br Conclusion br Introduction Multiple myeloma is
Introduction Multiple myeloma is a malignant plasma cell disorder, comprising approximately 10% of all haematological malignancies, and its incidence is increasing . The pathogenesis is complex, culminating in malignant transformation of clonal plasma cells. The aetiology is not well established, although a number of case-control and cohort studies have reported on the possible associations. Previous studies reported no consistent association between multiple myeloma and socioeconomic status, income, and education [2,3]. However, a familial history of myeloma in a first-degree relative has been reported to increase the risk of myeloma by 2–6 times [4,5]. A previous study reported that the incidence of multiple myeloma was approximately 60% lower in a Chinese population compared with a non-Chinese population, and that the lower rates were maintained in migrants, showing a strong genetic component as evidenced by ethnic differences . Furthermore, an association between increasing body mass index (BMI) and the risk of myeloma has been detected in several studies [7–9]. Aetiological evidence on the effects of alcohol consumption and tobacco use on the risk of multiple myeloma is limited [10–14]. There is currently inconsistent or limited evidence regarding the association between the risk of myeloma and various factors, including reproductive and hormonal factors , occupational exposure , chronic immune stimulation , and autoimmune disorders [5,18]. Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that inhibit cyclooxygenase (COX) activity and its production of inflammatory prostaglandins. COX-2 expression is associated with inflammation and numerous neoplasms, including multiple myeloma, and COX-2 positivity has been shown to be associated with a poor outcome [19,20]. COX-2 is also expressed in pre-malignant neoplasms, and an animal study showed that the up-regulation of COX-2 was sufficient to stimulate the transformation of normal SM-164 into invasive cancer and metastatic disease . Chronic inflammation can activate stromal fibroblasts leading to enhanced COX-2 expression and the secretion of inflammatory prostaglandins. In turn, stromal cells expressing COX-2 and inflammatory prostaglandins can induce hematopoietic neoplasms to become malignant . Aspirin, which is a commonly used drug, can irreversibly inactivate COX-1 and COX-2 via covalent bond formation . Aspirin may also inhibit nuclear factor-kappaB  and interleukin-6 , which have been implicated in the development of multiple myeloma. Epidemiological studies have shown that regular aspirin use may be associated with a lower risk of Hodgkin lymphoma [26,27], and non-Hodgkin lymphoma [28,29]. Studies investigating the risk of multiple myeloma have suggested that aspirin might be chemopreventive , whereas others have shown no beneficial effect [31–34]. In order to understand the association, and to evaluate the magnitude and quality of the supporting evidence, we performed a systematic review and meta-analyses of observational studies that evaluated the effect of regular aspirin use on the risk of developing multiple myeloma.
Materials and methods
Results Fig. 1 shows the study inclusion process. We identified 368 studies from our literature search of the five databases. After removing 47 duplicates, we assessed 321 titles and abstracts, and excluded 296 records that did not meet the inclusion criteria. The full text of 25 citations was examined in more detail. Five studies fulfilled the inclusion criteria and were included in the systematic review. No unpublished relevant studies were obtained.
Discussion Preclinical studies have suggested that aspirin might modify the risk of cancer. The anti-neoplastic effect of aspirin is thought to be mediated via inactivation of COX-2 , nuclear factor-kappaB , and inflammatory cytokines , which are frequently expressed in neoplastic lesions and the tumour microenvironment. While these cancer-modifying effects are biologically plausible, clinical studies have not consistently shown these results, and this was reflected in our study. Understanding the complex relationship between aspirin and the risk of multiple myeloma is challenging. The latency period for development of myeloma can be 10–20 years, and there is a possibility of reverse causality. In addition, despite the majority of studies adjusting for numerous covariates, it was impossible to eliminate the potential of residual confounding variables, especially confounding by indication bias.