Chidamide and venetoclax synergistically exert cytotoxicity on multiple myeloma by upregulating BIM expression

Area of Science:

• Hematologic Malignancies
• Cancer Therapeutics
• Pharmacology

Background:

• Multiple myeloma (MM) is a common hematologic malignancy with high relapse rates.
• Relapsed or refractory multiple myeloma (RRMM) necessitates novel therapeutic strategies.
• Chidamide (HDAC inhibitor) and venetoclax (BCL2 inhibitor) are promising agents for RRMM.

Purpose of the Study:

• To investigate the synergistic anti-myeloma effect of chidamide and venetoclax.
• To explore the underlying mechanisms of the combination therapy.
• To evaluate the therapeutic potential of this combination for RRMM.

Main Methods:

• In vitro studies using human myeloma cell lines (HMCLs).
• Assessment in primary MM cells and MM xenograft mouse models.
• Analysis of cell cycle, DNA damage, and protein expression (BCL-XL, BIM).

Main Results:

• Chidamide and venetoclax demonstrated synergistic anti-myeloma activity (CI < 1) in vitro and in vivo.
• The combination induced G0/G1 cell cycle arrest and increased DNA double-strand breaks.
• Synergy was linked to BCL-XL downregulation and BIM upregulation, with BIM playing a critical role.

Conclusions:

• The combination of chidamide and venetoclax exhibits significant therapeutic potential for multiple myeloma.
• This combination represents a potent alternative salvage therapy for RRMM.
• Further clinical investigation is warranted to validate these findings in RRMM patients.