Results from a recent retrospective study suggest that smoldering myeloma patients with a high percentage of plasma cells in the blood are more likely to progress to active myeloma within two years of diagnosis, as compared to patients with a lower percentage of plasma cells.

Patients with more than 5 billion plasma cells per liter of blood or more than 5 percent of their blood cells in the blood being plasma cells were defined as having a ‘high percentage’ of plasma cells in the blood.

“[Our results suggest that] if patients with smoldering myeloma have high levels of circulating plasma cells, they would need closer follow-up,” said Dr. Vincent Rajkumar from the Mayo Clinic and lead investigator of the study.

However, he cautioned that additional data would be needed before making a definitive recommendation.

“We are trying to establish the cutoffs to be used when circulating plasma cells are detected,” added Dr. Rajkumar.

Smoldering multiple myeloma, also called inactive or asymptomatic myeloma, is an early stage of myeloma in which the person does not yet show any symptoms such as bone or kidney damage.

According to the researchers, results from recent studies have suggested that the risk of progression from smoldering to symptomatic myeloma is 10 percent per year for the first five years. This risk reduces to 3 percent per year for the next five years, and to 1 percent per year thereafter.

The following factors have been shown to increase the risk of progression from smoldering to symptomatic myeloma: (i) 10 percent or higher of plasma cells in the bone marrow, (ii) a monoclonal protein (M-spike) level of 3 g/dL or higher, (iii) 95 percent or higher of abnormal plasma cells as assessed by a technique called immunophenotyping, and (iv) an abnormal immunoglobulin free light chain (FLC) ratio.

A recent study has also shown that smoldering myeloma patients with at least 60 percent plasma cells in the bone marrow are 5.6 times more likely than others to progress to active myeloma (see related Beacon news).

The current standard of care for smoldering myeloma is a ‘watch and wait’ approach, whereby treatment with chemotherapeutic drugs is started only after the patient progresses to active myeloma. This approach is thought to reduce side effects by limiting the period of exposure to drugs, without lowering overall survival.

However, a recent study showed that treatment with a combination of Revlimid (lenalidomide) and dexamethasone (Decadron) can delay disease progression in high-risk smoldering myeloma patients (see related Beacon news). This finding indicates that high-risk patients may benefit from early treatment.

Recent work has focused on the identification of parameters that can reliably detect high-risk patients.

In the current study, researchers sought to determine if a high frequency of plasma cells in the blood is associated with an increased risk of progression to symptomatic myeloma.

In particular, they sought to determine a threshold level of plasma cells in the blood, above which smoldering myeloma patients would have about a 90 percent chance of early progression to active myeloma.

The researchers retrospectively analyzed data from 91 patients who were diagnosed with smoldering myeloma at the Mayo Clinic between 1994 and 2007. Blood cells from these patients had been examined microscopically for the frequency of plasma cells.

Using a special slide-based assay that is very sensitive in detecting plasma cells, patients with more than 5 million plasma cells per liter of blood or more than 5 percent of their immunoglobulin positive cells in the blood being plasma cells were defined as having a ‘high percentage’ of plasma cells in the blood.

The investigators noted that 15 percent of patients had high levels of circulating plasma cells.

Median follow-up time was 9.3 years for patients who had high levels of plasma cells in the blood, and 6.4 years for others.

Results from the study showed that 71 percent of patients with a high percentage of plasma cells in the blood progressed within two years, as compared to 25 percent of smoldering myeloma patients with fewer plasma cells.

When the researchers raised the threshold value to 6 million plasma cells per liter of blood or 6 percent plasma cells, they found that 77 percent of patients above the cutoff progressed within two years.

Further, with a threshold of 10 million plasma cells per liter of blood or 25 percent plasma cells, 86 percent of patients above the cutoff progressed within two years.

Based on these results, the researchers conclude that a high frequency of plasma cells in the blood can be used to identify smoldering myeloma patients at a remarkably high risk of progression within two to three years of diagnosis.

In addition, the researchers found that patients with high levels of plasma cells in the blood had lower levels of plasma cells in the bone marrow (13.5 percent) than patients with low circulating plasma cells (20 percent). Based on this result, the researchers conclude that high levels of plasma cells in the blood cannot be predicted based on the level of plasma cells in the bone marrow.

“Our finding suggests that one cannot predict the level of circulating plasma cells based on extent of marrow involvement,” said Dr. Rajkumar. “But as the level of marrow involvement exceeds a certain threshold, I think there will be a greater probability of circulating plasma cells.”

Median time to disease progression was 1 year for patients with high levels of plasma cells in the blood, as compared to 4.8 years for others. Time to progression remained significantly different after adjusting for age differences in the high and low plasma cell groups.

Previous studies have shown that M-spike levels exceeding 3 g/dL are a risk factor for progression to symptomatic disease.

In this study, the researchers found that time to progression was significantly shorter in patients with M-spike levels exceeding 3 g/dL (2.5 years), as compared to others (4.8 years).

They then tested if the two risk factors, high levels of plasma cells in the blood and M-spike levels exceeding 3 g/dL, could be used to predict time to disease progression. While time to progression for patients with neither risk factor was 5.4 years, it was 2.5 years those with one risk factor, and 1 year for those with both risk factors.

In addition, patients with high levels of plasma cells in the blood showed significantly shorter overall survival times (4.1 years from smoldering myeloma diagnosis), as compared to those with low levels (12.3 years). Overall survival after progression to active myeloma was 2.6 years for patients with high levels of plasma cells in the blood, as compared to 5.5 years for others.

For more information, please refer to the study in Leukemia (abstract).