Association Of Cereblon Gene Expression With Lenalidomide Efficacy In Treating POEMS Syndrome

Background and Objectives:POEMS syndrome is a plasma cell disorder with a risk of disease relapse or progression. The pathogenesis of POEMS syndrome is not well understood. Recently, lenalidomide has emerged as a therapeutic option and shown promising roles in treating POEMS syndrome. However, there were still a number of patients who failed to respond to lenalidomide therapy. Studies in multiple myeloma have confirmed cereblon as the direct target of lenalidomide, and high cereblon expression was associated with better response to lenalidomide therapy. IKZF1 and IKZF3, as direct substrates of cereblon, were also essential in lenalidomide therapy. However, no statistical difference in cereblon expression was observed between responders and nonresponders in the study of low/int-1 MDS patients without del (5q), which indicated that lenalidomide may target other molecules. Currently, there’s no research focusing on the association between cereblon expression and lenalidomide efficacy in treating POEMS syndrome. This study aimed to correlate cereblon, IKZF1, IKZF3 expression levels with response to lenalidomide-based treatment in newly diagnosed POEMS syndrome patients, and to analyze the association of cereblon, IKZF1, IKZF3 with prognostic parameters.Methods:Newly diagnosed POEMS syndrome patients from clinical trial (a single center, prospective, open-label phase II study to determine the efficacy and safety of lenalidomide plus dexamethasone in patients with newly diagnosed POEMS syndrome) were followed up in this study and baseline information, clinical data were recorded to evaluate the efficacy and safety of lenalidomide therapy in POEMS syndrome patients. Analysis of prognosis was also made.We collected bone marrow and biopsy samples from newly diagnosed POEMS syndrome patients in Peking Union Medical College Hospital from March,2014, to April, 2015. For each bone marrow samples, CD138 positive cells were sorted using monoclonal antibody (anti-CD 138)-tagged magnetic microbeads, and real-time polymerase chain reaction was performed to detect cereblon, IKZF1, IKZF3 mRNA expression levels. Immunohistochemical staining on paraffin-embedded bone marrow sections were used to assess the expression of CRBN, IKZF1, and IKZF3 protein levels. Both cereblon, IKZFl, IKZF3 mRNA and protein levels were compared between lenalidomide responders and nonresponders.Results:Forty-one newly diagnosed POEMS syndrome patients were included in our clinical trial and median Overall Neuropathy Limitation Scale (ONLS) score was 4 (1-10). All patients received lenalidomide plus dexamethasone regimen and median follow-up time was 10 months (2-14 months). Total response rate of hematologic, neurologic, serum VEGF and water overload were 70%,90.2%,77.5%,100%, respectively. No drug related death was observed in this study. Only one patient present with grade 3 rash. Two patients (4.9%) died from disease progression and one patient (2.5%) transferred to autologous stem cell transplantation when disease progression was noticed. One-year progression free survival (PFS) and overall survival (OS) were 92.7% and 95.1%, respectively. In response group, one-year PFS was much higher than non-response group (p= 0.0006), and one-year OS in responders and non-responders were 100% and 73%, respectively (p= 0.0055).We further found that mean cereblon mRNA expression level in bone marrow plasma cells in POEMS syndrome patients were 2.51%and 0.44%, respectively in response and non-response group (p= 0.005). While IKZF1 mRNA level were 1.51% and 0.18%in two groups (p= 0.002) and IKZF3 mRNA expression were 2.07%and 0.51%, respectively (p = 0.076). While in protein expression level, a statistical difference was only found between CRBN expression and lenalidomide efficacy (p= 0.029). Moreover, in our study, we revealed that higher IKZF1 gene levels were associated with longer PFS in POEMS syndrome patients treated with lenalidomide (p-0.02).Conclusions:Lenalidomide has shown promising roles in the treatment of newly diagnosed POEMS syndrome patients. However, individual difference still exists. Our study has revealed that higher cereblon, IKZF1 gene expression in bone marrow plasma cells were associated with better response to lenalidomide therapy. Moreover, higher IKZF1 mRNA expression in plasma cells were closely related to better prognosis of POEMS syndrome patients.