The International Myeloma Working Group, a group of top myeloma doctors, recently published a report identifying risk factors for disease progression in patients with the multiple myeloma precursor diseases, monoclonal gammopathy of undetermined significance and smoldering myeloma. In addition, the myeloma experts established guidelines for the monitoring and management of these two conditions.  This article, Part 2 in a series, covers the results for smoldering myeloma. Part 1 covers the results for myeloma monoclonal gammopathy of undetermined significance.

The International Myeloma Working Group identified the following risk factors for patients with smoldering, or asymptomatic, myeloma: the amount of monoclonal protein, the number of bone marrow plasma cells, and the free light chain ratio.

A smoldering myeloma diagnosis is made when monoclonal (M) protein levels are 30 g/l or greater and the proportion of plasma cells in the bone marrow is 10 percent or greater, but there is no associated organ damage.

The International Myeloma Working Group (IMWG) emphasizes that smoldering myeloma must be distinguished from monoclonal gammopathy of undetermined significance (MGUS) because there is a higher risk of progression to multiple myeloma or a related disorder for smoldering myeloma patients.

The frequency of progression to multiple myeloma or a related disease is 10 percent per year in patients diagnosed with smoldering myeloma as compared to 1 percent per year in MGUS patients.

In a previous study, researchers found that five years following a smoldering myeloma diagnosis, 51 percent of patients were predicted to progress to active myeloma or a related disease.  This number increased to 73 percent by 15 years post-diagnosis.

Smoldering Myeloma Risk Factors

In smoldering myeloma, the IMWG identified the amount of the M-protein and the number of plasma cells in the bone marrow as the most important risk factors of disease progression.

In smoldering and multiple myeloma, the M-protein is overproduced by plasma cells and cannot effectively fight infections.

Patients with both 10 percent or greater bone marrow plasma cells and 30 g/l or greater of M-protein were found to be at the greatest risk of disease progression.

Patients with 10 percent or greater bone marrow plasma cells and 30 g/l or greater of M-protein had a risk of disease progression of 87 percent at 15 years, while those with 10 percent or greater bone marrow plasma cells and less than 30 g/l of M-protein had a risk of disease progression of 70 percent at 15 years. Patients with less than 10 percent bone marrow plasma cells and 30 g/l or greater of M-protein had the lowest risk of disease progression (39 percent) at 15 years.

The free light chain ratio was identified as an additional independent factor for disease progression. An abnormal free light chain ratio was associated with higher rates of progression. In healthy individuals and the majority of myeloma patients, an immunoglobulin is composed of two light chains bound to two heavy chains. In some patients, the light chains are separated, creating abnormal “free” light chains in their blood stream.

Abnormal MRI scans of the spine have also been demonstrated to be an increased risk factor for progression.

Smoldering Myeloma Monitoring and Management Guidelines

The IMWG recommends patients have blood and urine analyses done both at the time of diagnosis with smoldering myeloma and two to three months thereafter.  At the time of diagnosis, the IMWG also considers a bone marrow biopsy and a bone scan mandatory procedures.

If the results of initial tests are stable, patients should be monitored every four to six months for a year.  At the end of the year, if results are still stable, evaluation can be extended to once every 6 to 12 months.

Conclusion

Dr. C. Ola Landgren, researcher at the National Institutes of Health and investigator in this study, believes there remains a need to find specific tests to determine which patients will progress to multiple myeloma.

He stated, however, that the guidelines published in the IMWG report “serve as a clinical tool to focus routine labs and clinical work-up on the precursor patients, who, based on crude clinical markers, are more likely to progress. There is no doubt this is a step in the right direction!”

He added, “I truly think there will be a change in the myeloma field during the coming years.  Instead of waiting for the precursor disease to get active and to spread to full-blown multiple myeloma before the doctor will start therapy, I think we will see new targeted treatment concepts, based on molecular profiling/imaging and biologic biomarkers. These strategies will better guide the doctor to start earlier therapy, and they will have abilities to monitor chronic disease management/cure.”

In order to determine specific differences between progressors and non-progressors, Dr. Landgren is conducting a series of studies at the National Institutes of Health on patients with MGUS or smoldering myeloma. He is welcoming patients from around the country to contact Mary-Ann Yancey at  if they are interested in participating in the studies.

For more information, please see the IMWG report (abstract).