# Therapeutic Potential of Venetoclax and Selinexor in Targeting Hypoxia‐Induced Vulnerabilities in Multiple Myeloma

## TL;DR

This study explores how combining venetoclax and selinexor can target hypoxia-related weaknesses in multiple myeloma cells, improving treatment effectiveness.

## Contribution

The study identifies a novel therapeutic synergy between venetoclax and selinexor under hypoxic conditions in multiple myeloma.

## Key findings

- Venetoclax showed increased cytotoxicity and caspase activity under hypoxia.
- Selinexor reduced cell viability and increased apoptosis in MM cells.
- The combination therapy overcame resistance in bortezomib-resistant MM cells and worked in PCL samples.

## Abstract

Multiple myeloma (MM) is a blood cancer marked by the abnormal clonal growth of plasma cells. Hypoxia plays a critical role in the progression and treatment resistance of MM.

This study investigates the expression of B‐cell/CLL lymphoma 2 (BCL2) family genes. We also investigated the activity of BCL2 and exportin‐1 (XPO1) inhibitors and the potential therapeutic synergy of venetoclax and selinexor under hypoxic conditions.

Analysis of publicly available datasets revealed hypoxia‐induced upregulation of
BCL2
and
BCL2‐like 11 (
BCL2L11), while
BCL2‐associated agonist of cell death (BAD) expression was suppressed. Venetoclax, a selective BCL2 inhibitor, demonstrated enhanced cytotoxicity and increased caspase‐3/7 activity under hypoxic conditions. Selinexor exhibited potent anti‐myeloma effects, including dose‐dependent reductions in cell viability and increased apoptotic activity. Combining selinexor with venetoclax under hypoxia produced anti‐myeloma effects, significantly reducing cell viability, increasing apoptosis, and disrupting the mitochondrial membrane potential. This combination effectively overcame resistance in bortezomib‐resistant MM cells and demonstrated efficacy in primary plasma cell leukemia (PCL) samples.

These findings highlight the potential of selinexor and venetoclax combination therapy to exploit hypoxia‐induced vulnerabilities in MM cells.