Malignant Progression of Monoclonal Gammopathy of Undetermined Significance: A Systematic Review and Meta-Analysis

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell dyscrasia that occurs in 3-5% of patients above the age of 50. In addition to its known progression to multiple myeloma (MM), MGUS is associated with higher risks of second malignancies. The progression from MGUS to more advanced diseases has a significant impact on overall survival. This systematic review and meta-analysis therefore aimed to comprehensively evaluate the incidence of malignant progression and the development of second malignancies in patients with MGUS.

Methods: The protocol of our study was registered in PROSPERO with ID(CRD42018092067). Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive electronic search in nine electronic databases, including PubMed, Google Scholar, POPLINE, WHO health library, System for Information on Grey Literature in Europe, Scopus, Web of Science, Virtual Health Library, and The New York Academy of Medicine. The following predetermined search terms were used: (monoclonal gammopathy of undetermined significance or MGUS); (incidence or progression or transformation); (myeloma or lymphoma or amyloidosis or macroglobulinemia or leukemia or plasmacytoma or malignancy or malignant). Risk of bias was assessed using the National Institute of Health (NIH) study quality assessment tool. Random-effects model was used to synthesize the pooled event rates of MGUS progression and development of second malignancies. Statistical heterogeneity was evaluated using Cochran's Q statistics and I² tests, with p-value≤0.10 or I² value>50% considered as statistically significant. Sub-group analysis based on the duration of follow-up was conducted to obtain rates of progression in patients who were followed-up for 0-5 years, 5-10 years, and more than 10 years. Meta-regression based on age, gender, immunoglobulin subtype of MGUS, and publication year was performed to explore any statistically significant heterogeneity if there were more than 10 studies. Publication bias was assessed using Begg's funnel plot and Egger's regression test if the number of studies was more than 10.

Results: A total of 4690 articles were identified. Of those, 315 articles were found eligible for full-text screening. We finally included 48 studies for analysis including a total of 20945 patients with a mean age of 64.1 years. The mean duration of follow-up was 7.43 (1.8-34.1) years. The overall cumulative rate of MGUS progression and development of second malignancies was 8.6% (95% CI, 7.2-10.2%). The rates stratified based on years of follow-up were 6.9% (95% CI, 5.3-8.9%) at 0-5 years, 8.8% (95% CI, 6.4-11.8%) at 5-10 years, and 14.9% (95% CI, 10.8-20.2%) beyond 10 years. Rates of progression to MM, Waldenstrom macroglobulinemia, and amyloidosis were 5.8% (95% CI, 4.7-7.2%), 2.1% (95% CI, 1.1-4.0%), and 0.7% (95% CI, 0.3-1.5%) respectively. The rates of development of non-Hodgkin lymphoma and leukemia were 2.5% (95% CI, 1.5-4.3%) and 1.4% (95% CI, 0.4-4.4%) respectively. The rate of development of solid tumors was 6.4% (95% CI, 2.5-15.4%). Meta-regression for evaluation of statistical heterogeneity was performed for most outcomes, except for those with less than 10 studies (leukemia, amyloidosis, solid tumors, and follow-up beyond 10 years). Age and publication year were the source of heterogeneity in most. Overall risk of progression does not vary with MGUS subtypes. There was no publication bias based on Begg's funnel plot and Egger's regression test.

Conclusions: The risks of MGUS malignant progression and development of other hematological/solid malignancies remain significant, approximating 15% after 10 years of diagnosis. Future efforts could be directed toward better cancer surveillance and deferral of malignant progression among patients with MGUS.