Two recent papers shine a light on monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition that is prevalent in the general population, affecting about 3% of individuals aged 50 years and older and 5.3% of those 70 years or older.
It is associated with a modest but persistent lifetime risk for progression to incurable cancer, including multiple myeloma. One of the papers, published in the New England Journal of Medicine (NEJM), outlines the outcomes that were seen in a long-term population study.
The other paper, published in Blood, outlines current management of individuals who are diagnosed with MGUS, which is often an incidental finding and is primarily identified by physicians who are not hematologists.
Despite its high prevalence in the general population, there is “surprisingly limited evidence to inform best clinical practice both at the time of diagnosis and during follow-up,” say the authors of the Blood paper, Ronald S. Go, MD, and S. Vincent Rajkumar, MD, both from the Mayo Clinic, Rochester, Minnesota.
They point out that the number of Americans aged 65 years and older is projected to double by 2050, so the number of individuals diagnosed with MGUS could climb to well over a million within the next 3 decades.
Outcomes Outlined
Long-term outcomes that can be expected are outlined in NEJM paper, also authored by researchers from the Mayo Clinic, led by Robert A. Kyle, MD, and with Dr Rajkumar as senior author. This paper reports on 1384 individuals with MGUS who were diagnosed at their clinic over a 34-year period (between 1960 and 1994).
This cohort was followed for 14,130 person-years (median follow-up, 34.1 years; range, 0 to 43.6 years), and during this time, 1300 patients (94%) died.
From the total of 1384 individuals who were followed, 147 individuals (11%) eventually progressed to multiple myeloma, lymphoma with an IgM serum M protein, AL amyloidosis, macroglobulinemia, chronic lymphocytic leukemia, or plasmacytoma. Of the patients who had disease progression, 5 are still alive.
The risk of developing these disorders was 6.5 times greater than in the control population.
In addition, overall survival (OS) was shorter among patients with MGUS than among a matched control population ( median OS, 8.1 vs. 12.4 years; P < .001).
The cumulative risk for progression (not accounting for death due to competing risk) was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years.
Significant Difference Between Two Types
Dr Kyle and colleagues note the significant differences in the risk for progression between patients with IgM MGUS (n = 210, 15.6% of the total cohort) and those with non-IgM MGUS (n = 1129, 83.8% of the total cohort).
The risk for progression was 1.1 events per 100 person-years among the smaller subgroup of patients with IgM MGUS and 0.8 events per 100 person-years among those with non-IgM MGUS (P < .001).
Two risk factors—an abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter)—were associated with a 55% risk for progression at 20 years in the IgM MGUS population, as compared with a 41% risk among patients with one risk factor and 19% for those with neither risk factor.
In the larger subgroup of patients with non-IgM MGUS, the risk for progression at 20 years was 30% among those who had the two risk factors, 20% among those with one risk factor, and 7% among those who had neither risk factor.
The overall survival rate at 30 years was 4% for patients with IgM MGUS and 7% for the non-IgM MGUS cohort (P = 0.12).
“Despite MGUS being a prevalent disorder that is associated with a modest but persistent lifetime risk of progression to incurable cancer, there are limited data at present to indicate that screening for MGUS or monitoring improves outcomes in patients,” the authors of the NEJM report conclude
In the Blood paper, Dr Go and Dr Rajkumar agree and say the question of follow-up frequently arises in clinical practice.
Despite a lack of prospective data supporting routine follow-up of these patients, they point to two population-based studies showing better overall survival in patients with multiple myeloma who had been previously diagnosed with MGUS or followed up before they had progressed to multiple myeloma (JAMA Oncol. 2015;1:168-174; Clin Lymphoma Myeloma Leuk. 2015;15:177-186).
Who Should Be Tested for MGUS?
In the Blood paper, Dr Go and Dr Rajkumar outline an approach to performing diagnostic work-ups and managing patients with MGUS, based on their own clinical experience and current data.
They write that they usually test for the presence of monoclonal gammopathy in patients presenting with clinical symptoms and signs suggesting a lymphoplasmacytic malignancy, although they add that most of these symptoms and signs are nonspecific.
As a result, when M-proteins are tested for, an alternative explanation for the clinical presentation is typically found in most cases, and patients with positive test results are labeled as having an “incidental diagnosis of MGUS,” they write.
MGUS is common and lymphoplasmacytic malignancies are rare, so the chance of detecting such a cancer in regular practice is rare, they comment.
“We also look for monoclonal gammopathy if a patient has a nonmalignant disease known to be a cause of, or associated with, monoclonal gammopathy, especially if the treatment requires control or eradication of the plasma cell clone,” write the authors.
Which Patients Should Be Followed?
The authors note that their own recommendations for follow-up largely conform to the guidelines of the International Myeloma Working Group, and they suggest that all patients with MGUS should be reassessed in 6 months.
Those with low-risk MGUS need additional follow-up only if symptoms suggesting lymphoplasmacytic malignancies develop because this group has only a 2% risk for progression over a 20-year period.
All other patients should have an annual follow-up, and the discontinuation of follow-up visits can be considered for those with a life expectancy of less than 5 years and/or who are 80 years old. This recommendation, the authors say, is consistent with screening guidelines for other common yet potentially curable cancers.
Progression and Complications
Dr Go and Dr Rajkumar note that there are three subtypes of MGUS: IgM MGUS, non-IgM MGUS, and light-chain MGUS. Each type has its own distinct rate and type of progression. But increases in M-protein or serum free light chain levels should raise concern, write the authors, although only about 50% of patients experience this before disease progression.
In addition to changes in M-protein level, clinicians should consider progression if other unexplained signs and symptoms develop, including anemia, cardiomyopathy, fractures, hepatomegaly, hypercalcemia, and renal insufficiency, the authors write.
Additional testing, including bone marrow biopsy and imaging studies, should be performed if there is any concern that the disease is progressing.
Other than progression to malignancy, MGUS has been associated with more than 130 different diseases, they point out. Most of these reported associations are likely coincidental, although some have been verified as being related to a MGUS diagnosis. These include monoclonal gammopathy–associated peripheral neuropathy, monoclonal immunoglobulin deposition disease, and monoclonal gammopathy–associated proliferative glomerulonephritis.
Potential Harms of a MGUS Diagnosis
The potential harms associated with a MGUS diagnosis “is a topic that is rarely, if ever, broached between patients and providers, or even considered in academic debate,” Dr Go and Dr Rajkumar write.
Many studies have demonstrated that the psychological distress experienced by patients with nonmalignant hematologic diseases, including MGUS, is just as profound as it is for a patient with a malignancy. While this may be partly because patients are evaluated at cancer centers or receive care from a hematologist who also cares for patients with cancer, “paying more attention to the psychological concerns of MGUS patients is warranted,” say the authors.
As with other cancer types where screening is initiated, overdiagnoses of lymphoplasmacytic malignancies, especially the smoldering type, are also inevitable. “Harms of overtreatment and surveillance are well documented in cases of solid tumors but have yet to be studied in MGUS or monoclonal B-cell lymphocytosis, the precursor to B-cell chronic lymphocytic leukemia,” they write.
The economic cost of MGUS follow-up also has to be considered because it is “substantial.” There are about 500,000 individuals with a diagnosis of MGUS in the United States, and if each one is getting yearly follow-up, the annual healthcare cost is estimated to be more than $100 million annually.
“We need studies targeted to populations that are at the highest risk of developing MGUS,” they conclude, and patients must be routinely engaged in “an informed conversation incorporating the absolute risk of MGUS progression and comorbidity-adjusted life expectancy prior to recommending a follow-up program.”
The Blood paper was supported by research funding from the Mark A. and Elizabeth N. Binks Fund, from the Mayo Clinic Department of Medicine Innovation Award, and by research grants from the National Institutes of Health National Cancer Institute. The authors have disclosed no relevant financial relationships.
The NEJM study was funded by the National Cancer Institute. Dr Kyle has disclosed no relevant financial relationships, but three coauthors report relationships with pharmaceutical companies outside the submitted work.
Blood. 2018;131(2):163-173. Abstract
N Engl J Med. 2018;378:241-249. Abstract
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