Page 237 - Haematologica Vol. 109 - July 2024

ARTICLE - Prior cancers and risk of MGUS
S. Rögnvaldsson et al.
could lead to the emergence of MM and WM or other LPD as second primary malignancies. These comprise thera- py- and disease-related carcinogenic effects,9 including immune dysfunction which is critical to the progression of MGUS.10 Furthermore, there may be shared genetic or environmental factors. There is limited epidemiological evidence that having a solid or myeloid cancer decreases or increases the risk of MM, respectively.11 Similar, conflict- ing results have been found in the patterns of cancers in family members of those who have had WM.12 In contrast, other LPD, in particular chronic lymphocytic leukemia, have been associated with prior cancer. However, this may be due to biased detection of asymptomatic chronic lym- phocytic leukemia during follow-up.13 We are not aware of any studies that have examined the risk of MGUS and its progression in those with a prior cancer.
We were motivated to assess the relationship of prior cancers and the development of MGUS in the unique population-based and screened Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study cohort and the progression of MGUS in a large population-based MGUS registry from Sweden with up to 36 years of follow-up. By doing so we aimed to improve our understanding of the etiology of MGUS and its progression, and thereby the pathways that lead to MM, WM, and other LPD. Further- more, cancer is common in the general population with more than 40% of individuals estimated to develop cancer during their lifetime.14 If those who have prior cancer have elevated risks of MGUS or its progression, they may be a target population for MGUS screening.
Methods
The study included two cohorts. The first cohort was ac- quired from the iStopMM study, a population-based screen- ing study for MGUS. In total, 75,422 Icelanders ≥40 years old (51% of the total eligible population) were screened by serum protein electrophoresis and free light chain assay. Those with a prior history of MM, WM or other LPD were excluded. The study has been described elsewhere.15 The second cohort was acquired from a population-based MGUS registry including 13,790 subjects diagnosed in Swe- den between 1987 and 2013. This registry has also been described in greater detail elsewhere.16
Prior and subsequent cancer diagnoses were acquired from the Icelandic and Swedish cancer registries, which have both been shown to have high accuracy and timeliness.17,18 Additional diagnoses of subsequent WM and chronic lym- phocytic leukemia were acquired from the Swedish Patient Registry.19 Prior cancers were analyzed as any cancer, solid cancers, non-melanoma skin cancer, and myeloid cancer (Online Supplementary Table S1). The timing of prior can- cers was grouped as <1, 1-5, 5-10, and >10 years before screening.
For the statistical analysis, we first assessed the risk of MGUS at screening after a prior cancer diagnosis in the iStopMM study cohort using a case-control design. Logistic regression was used to estimate odds ratios (OR) for MGUS for those with a prior cancer diagnosis with stratification by cancer subtype, by the timing of the prior cancer, and by MGUS isotype, adjusting for sex and age as a non-linear variable using four-knot restricted cubic splines. Second, we assessed the association of a prior cancer before MGUS diagnosis in the Swedish cohort, and subsequent MGUS progression. Because MGUS can be a temporary diagnosis before the diagnosis of MM or related disorders, partic- ipants were followed from 3 months after the diagnosis of MGUS to the MGUS progression or censoring at death and end of follow-up. To account for the competing risk of death we used Fine-Grey survival models to estimate sub-distribution hazard ratios (sHR) and adjusted for age and sex.
The study was approved by the Icelandic Science Ethics Committee and the Regional Ethics Board of Stockholm.
Results
A total of 74,654 participants in the iStopMM study were included, of whom 3,579 had MGUS. At total of 9,891 par- ticipants had at least one of a total of 10,598 prior cancer diagnoses, of whom 70%, 29%, and 1% had solid, non-mel- anoma skin, and myeloid cancer, respectively (Table 1). A prior history of cancer was associated with a 10% increased risk of developing MGUS overall (OR=1.10; 95% confidence interval (CI): 1.00-1.20) (Figure 1). This difference was only observable for prior cancer within a year before screening for MGUS overall and non-IgM MGUS (OR=1.36; 95% CI: 1.07- 1.74 and OR=1.57; 95% CI: 1.18-2.08) (Figure 2). No specific prior cancer category or solid cancer subtype was found to be associated with MGUS at screening except the combined category of hepatic, biliary, and pancreatic cancer as well as cancers of the urinary tract (OR=2.59; 95% CI: 1.39-4.48 and OR=1.27; 95% CI: 1.00-1.61, respectively) (Online Sup- plementary Table S2). A sensitivity analysis was performed to rule out that this effect was driven by those who had previously known MGUS before screening, for whom the date of MGUS screening was moved to the date of MGUS diagnosis. This did not affect the results (data not shown). Of the 13,790 participants in the Swedish cohort, 1,834 (13%) had a prior cancer diagnosis before MGUS and 1,658 (12%) subsequently experienced MGUS progression (Table 2). Those who had any prior cancer did not have a signifi- cantly increased risk of MGUS progression overall (sHR=1.14; 95% CI: 0.97-1.34; P=0.11) but those with a prior myeloid cancer had a significantly lower risk of MGUS progression (sHR=0.37; 95% CI: 0.16-0.89; P=0.028) (Figure 3). However, only five individuals with a prior history of myeloid cancer progressed during the study period. There was no statis-
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