The mode and risk of disease progression significantly differs for patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and those with non-IgM MGUS, Robert A. Kyle, MD, and his colleagues reported in the New England Journal of Medicine.
The risk for progression among IgM MGUS patients was 1.1 events/100 person-years, compared with 0.8 events among those with non-IgM MGUS – a significant difference. The researchers also found that risk is related to monoclonal (M) protein level and abnormal serum-free, light-chain assay results for both forms of MGUS.
Further, risk of progression varied with duration of follow-up in IgM MGUS, unlike non-IgM MGUS. However, for MGUS in general, “the risk of progression to myeloma or a related disorder is much less than the competing risk of death due to other causes,” Dr. Kyle, of the Mayo Clinic, Rochester, Minn., and his associates wrote.
The findings should help to determine the appropriate type of monitoring for MGUS patients, the researchers concluded.
The researchers reported results of the longest-yet follow-up study of MGUS patients. The team described median 34-year follow-up data on 1,384 patients with MGUS –70% with IgG type, 12% with IgA type, 15% with IgM type, and 3% with a biclonal gammopathy. (The patients formed the basis of an initial 2002 report.) They were diagnosed during 1960-1994, at a mean age of 72 years. Of these patients, 1,300 (94%) have died.
Among the 210 patients with IgM MGUS, the risk of progression was 2%/year in the first 10 years after diagnosis and 1%/year thereafter. Risk of progression did not vary during the follow-up of patients with non-IgM MGUS.
“The initial concentration of the serum M protein and the serum-free, light-chain ratio were the most important univariate risk factors for progression to a plasma cell disorder among patients with IgM or non-IgM MGUS. Combined, these two variables provided prognostic value in both IgM MGUS and non-IgM types of MGUS,” the authors wrote.
They explained that the difference may lie in the origins of MGUS. “IgM MGUS typically arises from a CD20+ lymphoplasmacytic cell that has not undergone switch recombination. … In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone switch recombination.”
During follow-up, 11% of the group (147) developed an MGUS-related disorder, including multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. This represents a 6.5-fold increased risk compared to the age- and sex-matched background population. Patients with IgM MGUS had a higher risk of progression than did those with non-IgM MGUS (relative risk, 10.8 vs. 5.7).
The overall risk of progression to a plasma cell–related disorder 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 IgM MGUS, the presence of high serum M protein (at least 1.5 g/dL) and an abnormal serum-free, light-chain ratio increased the risk of progression to 55% at 20 years, compared with a 41% risk among those patients with one risk factor and 19% among those with neither factor.
Among patients with non-IgM MGUS, the presence of both factors conferred a 30% risk of progression by 20 years. The risk was 20% among those with one factor and 7% among those with neither.
Compared with a control population, patients experienced about a 4-year shorter median survival time (8.1 vs. 12 years). Patients with IgM MGUS had worse 30-year overall survival than those with non-IgM MGUS (4% vs. 7%).
“There were 474 excess deaths in the cohort and 142 persons who had progression to multiple myeloma or a related disorder – findings that indicate that many additional deaths cannot be attributed to disease progression,” the authors noted.
The majority of deceased patients had died from non-plasma cell disorders (87%), including cardiovascular and cerebrovascular events, and nonplasma cell cancers. “In addition to the risk of malignant progression, this finding may be related to potentially serious disorders that led to the initial unexpected diagnosis of MGUS.”
The study was funded in part by the National Cancer Institute.
Dr. Kyle disclosed financial relationships with Celgene, Bristol-Myers Squibb, Amgen, Pharmacyclics, and Pfizer.
SOURCE: Kyle RA et al. N Engl J Med. 2018;378:241-9.