High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone

Abstract

SummaryCereblon (CRBN) has recently been identified as a target for immunomodulatory drugs (IMiDs) and its downregulation has been linked to resistance to lenalidomide. Here, we studied CRBN expression by real time polymerase chain reaction in 49 bone marrow samples of newly diagnosed patients with multiple myeloma treated with lenalidomide and dexamethasone. Median CRBN expression was 3Á45 in patients who achieved complete response, and 3Á75, 2Á01, 0Á78, and 0Á70 in those with very good partial response, partial response, stable disease and progressive disease respectively. CRBN expression levels correlated significantly with response to lenalidomide treatment (r = 0Á48; P < 0Á001). Among established prognostic parameters, only beta-2-microglobulin correlated with cereblon (r = 0Á66; P < 0Á001). A close association of CRBN with interferon regulatory factor 4 (IRF4) (P < 0Á001) and with CTNNB1 (P < 0Á001) was found. Overall, a statistically significant association between baseline CRBN expression and response in MM patients treated with lenalidomide is shown. CRBN expression is closely associated with IRF4, which is an important target of IMiD therapy.

Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma

“…9 Recent clinical correlative studies have observed a positive association between CRBN and response to thalidomide maintenance and up-front lenalidomide and dexamethasone therapy. 11,12 Furthermore, we have observed CRBN and IRF4 mutations in drug-refractory patients, supporting the key role of CRBN in the response to IMiDs. 13,14 Finally, we have reported that CRBN expression is highly predictive of response and survival outcomes after pomalidomide therapy.…”

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

“…Although a role of mutant IRF4 in IMiD resistance remains to be established, CRBN is the central mediator of IMiD action, and its expression is essential for the anti-MM effects of IMiDs. [12][13][14][15][16] Notably, all CRBN-mutated patients (n 5 6) and 10 (91%) of 11 of the CRBN pathway-mutated patients were unresponsive to IMiD-based treatment at the time of tumor sampling (the IMiD-refractory status of 1 patient was unknown) suggesting an association of these mutations with IMiD response. Thus far, CRBN mutations are largely absent in the publically available MM sequencing data that, of note, include mostly untreated patients.…”

“…Cereblon (CRBN) was recently identified as being essential for the anti-MM activity of IMiDs. [11][12][13][14][15][16][17][18] To date, the reported incidence of mutations in proteasome subunits, the CRBN pathway, or the steroid receptor is low, and mutations in these genes, except in single case studies 19,20 or in vitro cell line analyses, 20,21 have not yet been identified as a major source of primary or acquired drug resistance in larger MM data sets.…”

A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma

“…17 In addition, the Ikaros and Aiolos transcription factors have recently been identified as substrates of CRBN 18,19 and may be proximal biomarkers for its clinical activity. Analysis of protein expression indicates that the clinical response to FRD therapy is independent of CRBN and IMIDs-related markers Ikaros and Aiolos, suggesting that panobinostat has an independent contribution to duration of response to FRD.…”