ILLUSTRATIVE CASE SERIES

Monoclonal Gammopathy of Undetermined Significance

By William B. Ershler, MD

A 64-year-old commercial airline pilot was seen by his primary physician because of a bothersome, non-productive cough. He has a history of asthma but requires no medications other than occasional albuterol inhalation. Physical examination was unremarkable, as were the complete blood count and chest x-ray. However, the serum chemistry revealed an elevated total serum protein of 8.9 g/dL with a normal albumin of 3.8 g/dL. Serum electrolytes, creatinine, blood urea nitrogen, and calcium were within normal limits. A serum protein electrophoresis was obtained and this revealed a monoclonal spike of 1.9 g/dL. Immunoelectropheresis demonstrated the presence of a monoclonal IgA/l. The patient was referred for opinion regarding diagnosis and management.

DISCUSSION

This patient presented with an unrelated problem but was discovered to have an elevated serum protein and a monoclonal immunoglobulin, suggesting the likely diagnosis of monoclonal gammopathy of undetermined significance. To confirm this and to be certain that criteria for myeloma or the intermediate smoldering multiple myeloma (SMM) are not met, bone x-rays should be obtained and bone marrow sampled.

If monoclonal gammopathy of undetermined significance (MGUS) criteria are met, we would advise quarterly visits at a minimum to assess the stability of his plasma cell dyscrasia. Here, interval history, physical exam, CBC, chemistry panel (including creatinine, total protein, and calcium), and measurement of the monoclonal (M) protein, either by serum protein electrophoresis or quantitative IgA level would be catalogued.

Not all patients will require quarterly visits but the presence of certain risk factors for myeloma development (IgA isotype, > 1.5 g/dL M protein, discussed below) would warrant active surveillance. If he were to demonstrate progression to SMM within a year or less, one might be tempted to consider introducing definitive myeloma therapy at that time, acknowledging that there is little trial-based evidence on which to base this recommendation. However, in light of his relatively young age and absence of comomorbidity, this may well be the optimal time to provide aggressive cytoreductive therapy. Such, however, is currently not the standard approach, and if treatment is to be introduced it would be best to consider enrolling in a clinical trial. There are several ongoing trials for treatment of MGUS, and particularly SMM, and the reader is directed to a recent comprehensive review written by Korde and colleagues,1 which includes a listing of completed and ongoing interventional studies. Despite the sense that early treatment would be advantageous, published reports to date have not been convincing with regard to an impact on overall survival, although progression-free survival and decreased skeletal events have been observed in selected studies. Furthermore, there is now heightened concern about the occurrence of second malignancies in treated myeloma patients,2 and this may be particularly germane for those with a projected long treatment course. Thus, the standard of care remains continued surveillance for patients with MGUS SMM and intervention only when criteria for multiple myeloma are established.

RISK STRATIFICATION

In earlier days, the demonstration of a monoclonal protein in this setting (asymptomatic, otherwise healthy patient) was often considered an incidental finding3 — the so-called "benign monoclonal gammopathy," particularly when it occurred in older patients. Although it has long been recognized that some patients with this disorder go on to develop multiple myeloma,4 this had been considered the exception rather than the rule. However, it became clear by the mid-1970s that the finding was associated with a significantly higher risk for developing multiple myeloma, Waldenstrom macroglobulinemia, amyloidosis, and other related disorders. Accordingly, in 1978, Kyle proposed the term MGUS be substituted for benign monoclonal gammopathy.5 In a comprehensive analysis of Mayo Clinic patients with MGUS, certain risk factors for progression to myeloma were identified, and a stratification model established (see Table 2). The identified risk factors are: 1) M protein level > 1.5 g/dL; 2) non-IgG M component (e.g., IgA); and, 3) abnormal serum free light chain ratio. That same Mayo group published a report6 including more than 1000 MGUS patients demonstrating the 20-year progression to myeloma increased incrementally with the number of risk factors present (see Table 2). Thus, for all MGUS patients, the risk is approximately 1% per year, but more than half of those with all three risk factors will develop myeloma over the same time span.

Thus, MGUS and SMM are now considered precursors of plasma cell malignancy. It is likely that most, if not all, patients with the diagnosis of multiple myeloma had prior MGUS, albeit of varying duration. With the prevalence of MGUS approaching 5% in the 50 years and older population, and with expanding life expectancy with the median survival for those who are currently 50 years old approximately 35 additional years, it is very likely that the coming decades will see strikingly more myeloma patients, particularly in those 75 years and older.

References

1. Korde N, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): Novel biological insights and development of early treatment strategies. Blood 2011;117:5573-5581.

2. Thomas A, et al. Second malignancies after multiple myeloma: From 1960s to 2010s. Blood 2012;119:2731-2737.

3. Waldenstrom J. Studies on conditions associated with disturbed gamma globulin formation (gammopathies). Harvey Lect 1960;56:211-231.

4. Norgaard O. Three cases of multiple myeloma in which the preclinical asymptomatic phases persisted throughout 15 to 24 years. Br J Cancer 1971;25:417-422.

5. Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978;64:814-826.

6. Rajkumar SV, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005;106:812-817.