Multiple Myeloma Molecular Subtypes Are Already Present In MGUS And Smoldering Myeloma Patients
Results of a recent observational study show that all known molecular subtypes of multiple myeloma are already present at the early, smoldering myeloma and monoclonal gammopathy of undetermined significance stages of the disease.
According to the investigators, these findings indicate that the various molecular subtypes of myeloma, which have different genetic characteristics, are established early in the course of the disease.
The researchers defined the different molecular subtypes of myeloma they investigated based on a method called gene expression profiling. Using this method, they found that one subtype in particular was associated with increased risk of progression from the early disease stages to multiple myeloma.
When the researchers combined gene expression profiling with laboratory test results to predict the risk of progression, they found that gene expression profiling results indicating an increased risk score, the amount of monoclonal protein in the blood (M-spike), and the amount of free light chains in the blood emerged as significant factors for the risk of progression.
After building a risk model based on these three factors, the researchers estimated that patients with two or three of these factors had a significantly higher risk of progression at two years (67 percent) than patients with one risk factor (22 percent) or no risk factor (3 percent).
When the researchers applied the new risk model to smoldering myeloma patients alone, they found that smoldering myeloma patients without any of the three risk factors had the same low risk of progression to symptomatic myeloma as patients with monoclonal gammopathy of undetermined significance (MGUS).
In addition, the researchers found that the presence of MRI-detected focal lesions – areas of abnormal cells in the bone marrow – was also associated with increased risk of progression in patients with all molecular subtypes.
“This is the first prospective trial in this clinical entity,” the study’s lead investigator, Dr. Madhav Dhodapkar from Yale University, told The Beacon. “It demonstrates that incorporating genomic and modern imaging tools in the management of these patients may provide improved assessment of risk of disease progression.”
The investigators recognize, however, that their study has some limitations. They explain that, due to the relatively short follow-up period, the analysis is biased toward factors predicting early disease progression. They add that further follow-up is needed to better identify predictors of risk in lower-risk patients.
“Current analysis is mostly directed towards patients likely to progress early,” Dr. Dhodapkar acknowledged. “However, with more follow-up, we will likely learn which patients are at risk for more delayed progression.”
The investigators also note that further studies are necessary to understand the usefulness of gene expression profiling in MGUS patients because many MGUS patients may not have enough of the plasma cells required to conduct gene expression profiling.
Nevertheless, the investigators think that the addition of genomic analyses to the routine management of the disease may improve the implementation of risk-adapted approaches to prevent the progression of the disease.
“I think the importance of the genetics of these precursor states is now beginning to emerge from several studies,” said Dr. Dhodapkar. “However, this will be most important when the field tries to move toward preventing this malignancy.”
Recent research indicates that myeloma is a continuum of disease, from MGUS to smoldering myeloma to multiple myeloma, and all cases of multiple myeloma are preceded by the precursor diseases.
MGUS is a plasma cell disorder characterized by an elevated level of monoclonal (M) protein in the blood. Unlike myeloma patients, however, MGUS patients do not have any myeloma-related symptoms, such as elevated calcium levels, kidney damage, anemia, or bone lesions.
Smoldering myeloma is also a plasma cell disorder in which the patient does not display any myeloma-related symptoms. Smoldering myeloma patients have more myeloma cells in their bone marrow and higher levels of M protein in the blood compared to MGUS patients.
Typically, MGUS and smoldering myeloma patients do not receive treatment unless their disease progresses and symptoms appear.
The risk of progression from MGUS to symptomatic myeloma is about 1 percent per year.
The risk of progression from smoldering to symptomatic myeloma is 10 percent per year for the first five years after a smoldering myeloma patient’s diagnosis. This risk reduces to 3 percent per year for the next five years, and to 1 percent per year thereafter.
Myeloma consists of several molecular subtypes that can be classified in several different ways. Previous studies have demonstrated that certain molecular subtypes result in more aggressive symptomatic myeloma.
In the current study, researchers sought to explore the factors affecting the risk of progression from the myeloma precursor diseases MGUS and smoldering myeloma to symptomatic multiple myeloma.
According to the study investigators, understanding these factors “will allow patients with the highest risk to be considered for innovative therapies aimed at preventing clinical [symptomatic] multiple myeloma.”
In particular, the investigators sought to assess the role of gene expression profiling in patients with MGUS and smoldering myeloma. They tested whether molecular subtypes of myeloma defined using gene expression profiling are present in the precursor disease stage, and whether certain subtypes are associated with an increased risk of progression to symptomatic myeloma.
Gene expression profiling is a technique that simultaneously measures the activity of thousands of genes in a patient’s myeloma cells, creating a snapshot, or profile, of everything going on inside the cells.
In addition, the researchers sought to evaluate the role of modern imaging techniques, in particular magnetic resonance imaging (MRI) results, as predictors for progression.
Current guidelines for the diagnosis of myeloma bone disease require X-ray imaging of the spine. Magnetic resonance imaging (MRI) has recently emerged as a useful tool to evaluate focal lesions in the bone marrow (see related Beacon news). These lesions, or areas of abnormal cells, are solely within the patients’ bone marrow. They are not lesions in the outer (hard) area of the bone – lesions which are often called “lytic lesions.”
Recent studies have found that abnormal MRI results are associated with increased risk of progression in patients with MGUS or smoldering myeloma.
The study enrolled 375 patients at 69 different locations across the United States between June 2003 and January 2011.
The analysis was based on data from 331 patients, 46 percent of whom had MGUS and 54 percent of whom had smoldering myeloma.
Approximately half of the patients (43 percent) were over the age of 65.
Patients underwent detailed testing at enrollment, including laboratory testing, gene expression profiling, and imaging.
The investigators conducted successful gene expression profiling in 38 percent of patients.
Imaging involved standard X-ray examination, and, when possible, MRI of the entire spine was used to identify focal lesions. In total, 47 percent of patients underwent MRI testing.
The median follow-up time was 43 months.
The investigators found that all the molecular subtypes of myeloma were already present in the precursor stages of myeloma.
Of the known myeloma molecular subtypes, only the “proliferation” subtype was associated with an increased risk of progression to symptomatic myeloma. The “proliferation” subtype is a type of myeloma in which the cancer cells grow and multiply more quickly than usual.
Overall, 16 percent of patients experienced disease progression that required initiation of anti-myeloma treatment. The most common mode of progression was the development of bone disease, which occurred in half of all cases.
The risk of disease progression at two years was 2 percent among MGUS patients and 23 percent among smoldering myeloma patients, which, according to the investigators, is consistent with current estimates.
When the researchers combined gene expression profiling with laboratory variables to predict the risk of progression, they found that gene expression profiling results indicating an increased risk score, the amount of monoclonal protein in the blood (M-spike), and the amount of free light chains in the blood emerged as significant factors for the risk of progression.
After building a risk model based on these three factors, the researchers found that patients with two of these factors had a significantly higher risk of progression at two years (67 percent) than patients with one risk factor (22 percent) or no risk factor (3 percent).
When the researchers applied the new risk model to smoldering myeloma patients alone, they found that smoldering myeloma patients without any of the three risk factors had the same low risk of progression as patients with MGUS.
The investigators note that gene expression profiling may potentially substitute for measurement of abnormal plasma cells in the bone marrow in the evaluation of risk. Measuring levels of plasma cells can be challenging and invasive.
MRI imaging of the spine revealed focal lesions in 16 percent of patients tested.
The presence of multiple MRI-detected focal lesions was associated with increased risk of progression to symptomatic myeloma. However, only 3 percent of patients had multiple lesions. The investigators state that further studies are necessary to validate this finding.
MRI testing is an expensive process. Dr. Dhodapkar said that MRI may be used “in cases with lack of clarity regarding risk of disease using more standard parameters.”
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