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The Combination of Panobinostat and Melphalan for the Treatment of Patients with Multiple Myeloma
Maria Gkotzamanidou1, Evangelos Terpos2, Meletios A Dimopoulos2
1Oncology Department, 251 Hellenic Air-Force General Hospital, 155 61 Athens, Greece.
Abstract:
Histone deacetylase inhibitors show synergy with several genotoxic drugs. Herein, we investigated the biological impact of the combined treatment of panobinostat and melphalan in multiple myeloma (MM). DNA damage response (DDR) parameters and the expression of DDR-associated genes were analyzed in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from 26 newly diagnosed MM patients. PBMCs from 25 healthy controls (HC) were examined in parallel. Compared with the ex vivo melphalan-only treatment, combined treatment with panobinostat and melphalan significantly reduced the efficiency of nucleotide excision repair (NER) and double-strand-break repair (DSB/R), enhanced the accumulation of DNA lesions (monoadducts and DSBs), and increased the apoptosis rate only in patients’ BMPCs (all p < 0.001); marginal changes were observed in PBMCs from the same patients or HC. Accordingly, panobinostat pre-treatment decreased the expression levels of critical NER (DDB2, XPC) and DSB/R (MRE11A, PRKDC/DNAPKc, RAD50, XRCC6/Ku70) genes only in patients’ BMPCs; no significant changes were observed in PBMCs from patients or HC. Together, our findings demonstrate that panobinostat significantly increased the melphalan sensitivity of malignant BMPCs without increasing the melphalan sensitivity of PBMCs from the same patients, thus paving the way for combination therapies in MM with improved anti-myeloma efficacy and lower side effects.
Insights
Panobinostat enhances melphalan
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase inhibitors like panobinostat can synergize with genotoxic drugs.
- Multiple myeloma (MM) is a cancer of plasma cells.
Purpose of the Study:
- To investigate the combined effect of panobinostat and melphalan on multiple myeloma cells.
- To assess the impact on DNA damage response (DDR) and gene expression.
Main Methods:
- Analysis of DDR parameters and gene expression in bone marrow plasma cells (BMPCs) and peripheral blood mononuclear cells (PBMCs) from MM patients and healthy controls.
- Ex vivo treatment with melphalan alone and in combination with panobinostat.
Main Results:
- Combined treatment significantly reduced DNA repair efficiency (NER and DSB/R) and increased DNA lesions and apoptosis in MM patients' BMPCs.
- Panobinostat pre-treatment decreased expression of key DDR genes (DDB2, XPC, MRE11A, PRKDC, RAD50, XRCC6) in patients' BMPCs.
- These effects were specific to malignant BMPCs, with minimal changes in PBMCs from patients or healthy controls.
Conclusions:
- Panobinostat increases melphalan sensitivity specifically in malignant multiple myeloma cells.
- This targeted effect suggests a potential for combination therapy with improved efficacy and reduced side effects.
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