Panobinostat: a review of trial results and future prospects in multiple myeloma

Abstract

Multiple myeloma is an incurable often devastating disease that is responsible for 1–2% of all cancers. Multiple myeloma is the second most common hematologic malignancy. Over the past two decades, advances in therapy have doubled life expectancy. Unfortunately, all patients ultimately relapse. Novel agents (immunomodulatory drugs and proteasome inhibitors) have changed the outlook for patients, but further breakthroughs are needed. Epigenetic treatments offer potential for advancing therapy by modifying oncogene responses. The acetylation status of various proteins can affect the availability of chromatin for transcription. This response may be modulated epigenetically to advantage using histone deacetylase inhibitors like panobinostat.

Keywords:

• epigenetics
• histone deacetylase inhibitors
• immunomodulatory drugs
• LBH589
• multiple myeloma
• panobinostat
• proteasome inhibitors

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Epigenetic changes in plasma cells can lead to a malignant phenotype. Manipulation of the epigenetic profile of multiple myeloma (MM) with histone deacetylases inhibitors can produce in vitro and in vivo inhibition of MM.

• Panobinostat (LBH589) is a pan-deacetylase (DAC) inhibitor with activity against histone deacetylases I, II and IV enzymes at nanomolar concentrations.

• The PANORAMA-1 trial, an international randomized, double-blind, Phase III study evaluating the PFS benefit of the addition of panobinostat versus placebo to bortezomib and dexamethasone in patients with relapsed and refractory MM demonstrated a clear benefit in PFS for relapsed and refractory MM patients. The combination of bortezomib, dexamethasone and panobinostat as compared with bortezomib and dexamethasone studied in PANORAMA-1 achieved its primary end point with a PFS of 1 year in the panobinostat arm and 8.1 months in the standard treatment arm (p < 0.0001; HR: 0.63; 95% CI: 0.52–0.76).

• The side-effect profile of panobinostat is acceptable but potentially limiting concerns are gastrointestinal toxicity and myelosuppression. A formulation of panobinostat with less gastrointestinal toxicity will be important when the drug is brought to the market.

Notes