Page 192 - 2020_11-Haematologica-web

Letters to the Editor
Number at risk
Years Years
Figure 1. Kaplan-Meier graph illus- trating the cumulative hazard of peripheral neuropathy (PN) through- out the study period by assigned study group. MGUS: monocloncal gammopathy of undetermined sig- nificance; DM: diabetes mellitus.
MGUS was associated with a 0.8-fold risk of PN as com- pared to DM (HR=0.8; 95%CI: 0.7-0.9, P=0.02). Participants with MGUS and DM had a 2.1-fold risk of PN as compared to those with DM alone (MGUS and DM: HR= 2.1; 95%CI: 1.7-2.5; P<0.001) (Table 1 and Figure 1). Although these findings could suggest a syner- gistic effect of MGUS and DM, it is more likely that excess PN caused by MGUS is being detected during DM or MGUS follow-up in individuals with DM and MGUS as compared to those with DM alone. These findings indicate that PN is truly associated with MGUS, contra- dicting previous findings that questioned this.4
In the secondary analysis, 1,368 participants pro- gressed to MM, 449 progressed to WM, and 173 pro- gressed to AL (Table 2). PN was associated with lower risk of MM (HR=0.7; 95%CI: 0.5-0.9; P=0.02) but was not associated with WM progression (HR=1.3; 95%CI: 0.9-1.9; P=0.2). PN has been shown to be more common in IgM MGUS3 that rarely progresses to MM, but rather to WM,8 potentially leading to selection bias. Unfortunately, isotype data are not available for this cohort making it difficult to interpret these results. However, these findings could indicate that PN is unlike- ly to be associated with increased risk of MM or WM, suggesting that the development of PN in MGUS might be unrelated to progression of the underlying plasma cell disorder.
Interestingly, we found PN to be associated with a 2.9- fold risk of MGUS progression to AL (HR=2.9; 95%CI: 1.8-4.6; P<0.001). Furthermore, we found that nine out of the 11 individuals (82%) with PN at diagnosis who later progressed to AL did so within a year of MGUS diagnosis. Diagnosis of AL can be difficult, leading to under-recognition and a delay in diagnosis of AL.9 Furthermore, virtually all cases of AL are preceded by MGUS,10 so it is likely that these participants had AL, not MGUS, at inclusion. These findings stress the importance
of a thorough evaluation for AL in individuals with MGUS and PN, especially at MGUS diagnosis.
We found PN to be associated with a 1.3-fold risk of death in MGUS (HR=1.3; 95%CI: 1.2-1.5; P<0.001). When associated with other disorders, PN can lead to falls and fractures11-13 which might contribute to this increased risk of death. However, PN is also associated with various other diseases that might lead to increased risk of death, such as other cancers and alcohol misuse.6 Therefore, it is unclear whether this represents a causal relationship. Further studies are needed to validate these findings.
Our study has several strengths. We included a nation- wide population of 15,351 MGUS cases and 58,619 matched controls diagnosed over a 28-year period. Data were acquired with high accuracy and completeness from well-established registries. As far as we know, this is the largest study of MGUS-associated PN so far. Secondly, by including clinical data from routine care, the study provides an insight into the real-world care of indi- viduals with MGUS. Finally, by also stratifying partici- pants for DM, we mitigated detection bias that would otherwise have affected the results of this type of study.
The study also has important limitations. Firstly, PN diagnoses were acquired from diagnostic coding without data on the underlying symptoms or diagnostic tests, relying on detection, and accurate diagnosis of PN by physicians. By stratifying for DM, we mitigated some of the effects of any unequal detection and reporting of PN in the cohort. Secondly, study participants were not screened for MGUS, but were diagnosed during the work-up of other medical problems, leading to biased selection of participants with other medical problems into the MGUS group. Furthermore, MGUS might have been diagnosed as a result of PN. However, this applies to all real-world MGUS populations, and individuals with PN before MGUS diagnosis were excluded from analyses
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haematologica | 2020; 105(11)