Reduced IL‐33 plasma levels in multiple myeloma patients are associated with more advanced stage of disease

Multiple myeloma (MM) is a clonal neoplasm of the bone marrow-resident long lived plasma cells. Like normal plasma cells, MM cells depend on their interactions with bone marrow stromal cells for the survival and production of essential cytokines (Minges Wols et al, 2002). Interleukin-33 (IL-33) is an IL-1 family member that is constitutively expressed by endothelial and epithelial cells (Joshi et al, 2010) and which appears to drive T helper cell type 2 (Th2) responses in several organs (Cevikbas & Steinhoff, 2012). This study analysed the plasma levels of IL33 in 44 MM patients (19 males, 25 females; mean age 66 9 years) and in 13 patients with monoclonal gammopathy of undetermined significance (MGUS; five males, eight females; mean age 63 12 years). No patients had received any treatment for MM during the previous seven days. The study was conducted according to the principles of the Declaration of Helsinki. Informed written consent was obtained. Plasma from 63 sex-matched and age matched normal subjects (35 males, 28 females; mean age 64 11 years) were also included as controls. None of the patients or control subjects had symptoms or laboratory signs of active infections, inflammatory diseases, diabetes, obesity, neurological diseases or severe uraemia. According to the Durie–Salmon staging system, 13 patients were MM disease stage I, 13 patients were stage II, and 18 patients were disease stage III. The paraprotein class was immunoglobulin G (IgG) in 24 patients and IgA in 18 patients; two patient had non-secretory disease. 26 subjects had lytic bone disease and/or pathological fractures. Thirty patients presented an Eastern Cooperative Oncology Group (ECOG) performance status <2 while 14 patients had an ECOG >2. Median plasmocytosis of bone marrow was 47% (range 35–90%). Of the 13 MGUS subjects, the paraprotein class was IgG in 9 and IgA in 4. IL-33 protein levels were measured using the commercially available DuoSet enzyme-linked immunosorbent assay Development System kits (R&D Systems; Minneapolis, MN, USA). The detection limit was 4 0 pg/ml. Data are presented as interquartile range (IQR) and range, except age, which is presented as mean standard deviation. Differences between data series were analysed by the Mann– Whitney test; differences between categorical groups were analysed by the Pearson chi square (v) test. Correlation between two variables was evaluated with Spearman’s rho. Statistical significance was set at P < 0 05. Twenty three of 44 (52 27%) MM patients, eight of 13 (53 33%) MGUS patients and 36 of 63 (57 14%) controls showed detectable levels of IL-33; there was no statistical significant difference in detectability between the three groups (v = 0 365, P = 0 833). IL-33 levels were statistically significantly different between the MM patients (297 8 and 1491 5 pg/ml) and MGUS patients (312 775 and 1579 9 pg/ml) and those measured in controls (1375 3 and 2035 4 pg/ml) (P = 0 001 and (P = 0 03, respectively) (Fig 1). The IL-33 levels in MM patients with kidney failure (creatinine level >88 4 lmol/l) were not statistically significantly different to MM patients who did not have kidney failure (creatinine level 88 4 lmol/l) (1151,75 and 1488 1 vs. 254 175 and 1002 8 pg/ml, P = 0 322). There was no statistically significant difference in IL-33 levels between MM patients with bone lesions and those without (205 1 and 1002 8 vs. 936 55 and 1483 2 pg/ml, P = 0 096). MM patients showed a negative correlation between IL-33 level and stage (P = 0 006, correlation coefficient = 0 692), but not between IL-33 level and Hb concentration (P = 0 301, correlation coefficient = 0 298), b2 microglobulin level (P = 0 817, correlation coefficient = 0 068), and monoclonal component (P = 0 091, correlation coefficient = 0 468). The development of MM involves a series of changes in the bone marrow microenvironment, favouring the growth of the tumour and failure of local immune control. Quantitative and functional alterations in CD4 and CD8 T cells have been described in MM, and cellular immune defects in MM have been shown to negatively correlate with survival (Pratt et al, 2007). A significant impairment of T-cell function has been also described for patients with MGUS (Prabhala et al, 2006). Cytokines and their receptors play essential roles in the development, maintenance and proper functioning of the immune system. In MM, these interactions may have tumour-promoting consequences (J€ ohrer et al, 2012). IL-33 is a recent addition to the ever-growing family of cytokines. To the best of our knowledge, this is the first study to demonstrate decreased concentrations of IL-33 in patients with MM, which might contribute to the changes in the immune system found in these patients. On the other