This study was conducted to determine the prevalence of diabetes mellitus and hypertension among patients with SMM. The results demonstrated a higher prevalence of diabetes (25.0%), hypertension (60.0%), and dyslipidemia (54.0%) among individuals with SMM compared to a healthy control group (8.0%, 41.0%, and 32.0%, respectively) at baseline. After 1, 3, and 5 years of follow-up, however, individuals with sustained SMM showed an increased risk of dyslipidemia, but not of diabetes or hypertension compared to the control group. The prevalence of diabetes at baseline (26.5%) was higher for the MM patients than that for the subjects in the control group. During the follow-up, the mean glucose levels and lipid profiles deteriorated significantly among the MM patients. The prevalence of diabetes, hypertension, and dyslipidemia continued to rise during the 5-year follow-up period. After the first year of follow-up, the risk of developing diabetes was higher, as was the risk of developing dyslipidemia, the latter with a subsequent elevation after 3 and 5 years of follow-up. The risk of developing hypertension did not change until 5 years of follow-up, when it was observed to rise. Our 27.0% prevalence of diabetes at MM diagnosis is about twice the rate reported by other studies [16,18,23]. Our 53% prevalence of hypertension was also higher than that reported in other studies on MM patients (38.0%  and 47.0% ). There were no sex-related differences, which can be at least partially due to the relatively small groups.
Numerous studies have reported associations of diabetes with all-site cancer , including a large population study in Israel . A meta-analysis published in 2012 showed an increased (although non-significant) risk of developing MM among individuals with diabetes . Various explanations have been proposed for the association of diabetes with cancer. Among the biological factors are hyperglycemia, hyperinsulinemia, overproduction of insulin-like growth factor-1 (IGF-1), increased expression of the IGF-1 receptor, and increased secretion of inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) . Several studies have reported associations of inflammatory markers with the incidence of type 2 diabetes [27-31]. The IGF system is clearly involved in almost every stage of development of MM, beginning with the proliferation of malignant cells and extending throughout survival, and even affecting resistance to medical treatments . The inflammatory process entails part of the pathogeny of MM, and IL-6 has a particularly important role in that process . Indeed, an increased level of inflammatory cytokines was associated with poor prognosis of MM [34-37]. IL-6 is considered a growth factor for myeloma cells and is also an important regulator of inflammatory proteins . Moreover, several studies have shown an association between the level of IL-6 and inflammatory proteins, such as C-reactive protein and antitrypsin alpha-1, and the prognosis of MM [34-36].
Hypertension is considered as being ubiquitous among MM patients and, until recently, this was believed to be due to the older age of the patients, the fact that more men are affected with the disease, and a consequence of the treatment with steroids. However, the findings of the current study revealed that hypertension was more prevalent among patients with SMM at baseline ─ and therefore not yet treated with steroids ─ than in the control group. Inflammation may also have a role in this setting, since patients with hypertension have an increased level of inflammatory cytokines [38-40], and given the fact that the inflammatory process is an important factor in the development of hypertension .
According to a national health study conducted on Israelis aged 21 years and older during 2013-2015 (INHIS 3), the prevalences of diabetes, hypertension, and dyslipidemia were 8.4%, 20.6%, and 30.2%, respectively . The data on diabetes and dyslipidemia of the current control group were similar to those values, but the prevalence of hypertension was about twice as high (41%). This may be explained by the older age of our study population (average 65 years), in which increased prevalences of these diseases are to be expected. While our MM patients had a higher prevalence and incidence of hyperlipidemia compared to the controls, similar comparisons were even seen in our patients with SMM who were in an untreated premalignant stage of MM, indicating increased cardiovascular risk in both groups.
Hyperlipidemic myeloma (HLM) is a rare variant of MM. In a review that summarized 53 cases of HLM, the typical clinical presentation was characterized by IgA myeloma, hyperlipidemia, skin xanthomas, and hyperviscosity . The precise mechanism for hyperlipidemia is still controversial: according to one hypothesis, paraproteins bind to lipoproteins and, thereby, inhibit their degradation .
In contrast, hypocholesterolemia is fairly common in MM patients [44-46]. A case-control prospective study by Yavasoglu et al  found low total cholesterol, LDL-C, and HDL-C levels in MM patients compared with controls, and noted that the lipid parameters were lower in advanced stages of disease. This suggests the hypothesis that hypocholesterolemia may be due to increased LDL clearance and utilization of cholesterol by myeloma cells.
A recent analysis from the Cancer Research Network showed a protective association between statin use and MM development . This association was more pronounced after 48 months or more of statin treatment, as well as in older patients (70 years or more) regardless of statin treatment duration. Another population-based cohort study of 4,957 MM patients, of whom 2,294 received statin treatment, revealed a statin treatment-related 21% reduction in all-cause mortality and a 24% reduction in MM-specific mortality . These findings emphasize the importance of early diagnosis and treatment of hyperlipidemia in patients with SMM and MM.
This study has a number of limitations largely due to its retrospective design. Some important data were missing, such as smoking in the present or past and details on family history of hyperlipidemia. A systematic follow-up of blood pressure measurements was not done for the MM and SMM groups, thus, individuals were considered to have hypertension only according to documentation of a diagnosis by their primary care physicians or the initiation of treatment for hypertension. In contrast, hypertension was assessed and recorded in the medical records of the individuals of the control group. Another drawback may be selection bias in the interpretation of the findings. Since the patients included in this study were being followed-up in the hematology department of a tertiary hospital, there is a greater chance that their disease would be severe and possibly with more background disease and, as a result, they may not necessarily represent the MM and SMM patients who are treated in the community. Finally, despite efforts to access all relevant clinical and laboratory data, the sample size was small, particularly at the end of the 5-year follow up. Together with missing data, this may explain the lack of statistical significance for some of the analyses.