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Mechanism of immunomodulatory drug resistance and novel therapeutic strategies in multiple myeloma.

OBJECTIVE
The mechanism of immunomodulatory drugs (IMiDs) resistance to multiple myeloma (MM) cells has been gradually demonstrated by recently studies, and some potential novel strategies have been confirmed to have antimyeloma activity and be associated with IMiD activity in MM.


METHODS
This article searched the Pubmed library, reviewed some recently studies related to IMiD resistance to MM cells and summarized some potent agents to improve IMiD resistance to MM cells.


RESULTS
Studies have confirmed that cereblon is a primary direct protein target of IMiDs. IRF4 not only is affected by the IKZF protein but also can directly inhibit the expression of BMF and BIM, thereby promoting the survival of MM cells. Additionally, the expression of IRF4 and MYC also plays an important role in three important signaling pathways (Wnt, STAT3 and MAPK/ERK) related to IMiD resistance. Notably, MYC, a downstream factor of IRF4, may be upregulated by BRD4, and upregulation of MYC promotes cell proliferation in MM and disease progression. Recently, some novel therapeutic agents targeting BRD4, a histone modification-related 'reader' of epigenetic marks, or other important factors (e.g. TAK1) in relevant signaling pathways have been developed and they may provide new options for relapse/refractory MM therapy, such as BET inhibitors, CBP/EP300 inhibitors, dual-target BET-CBP/EP300 inhibitors, TAK1 inhibitors, and they may provide new options for relapsed/refractory MM therapy.


CONCLUSIONS
Accumulated studies have revealed that some key factors associated with the mechanism of IMiD resistance to MM cells. Some agents represent promising new therapeutics of MM to regulate the IRF4/MYC axis by inhibiting BRD4 expression or signaling pathway activation.