Monoclonal gammopathy of undetermined significance : natural course and comorbidities

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by an
overproduction of monoclonal immunoglobulins. MGUS is asymptomatic but clinically relevant since annually
0.5-1.5% of individuals with MGUS will develop multiple myeloma (MM) or another malignant
lymphoproliferative disease. Individuals with MGUS are followed for signs of progression, however, so far this
management strategy has never been evaluated. Results from previous studies have shown that individuals with
MGUS have inferior survival and increased risk of thrombosis compared to individuals without MGUS, yet all
studies to date have been performed on clinically established cohorts of MGUS patients, introducing a high risk
of selection bias. Recently, a new entity called light-chain MGUS (LC-MGUS) has been identified. Very little is
known about the epidemiology and clinical course of LC-MGUS. 



In order to establish a clinically informative, correct, and easily applicable definition of LC-MGUS, and
describe the prevalence of MGUS and LC-MGUS in the population, we performed a large population-based
screening study. We screened more than 11,000 individuals from the Icelandic AGES-Reykjavik Study cohort
and the American PLCO Study cohort. The prevalence of MGUS was 4.8-5.2%. Based on findings from the two
cohorts and on statistical analysis of normal distributions, we propose a revised definition of LC-MGUS; (1) an
abnormal free light-chain ratio (<0.26 or >1.65), (2) an elevated involved light chain concentration (40 mg/L or
higher), (3) no M-protein on serum protein electrophoresis or immunofixation, and (4) no evidence of end-organ
damage that can be attributed to a lymphoproliferative disorder. The prevalence of LC-MGUS in our study using
this definition was 0.9-1.0%. The prevalence of LC-MGUS increased with age (p<0.001), was higher in men
(p<0.001), and more common among blacks (2.9%) than whites (0.7%) or Asian/Pacific Islanders (0.2%). The
revised definition of LC-MGUS captures the condition in fewer but clinically relevant individuals. 



We conducted three population-based studies with the purpose of studying the natural course and survival
of individuals with MGUS and LC-MGUS. We used the Icelandic AGES-Reykjavik Study cohort of 5,764
individuals, including 300 individuals with MGUS and 52 individuals with LC-MGUS, as well as a Swedish
cohort of 18,768 MGUS patients. Through the Swedish Cancer Register we identified all patients with MM
diagnosed from 1976 to 2013, as well as randomly sampled population-based controls. Individuals with MGUS
had a 1.2-fold (95% confidence interval (CI) 1.04-1.4) and individuals with LC-MGUS had a 1.6-fold (1.2-2.3)
increased risk of death compared to individuals without MGUS, during a median follow-up time of almost ten
years. The risk remained increased after progression to lymphoproliferative disease was taken into account. We
found a personal history of autoimmune disease to increase the risk of death significantly in both individuals
with MM (hazard ratio (HR) = 1.2, 1.2-1.3) and individuals with MGUS (HR = 1.4, 1.3-1.4). These findings
could be due to an underlying genetic susceptibility for both plasma cell disorders and other conditions, such as
autoimmune disease, or to the overproduction of light chains causing organ damage. We found that MM patients
with prior knowledge of MGUS had a better overall survival (median survival 2.8 years) than MM patients
without prior knowledge of MGUS (median survival 2.1 years). Among MM patients with a prior knowledge of
MGUS, a low M-protein concentration at MGUS diagnosis was predictive of worse survival in MM (HR = 1.9,
1.1-3.0), possibly due to patients with low M-protein concentration being followed less frequently. Our findings
support the recommendations of regular clinical follow-up of individuals with MGUS, regardless of M-protein
concentration. 



In further analysis of the AGES-Reykjavik Study cohort, we assessed the causes of death and risk of
thrombosis among individuals with MGUS and LC-MGUS and found an increased risk of death from cancer
(HR = 1.8, 1.6-2.3) and from heart disease (HR = 1.4, 1.1-1.8), adjusted for age and sex. We found that a history
of thrombosis was more common in individuals with LC-MGUS (25%) than individuals with MGUS (10%) or
without MGUS (12%), and that individuals with LC-MGUS had an increased risk of a history of arterial
thrombosis especially (crude odds ratio (OR) = 2.5, 95% CI 1.3-4.9), compared to individuals without MGUS.
During a median follow-up time of almost nine years, we detected an almost two-fold risk of arterial thrombosis
in individuals with LC-MGUS compared to individuals without MGUS (crude HR = 1.9, 1.1-3.2). No increased
risk of venous thrombosis was detected in individuals with MGUS or LC-MGUS. Our results suggest that
previously detected increased risks of thrombosis in MGUS have been due to confounding factors. Our findings
on LC-MGUS point towards an elevated risk of arterial, but not venous, thrombosis. 



In future investigations, we suggest attention is focused on characterizing the clinical, genetic, and
biochemical profiles of LC-MGUS, with the purpose of understanding the connection to cancer, to heart disease,
and to thrombosis