Predicting Progression of Smoldering Multiple Myeloma

ROCHESTER, Minn,, June 21 -- For smoldering multiple myeloma, the risk of progression to active disease may be predicted by a pair of factors at diagnosis, according to researchers here.

These factors are the level of serum monoclonal protein or the proportion of bone marrow plasma cells, or both, reported Robert A Kyle, M.D., of the Mayo Clinic, and colleagues, in the June 21 issue of the New England Journal of Medicine. They did a record review of 276 patients over 26 years.

Smoldering multiple myeloma, which accounts for about 8% of the malignancy, resembles monoclonal gammopathy of undetermined significance (MGUS), but MGUS is far less likely to progress to active disease or amyloidosis at 20 years, the investigators noted. Smoldering multiple myeloma has a 78% probability of progression, versus 21% for MGUS.

"Our study shows that the overall risk of progression in smoldering multiple myeloma is greatly influenced by the time elapsed since diagnosis, in contrast to the risk of progression in MGUS, which remains constant over time," they wrote

"We found that the overall risk of progression among patients with smoldering multiple myeloma was approximately 10% per year in the first five years and 3% per year in the next five years with a decrease to 1% per year thereafter. No such time-dependent change in risk occurs with MGUS."

Risk factors for the progression and outcome of smoldering multiple myeloma had been unclear, partly because criteria for diagnosing the disorder were defined only in 2003 by the International Myeloma Working Group.

The group defined smoldering multiple myeloma as an symptomatic disorder in which the patient has a serum monoclonal protein level of 3 g/dL or more or a proportion of plasma cells in the bone marrow of 10% or more but no end-organ damage.

The diagnosis of active multiple myeloma requires the presence of a monoclonal protein in serum or urine, plasma cells in the bone marrow, or plasmacytoma and end-organ damage related to plasma-cell proliferation. End-organ damage was defined as hypercalcemia, renal insufficiency, anemia, bone lesions, or recurrent bacterial infections.

The current findings emerged from a database search and review of the medical records of all Mayo patients from 1970 to 1995 who fulfilled the international criteria. Bone marrow aspirate and biopsy specimens were studied and patients were followed throughout the course of disease.

During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. The median age at diagnosis was 64, and 62% were men.

During 2,131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%)

The overall risk of progression was 10% per year for the first five years, approximately 3% per year for the next five years, and 1% per year for the last 10 years.

The cumulative probability of progression was 73% at 15 years, the researchers reported. The median time to progression was 4.8 years.

At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins.

The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model.

The cumulative probability of progression at 15 years was 87% for the 106 patients with ? 10% plasma cells and ?3 g/dL of monoclonal protein.

It was 70% for 142 patients with ? 10% plasma cells but less than 3 g/dL of monoclonal protein.

It was 39% for 27 patients with < 10% plasma cells and ?3 g/dL of monoclonal protein.

On the basis of this study, the researchers suggested that the standard of care for these patients should include close follow-up every few months.

Physicians should repeat the pertinent laboratory tests two to three months after the initial recognition of the disease to rule out an early active form. If the results are stable, the studies should initially be repeated every four to six months, they said.

Given the high risk of progression among some of these patients, along with the availability of new active agents for the treatment of active multiple myeloma, some patients should be offered participation in clinical trials, the authors suggested.

Ongoing trials are testing bisphosphonates, interleukin-1? inhibitors, clarithromycin, dehydroepiandrosterone, and thalidomide in the treatment of smoldering multiple myeloma in an attempt to delay progression to active disease.