Peripheral Neuropathy Is Associated with an Increased Risk of Fractures in Individuals with Monoclonal Gammopathy of Undetermined Significance: A Population-Based Study Including 15,351 MGUS Cases
Authors: Rögnvaldsson Sæmundur , Thorsteinsdottir Sigrun , Turesson Ingemar , Björkholm Magnus , Landgren Ola , Kristinsson Sigurður Yngvi 
Published: October 2019

Abstract
Introduction:
Monoclonal gammopathy of undetermined significane (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is relatively common in the general population with a reported prevalence of 4.2% over the age of 50. Although MGUS is usually considered asymptomatic, affected individuals have been shown to have an increased risk of fractures. This is believed to be related to an early form of MM bone disease characterized by abnormal bone architecture.
Peripheral neuropathy (PN) has also been shown to be associated with MGUS. Currently, the prevalence of PN in MGUS is unclear, with reports ranging from 3 to 70%. PN has been associated with an increased risk of falls and fractures, especially in diabetic neuropathy, the most common type of PN. However, we are not aware of any studies assessing how PN affects fracture risk in individuals with MGUS. Therefore, we were motivated to create a large population-based study to assess how PN affects the risk of fractures in MGUS.
Methods:
We included all MGUS cases diagnosed in Sweden between 1986 and 2013 and recorded in a registry of a nationwide network of hematology- and oncology centers or in the Swedish patient registry. We then cross-linked data from the Swedish Patient Registry, Cancer Registry, and Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study.
We created a multi-state survival model. At inclusion participants started providing person time into the PN or the non PN states depending on whether they had a previous diagnosis of PN or not. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time into the PN state after that. We then created a Cox proportional hazard regression model with the endpoint defined as the first fracture of any type after inclusion with participants being censored at diagnosis of MM or related disorders. We adjusted for sex, age, year of MGUS diagnosis and previous fracture in the 2 years before inclusion.
Results
At total of 15,351 individuals with MGUS were enrolled and followed for a median of 3.2 years, providing a total of 76,141 years of person time. Of those, 951 individuals provided a total of 3,497 years of person time with PN, being followed for a median of 2.7 years. A total of 3,121 fractures were observed, 2,970 among those without PN and 151 among those with PN. Results from an adjusted Cox regression model showed that those who had PN had a higher risk of having a first fracture than did those who did not have PN (hazard ratio (HR): 1.21, 95% confidence interval (95%CI): 1.02-1.42, p=0.027).
Discussion
In this large population-based study including 15,351 individuals with MGUS we found that individuals with MGUS who also have PN have an increased risk of fractures as compared to those who only have MGUS. In a previous study, we have already showed that PN does not affect the risk of MGUS progression. Therefore, it is unlikely that these findings are attributed to fractures caused by active undiagnosed MM. These findings suggest that the increased fracture risk observed in individuals with MGUS can at least partly be attributed to concomitant PN. We are currently validating these results within the iStopMM trial, a large prospective MGUS screening study.

Disclosures
Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees.