Determining the Importance of Careful Follow-up for Patients with MGUS
Abstract & Commentary
By Andrew S. Artz, MD
Division of Hematology/Oncology, University of Chicago Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: The benefit of regular follow-up for monoclonal gammopathy of unknown significance (MGUS) to detect progression to multiple myeloma (MM) remains unknown. The authors identified a cohort of 116 patients over 30 years that progressed from MGUS to MM with detailed records available. Optimal follow-up at approximately annual intervals occurred in 69%. For patients having optimal follow-up, only 16% were diagnosed with disease progression based on routine follow-up. In contrast, a diagnosis was rendered after serious symptoms (45%), less serious symptoms (25%), and incidental findings (11%) in most. Of those suboptimally followed, only one of 28 had a diagnosis from routine follow-up. Higher-risk patients defined by an IgG > 1.5 g/dL or non-IgG MGUS were more likely to be optimally followed and more likely to be diagnosed secondary to serial routine laboratory testing (21% vs. 7%). In conclusion, progression from MGUS to multiple myeloma is typically diagnosed by symptoms rather than routine follow-up, especially in low-risk patients.
Source: Bianchi G, et al. Impact of optimal follow-up of monoclonal gammopathy of undetermined significance on early diagnosis and prevention of myeloma-related complications. Blood. 2010:116.2019–2025.
Monoclonal gammopathy of undetermined signi-ficance (MGUS) is a common finding that may progress to multiple myeloma.1 Once a monoclonal protein in the urine or serum has been identified, one must distinguish MGUS from another plasma cell dyscrasia. A serum monoclonal protein concentration < 3 g/dL, fewer than 10% plasma cells in the bone marrow, and absence of lytic bone lesions, anemia, hypercalcemia, or renal insufficiency related to a plasma cell disorder defines MGUS, as opposed to myeloma or another plasma cell dyscrasia. The annual incidence of disease progression after an MGUS diagnosis has been estimated at 1% annually.
Recommendations suggest annual follow-up that includes a repeat serum protein electrophoresis in six months and annually thereafter to identify and prevent myeloma-related complications. The authors in this study attempt to assess the value of this empirically recommended strategy.
A portion of patients seen at Mayo Clinic for a diagnosis of MGUS had long-term clinical follow-up information as they resided in one region of the state, presumably where records could be abstracted. Over a 30-year period, the investigators found 116 MGUS patients who eventually progressed to symptomatic multiple myeloma (MM). The median age was 67 years, and 70% showed an IgG isotype. Optimal follow-up, defined as those having repeat serum protein electrophoresis at least every two years, occurred in 69%, whereas suboptimal follow-up was documented in 24%. As expected, higher-risk MGUS, characterized by an MGUS of 1.5 g/dL or more, or a non-IgG isotype appeared to account for a greater portion of optimal (or close) follow-up (81% vs. 64%, p = 0 .07). Seven percent progressed within one year and, thus, optimal follow-up could not be determined. Among optimal follow-up for MGUS, only 16% were diagnosed with MM secondary to routine follow-up. In 45%, serious complications resulted in a diagnosis, most commonly pathologic fractures. Another 25% reached a diagnosis of MM after the evaluation of less serious symptoms (e.g., bone pain), and 11% were diagnosed based on incidental findings. For 3%, the reason leading to the diagnosis could not be ascertained. For suboptimal follow-up, serious complications resulted in a diagnosis of MM at 54%, and incidental evaluation prompted an MM diagnosis in 25%. Only one of 28 (3%) undergoing suboptimal follow-up were diagnosed based on routine follow-up for those undergoing suboptimal monitoring (difference between optimal and suboptimal p = 0.1). Taking both optimal and suboptimal follow-up, two-thirds of the MM cases were diagnosed based on serious signs or symptoms.
The subset of MM having smoldering MM was higher in those with optimal follow-up at 30%, compared to 11% in those with suboptimal follow-up. The time from MGUS to MM diagnosis was shorter in optimal follow-up patients compared to suboptimal at 75 months vs. 116 months, respectively (p = 0.01). Overall survival, however, did not differ.
Commentary
MGUS represents a premalignant disorder associated with around a 1% incidence of progression to MM. Still, most MGUS patients will never develop MM. With increasing availability of routine laboratory testing and serum protein electrophoresis, MGUS may be increasingly recognized. The recommended follow-up after MGUS typically entails annual evaluation and extensive laboratory testing, including a serum protein electrophoresis. The benefit of this approach to detect MM early or avoid MM-related complications remains untested.
The authors identified a fairly substantial number of MGUS patients (n = 116) who eventually progressed to MM, and described presenting features at disease progression by whether follow-up was considered optimal or not. The major finding was that MM was only diagnosed in 16% related to routine laboratory findings in absence of symptoms or complications, despite optimal follow-up. Optimal follow-up did not reduce hospitalization or decrease MM-related complications. For 45% undergoing optimal follow-up, a serious MM-related complication (e.g., pathologic fracture) resulted in an MM diagnosis in between screening visits. At least for this subset, disease progression may be relatively rapid and difficult for intermittent screening to identify. Not surprisingly, optimal follow-up resulted in more cases of smoldering MM at 30%, compared to 11% (p = 0.05) for sub-optimal follow-up. Only two of 27 considered low risk had MM diagnosed by routine follow-up.
Several limitations must be noted. This retrospective study occurred over 30 years. Modern diagnostic testing may be more available and more sensitive to detect early progression due to light-chain testing and isoelectric focusing. For example, all nine MGUS patients diagnosed after 1999 underwent optimal follow-up. Although no benefit to optimal follow-up was found, the availability of new agents and bisphosphonates could alter the natural history of MM, once identified. The study did not report race and, considering the area in Minnesota from which the population was derived, one suspects few patients were African-American. Monitoring for optimal follow-up patients included patients who were seen every two years. The actual frequency, or how often patients were seen annually or less, was not reported. That said, in real practice, achieving annual follow-up for a prolonged period may be challenging, and this likely reflects a reasonable benchmark for adherence to annual follow-up. Finally, it is possible that some patients categorized as diagnosed with MM related to symptoms only reported such symptoms because of medical follow-up. Still, almost half of patients with optimal follow-up had a diagnosis of serious related signs or symptoms which likely did not relate to scheduled physician visits.
The authors suggest annual follow-up may not be beneficial, especially for MGUS patients at low-risk of progression to MM, in that many serious complications occur in between screening intervals, and early treatment of MM has not been shown to be beneficial. The authors note that for low-risk patients, the lifetime risk of MM is only 2% and, therefore, annual MM evaluation may not be necessary. Finally, many of the patients identified by screening had smoldering MM, for which treatment would likely be deferred. Others have suggested, at least in low-risk MGUS, that routine follow-up is not necessary.2 Although this sense is intuitively appealing, the fact that in this study many of the patients harbored so-called low-risk disease, and eventually progressed to MM, shows the limitations of our present tools to predict MM risk from MGUS.
This study highlights the problems with routine follow-up testing and mirror problems with cancer screening strategies. Many cases are missed in the screening interval and these are often more aggressive and cases identified at screening are often more indolent. As a retrospective study the precise risks and benefits of serial clinical and laboratory follow-up for MGUS patients cannot be determined. In short, routine annual follow-up for MGUS patients has a relatively low yield to identify progression to multiple myeloma.
References
1. Kyle RA, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006;354:1362-1369.
2. Iwanaga M, et al. Prevalence of monoclonal gammopathy of undetermined significance: Study of 52,802 persons in Nagasaki City, Japan. Mayo Clin Proc 2007;82:1474-1479.
The benefit of regular follow-up for monoclonal gammopathy of unknown significance (MGUS) to detect progression to multiple myeloma (MM) remains unknown.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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