A same-day assay predicts apoptotic response to combined BCL-2 and MCL-1 BH3-mimetic targeting in multiple myeloma...

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Multiple myeloma (MM) survival is improving with new treatments, but predicting response to novel agents remains challenging.
• Anti-apoptotic proteins B-cell lymphoma-2 (BCL-2) and myeloid cell leukaemia-1 (MCL-1) are crucial for MM cell survival.
• Dual targeting of BCL-2 and MCL-1 with BH3-mimetics like venetoclax and S63845 shows synergistic potential in MM.

Purpose of the Study:

• To develop and validate a rapid, short-term flow cytometric assay to predict patient response to dual BH3-mimetic therapy in multiple myeloma.
• To assess the predictive capability of a novel cytochrome c release assay for combination therapy sensitivity.

Main Methods:

• Six human myeloma cell lines (HMCL) and seven primary patient samples were treated with venetoclax and S63845, alone and in combination.
• A 4-hour flow cytometric assay measuring cytochrome c release was employed.
• Results were correlated with 48-hour Annexin-V apoptosis data.

Main Results:

• The 4-hour assay demonstrated synergistic effects of the venetoclax and S63845 combination in all tested HMCL.
• The assay results correlated with longer-term Annexin-V data, validating its predictive power for drug sensitivity.
• All primary MM samples, including those with high-risk genetic features (1q gain, t(4;14)), responded to the combination therapy.
• Normal stem cells remained unaffected by the dual BH3-mimetic treatment.

Conclusions:

• A novel, rapid 4-hour flow cytometric assay accurately predicts response to dual BCL-2/MCL-1 inhibition in multiple myeloma.
• This assay has the potential to guide personalized treatment selection for MM patients.
• The combination of venetoclax and S63845 is effective and safe in primary MM cells, including high-risk cases.