Monoclonal Gammopathy: Not So Benign

Abstract & commentary

Synopsis: In a large series of MGUS patients followed prospectively, transformation to multiple myeloma or other hematological malignancy, although present, was at a rate considerably lower than expected, based upon reports from retrospective series. Nevertheless, overall survival for MGUS patients was significantly less than that for the general population.

Source: Schaar CG, et al. Long-term follow-up of a population based cohort with monoclonal proteinemia. Br J Haematol. 2008;144:176-184.

Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence in serum of a monoclonal protein (M protein) in patients who have no other features of multiple myeloma, amyloidosis, or other hematological malignancy.1 Although at times considered 'Benign Monoclonal Gammopathy,' the progression of MGUS to multiple myeloma remains a real, but incompletely understood concern.2 Whereas there is general agreement on the prevalence of MGUS among individuals over the age of 70 years (about 3%),3,4 the rate of conversion to myeloma, or other hematological malignancy, remains unclear. Most relevant data in this regard are derived from retrospective studies, and depending on the criteria used for the definition of MGUS, the cumulative risk of transformation to myeloma has been reported to range from 11% to as high as 50% at 15 years.5-8

Prospective studies on the risk of malignant transformation in patients with MGUS, and the factors predictive of survival, have been lacking. The Dutch Comprehensive Cancer Centre West, comprising 1.6 million inhabitants, initiated a prospective, hospital-based cohort study on 1,464 patients with newly diagnosed monoclonal gammopathy, median age 73 (17-103) years. M protein-related diagnoses, patients' characteristics, laboratory investigations, bone marrow examinations, and skeletal X-rays were registered with a yearly follow-up. Examined outcomes were death or new diagnoses of multiple myeloma and non-Hodgkin lymphoma. Kaplan-Meier survival curves were compared with age- and gender-matched survival data from the total Dutch population. Cumulative malignant transformation was corrected for death using a competing risk model. Risk factors for transformation or death were analyzed by univariate and multivariate analyses.

Among 1,007 MGUS patients, malignant transformation was associated with rising M protein levels, IgA and IgM isotype, and occurred at a yearly rate of 0.4%. All MGUS patients survived less than a matched cohort of the Dutch population, even in the absence of M protein-associated comorbidity. Serum albumin levels at time of diagnosis appeared highly predictive for survival.

Commentary

Thus, although MGUS, in this large prospective trial, was associated with a low rate of malignant transformation, its presence was associated with an accelerated rate of death compared with the general Dutch population of the same age. The cumulative development of myeloma by 10 years was only 3.9%. This lower than expected number perhaps reflects the statistical methodology employing a competing risk analysis inasmuch as the death rate was 67% at 10 years. If this type of analysis had not been used, the cumulative transformation to myeloma would have appeared larger (6.6% at 10 years). Factors associated with transformation included the level and type of paraprotein (IgA and IgM at higher risk).

In multivariate analysis, factors associated with shortened survival included male gender, age > 60 years, and low-serum albumin. In fact, it was possible to divide the MGUS patients by serum albumin strata, which resulted in impressive survival differences, ranging from a median survival of less than two years for those with serum albumin of > 3 g/dL to more than 8.5 years for those with a serum albumin of > 4 g/dL.

Excluding patients initially diagnosed with MGUS, but who developed multiple myeloma, other hematological malignancy, or solid tumor, survival for those remaining with MGUS was considerably lower than the general age-matched population. An explanation for this is not readily apparent. Apparently, myeloma or not, MGUS is not benign!

References

1. Kyle RA. "Benign" monoclonal gammopathy — after 20 to 35 years of follow-up. Mayo Clin Proc. 1993;68:26-36.

2. Kyle RA, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569.

3. Axelsson U, et al. Frequency of pathological proteins (M-components) om 6,995 sera from an adult population. Acta Med Scand. 1966;179:235-247.

4. Kyle RA, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354: 1362-1369.

5. Baldini L, et al. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood. 1996;87:912-918.

6. Blade J, et al. Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol. 1992;81:391-394.

7. Gregersen H, et al. Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance. Br J Haematol. 2001;112:353-357.

8. Veneri D, et al. Malignant evolution of monoclonal gammopathy of undetermined significance: analysis of 633 consecutive cases with a long term follow-up. Haematologica. 2004;89:876-878.