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.”

Background

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 ^[1] 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 ^[2] 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 ^[3] 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.

Study Design

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.

Results

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.”

For more information, please refer to the study in the journal Blood ^[4] (abstract) and a related review article ^[5] (full text).