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MGUS and multiple myeloma:
Myeloma and MGUS are remarkably common problems; the distinction is very important. MGUS’s do not need treatment, are benign, but if followed long enough may evolve into myeloma. Of course, MGUS actually stands for monoclonal gammopathy of undetermined significance. In an excellent paper by Robert Kyle at the Mayo Clinic it was found that in the Minnesota counties in the Mayo Clinic catchment area that 2% of persons over the age of 50,and 3% of over 70 year-olds have monoclonal proteins [abnormally elevated antibodies or fragments thereof which are directed at only one target] when tested with serum protein electrophosesis and immunofixation. Typically, these monoclonal peaks (called M-peaks) were detected at concentrations of 3 gm/dL (or less). They did not have a significant urinary M-peak excretion, and lack the multiple myeloma findings of bone lytic lesions, elevated serum calcium levels (indicative of bone destruction), and rarely had kidney failure. MGUS patients never have over 10% marrow plasmacytes. The Kyle 2002 NEJM study of 11,009 person-year follow-up of 1,384 MGUS patients seen at the Mayo-clinic network over 25 years found that 115 progressed to myeloma, Waldenstrom’s lymphoma, primary amyloid, lymphoma, CLL,or plasmacytoma (relative risk of myeloma in MGUS patients=25 fold the normal population).The cumulative risk of progression from MGUS to one of these illnesses at 10 years=12%, at 20 years=25%, and at 25 years=30%. This is roughly a 1%/year risk of progression, with no real plateau over time.
Monoclonal peaks rarely disappear without treatment (overall disappearance rate is about 2%); lower M-peak patients seem to have a slightly lower risk of evolving over time. In fact, only the M-peak concentration was an independent predictor of progression. The IgA or IgM as the M-peak specificity gave a slightly worse transformation rate, but the non-IgG M-peak specificity did not stand out as predictive on multivariate analysis. Interestingly, depression of non-involved immunoglobulin subtypes generally did not predict MGUS progessors. Kyle suggested that MGUS patients should be monitored annually, but implied that those individuals with larger M-peaks (eg. 32% of patients with M-peaks >3 gm/dL progressed) should be watched more closely. Other studies have quoted a prevalence of 5% in over 70 year-olds. These elderly individuals likely have a lower rate myeloma transformation in part because of competing causes of mortality [they often die before transforming]. Close and regular surveillance of younger patients with MGUS is thus required and justified.
A new lab test, free serum light chain may be useful in identifying which patients may need more careful surveillance. One study of 1,148 patients (Rajkumar 2005) found a HR of 3.5 (that is, a 3.5 fold increase in transformation rates to MM) in patients having an abnormal kappa: lambda free light chain ratio, a finding which was independent of the type or size of the underlying monoclonal gammopathy. This study proposed a risk stratification system where non-IgG-high M-peak (>1.5 gm/dL)-abnormal FLC ratio [i.e. all three at once] individuals were at particularly high risk of MM transformation--55% at 20 year follow-up compared to 5% if none of these factors are present (and only a lifetime risk of 2% if competing causes of death are taken into account).
If you drill down into what causes this abnormality, it turns out that about 50% of MGUS and smoldering myeloma patients have mutations in the immunoglobulin heavy chain, generally a translocation at the 14q32 focus, often with a second partner gene mutation being present. Many postulate a “2 hit” process fo transformation of MGUS into MM, where a second gene mutation results in progression of the previous benign MGUS results in the full blown malignancy.
Management of MGUS
Kyle recommends surveillance every year; Rajkumar suggests follow-up at 6 months and then at 2 years for the low-risk group, or with the development of symptoms [hypercalcemia, anemia, renal failure, or bony lytic lesions]. For all other (non-low risk patients) Rajkumar suggests a 2nd 6 month check-up, and then an annual visit, if all is well. NO TREATMENT is of any proven benefit in patients with MGUS’s—nothing seems to be able to reduce the rate of malignant transformation. Personally, I generally do not do a marrow examination if the patient has no anemia, bony symptoms, hypercalcemia, and if the IgG M-peak is under 2 gm/dL or the IgA M-peak is under 1.5 gm/dL. I do not personally believe that IgM myeloma exists, and do not marrow IgM MGUS patients (but will do CT scanning in those individuals, looking for lymphoma.
Donald Gravenor MD