B07 HIGH EXPRESSION OF NUCLEAR CEREBLON IS ASSOCIATED WITH LONGER SURVIVAL IN PATIENTS WITH MULTIPLE MYELOMA TREATED WITH IMIDS

Patients with multiple myeloma (MM) demonstrate variable outcomes with treatment. With increasing treatment options, predictive factors for response and outcome are relevant to inform treatment choices. Immunomodulating agents (IMiDs) represent the cornerstone of MM treatment and act through binding to Cereblon (CRBN), affecting downstream targets of this E3 ubiquitin ligase. We hypothesized differential expression of effector or target proteins from the CRBN pathway to predict outcome in patients treated with IMiDs. Bone marrow (BM) biopsies were obtained from 148 newly diagnosed, transplant non-eligible patients with MM. Per HOVON-87/NMSG-18 trial protocol, these patients were treated with thalidomide or lenalidomide combined with melphalan and prednisone followed by thalidomide/lenalidomide maintenance (i.e. MPT-T or MPR-R). Immunohistochemistry was performed for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets interferon regulatory factor 4 (IRF-4) and cellular myelocytomatosis oncogene (c-MYC). Patients with response of VGPR or better have higher nuclear CRBN expression compared to patients with PR or worse (≥VGPR: median CRBN H-score=185 (interquartile range (IQR), 147-211) vs ≤PR median CRBN H-score=159 (IQR 129-193); p=0.02). Higher nuclear CRBN expression was associated with a longer progression-free survival (PFS) and overall survival (OS). For PFS a hazard ratio (HR) of 0.53 was found (95% confidence interval (CI) =0.37-0.77; p<0.001); for OS: HR = 0.59 (95% CI=0.38-0.90; p=0.02). The association between CRBN and OS varied with IRF-4 levels. In patients with IRF-4 levels above the median, a hazard ratio of 0.22 was found (95% CI=0.10-0.49; p=0.0002); in contrast, patients with IRF-4 levels below the median, had a hazard ratio of 0.82 (95% CI=0.44-1.53; p=0.5). For Ikaros, Aiolos and c-MYC no correlation with survival was found, either alone or in combination with CRBN. In conclusion, higher expression of nuclear CRBN was associated with a superior PFS and OS upon MPT or MPR treatment. Levels of nuclear CRBN protein, possibly in combination with IRF-4, may represent a biomarker for predicting treatment outcome in patients treated with IMiDs.