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Patients with monoclonal gammopathy of undetermined significance had a risk for progressing to multiple myeloma or another plasma-cell or lymphoid disorder, according to a 24-year study published in The New England Journal of Medicine.
Patients with monoclonal gammopathy of undetermined significance (MGUS) also had a shorter life expectancy than a matched control population.
MGUS is a condition in which an abnormal protein, known as a monoclonal protein, is produced in white blood cells in bone marrow. It occurs in about 3% of adults aged 50 years or older, often without symptoms, and the cause is unknown.
“MGUS is asymptomatic and is usually discovered when a physician is doing a number of blood tests on a patient,” Robert A. Kyle, MD, professor of laboratory medicine and pathology at Mayo Clinic in Rochester, Minnesota, told HemOnc Today. “We found that approximately 1% of patients with MGUS will progress to multiple myeloma, amyloid light-chain amyloidosis, lymphoma or Waldenström macroglobulinemia each year. These are serious malignant conditions that require therapy.”
Researchers analyzed 1,384 patients (54% men; median age, 72 years) diagnosed with MGUS between 1960 and 1994.
Median follow-up was 34.1 years (range 0 to 43.6).
Progression to multiple myeloma or another plasma-cell or lymphoid disorder served as the primary endpoint.
During 14,130 person-years of follow-up, MGUS progressed in 147 patients (11%), a rate 6.5 times (95% CI, 5.5-7.7) as high as the rate in the control population. Patients progressed to multiple myeloma (RR = 23.8; 95% CI, 19.3-29.1), non-Hodgkin lymphoma (RR = 1.6; 95% CI, 1-2.6), amyloid light-chain amyloidosis (RR = 8.8; 95% CI, 4.8-14.7), Waldenström macroglobulinemia (RR = 47.5; 95% CI, 25.3-81.3), chronic lymphocytic leukemia (RR = 0.6; 95% CI, 0.1-1.8) and plasmacytoma (RR = 12.6; 95% CI, 0.3-70.2).
Risk for progression, excluding death due to competing causes, was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years and 36% at 40 years.
Among patients with immunoglobin M (IgM) MGUS (15%), the presence of two adverse risk factors — an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein level ( 1.5 g per deciliter) — appeared associated with a 55% risk for progression at 20 years compared with 41% among patients who had one adverse risk factor, and 19% among patients who had neither risk factor.
Among patients with non-IgM MGUS (82%), the risk for progression at 20 years was 30% among those with both risk factors, 20% among those with one risk factor and 7% among those with neither risk factor.
“We showed that 1% of patients with MGUS continue to progress to one of these serious disorders at the same 1% per year rate for almost 35 years,” Kyle said. “Consequently, patients with MGUS must be followed with readily available laboratory tests at intervals of 1 to 5 years depending upon the patient’s risk factors.”
Those risk factors include the type of MGUS — IgM MGUS progresses more often than non-IgM MGUS — whereas non-IgM MGUS patients have either immunoglobin G or an immunoglobin A MGUS, according to Kyle.
“We showed that only 10% of patients with MGUS will develop multiple myeloma or related serious disease,” he said. “Ninety percent of patients with MGUS will die of heart disease, cerebrovascular disease (stroke) or a cancer unrelated to multiple myeloma such as cancer of the prostate, breasts, colon or lung.”
Patients with MGUS also had shorter median survival than the control population matched for age and sex (8.1 years vs. 12.4 years; P < .001). Five patients who progressed remained alive at the time of the analysis.
“That raises the possibility there may be other disorders associated with monoclonal gammopathy of undetermined significance that still need further study,” S. Vincent Rajkumar, MD, a hematologist and myeloma researcher at Mayo Clinic in Rochester, Minnesota, said in a press release.
“What we do know is that the incidence of MGUS increases with age, reaching a frequency of 7% to 8% among persons in their 80s,” Kyle said. “MGUS also is slightly more common among men than women. The reason for this is unknown and requires further study.” – Chuck Gormley
For more information:
Robert A. Kyle, MD, can be reached at Division of Hematology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905; email: kyle.robert@mayo.edu.
Disclosures: The NCI funded the study. Kyle reports personal fees from Amgen, Bristol-Myers Squibb, Celgene, Pharmacyclics and Pfizer outside the submitted work. Rajkumar reports grant support from the NCI during the conduct of the study. Please see the study for all other authors’ relevant financial disclosures.
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