# Anti-myeloma activity of the CXCR4 antagonist WZ811

## TL;DR

WZ811, a CXCR4 antagonist, shows anti-myeloma activity by reducing tumor viability and improving survival in preclinical models.

## Contribution

Demonstrates WZ811's efficacy against myeloma cells and its synergistic effects with existing anti-myeloma drugs.

## Key findings

- WZ811 reduced viability of myeloma primary cells and cell lines.
- WZ811 improved survival in a xenograft model and induced apoptotic and autophagic cell death.
- WZ811 synergized with doxorubicin, dexamethasone, bortezomib, lenalidomide, and pomalidomide.

## Abstract

The CXCR4-CXCL12 axis is crucial for the interaction between malignant plasma cells (PC) and their microenvironment in multiple myeloma (MM). Here, we show that CXCR4 expression is upregulated in MM cell lines and PCs during both premalignant and active stages of MM, compared to normal PCs from healthy donors. The CXCR4 antagonist WZ811 reduced the viability of MM PCs and cell lines, while tumor microenvironment cells from both MM patients and healthy donors exhibited significant resistance. In vivo, WZ811 significantly reduced tumor burden and improved survival. WZ811-mediated MM cell death involved disruption of mitochondrial transmembrane potential, externalization of transmembrane phosphatidylserine, activation of caspases, increased levels of autophagic proteins, and an increase in G0/G1 phase of the cell cycle. WZ811 also eliminated the MM stem cell-like side population, though slight resistance was observed with stromal cells. Additionally, WZ811 increased levels of CXCL12 and extracellular matrix molecules collagen IV and laminin in MM cells. Combining WZ811 with anti-MM agents showed synergism with doxorubicin, dexamethasone, bortezomib, lenalidomide, and pomalidomide, while antagonism was observed with carfilzomib, supporting the clinical assessment of WZ811 in MM.

WZ811 reduced the viability of myeloma primary cells and cell lines.WZ811 reduced tumor burden and improved survival in vivo xenograft model.WZ811 mechanisms involved apoptotic and autophagic cell death.WZ811 eliminated the MM stem cell-like side population.WZ811 synergized with DOX, DEX, BTZ, LEN, and POM.

WZ811 reduced the viability of myeloma primary cells and cell lines.

WZ811 reduced tumor burden and improved survival in vivo xenograft model.

WZ811 mechanisms involved apoptotic and autophagic cell death.

WZ811 eliminated the MM stem cell-like side population.

WZ811 synergized with DOX, DEX, BTZ, LEN, and POM.

The online version contains supplementary material available at 10.1007/s00109-026-02650-4.