”
Researchers identified SMM was more likely to advance, and advance sooner, in patients whose tissue samples had:
- alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]);
- the DNA repair pathway (deletion 17p, TP53, and ATM SNVs); and
- and MYC (translocations or copy number variations).
SMM: The Silent Symptoms
The goal of the study was to understand the heterogeneity within SMM to explore the genetic alterations that could better predict the high-risk group, said Bustoros.
“As a group, patients with smoldering myeloma have a 10 percent annual risk of developing myeloma, but it’s difficult to determine which are at the greatest risk,” he explained.
Patients with SMM do not always experience symptoms, nor do patients with SMM develop outright [overt] myeloma. SMM may seem to be a puzzling disease to many scientists due to its asymptomatic nature. Nonetheless, it is important to know that the same malignant cells are present during SMM, which is the asymptomatic stage to MM, said Bustoros.
The primary symptoms of MM include anemia, bone fractures, increased blood calcium, and kidney damage, he added.
Predicting SMM’s Unpredictable Nature
“The standard biomarkers for risk of progression are based on tumor burden, which is based on the number or percentage of abnormal cells within a bone marrow sample, M protein or free light chain levels,” Bustoros explained. “But the traditional risk models are not as accurate as we would like and do not reflect the biology of the disease.”
The recent study involved a genomic analysis of SMM tissue from 214 patients, the largest number of SMM tissue studied to date. Investigators collected bone marrow samples from the 214 patients at the time of diagnosis with SMM and sequenced the DNA within the tumor cells.
“The current risk model and methodology of novel risk stratification algorithms are applied to monitor and manage the SMM patients,” said Bustoros. “Understanding of the biological processes generating these mutations helped us meet our goal.”
The National Center for Biotechnology Information (NCBI) explained that Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) proteins are regulated through genetic alterations, changes in their transcription and mRNA processing, and through their interactions with other macromolecules in the cell.
NCBI stated that APOBEC mutagenesis correlates with metastatic mutational heterogeneity. Additionally, the NCBI reported that multiple signatures of somatic mutations have been identified in cancer genomes, notably a signature attributed to the APOBEC.
“Mutational signatures, such as APOBEC, are biological processes that cause patterns of mutations in the DNA of the tumor cells,” said Bustoros. “Certain signatures are associated with age. Aging signature is present in many cancers, especially in those occurring in older patient groups. APOBEC mutational signature had worse prognosis in breast cancer and other malignancies.”
In our study, we observed that APOBEC signature was enriched in patients who progressed and was associated with a shorter time to progression, he said.
Amy Gallagher is a contributing writer.