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HDAC Inhibitors in Multiple Myeloma

Panelists:
Published: Thursday, Sep 24, 2015

 
Panobinostat is an orally available histone deacetylase (HDAC) inhibitor that was approved the FDA based on results from the PANORAMA-1 study, which showed that panobinostat in combination with the proteasome inhibitor, bortezomib, improved progression-free survival compared with placebo plus bortezomib in pretreated patients with multiple myeloma. 

A predefined subgroup analysis of PANORAMA-1 among patients with multiple myeloma who had received prior bortezomib in addition to an immunomodulatory drug (IMiD)—either lenalidomide or thalidomide—showed an overall response rate of 58.4% with panobinostat compared with 41.4% for the control, states Morie A. Gertz, MD. A separate analysis that evaluated the depth of response in the trial showed that patients with complete or near-complete responses had a progression-free survival of 16.5 months.

Combination therapy with bortezomib and panobinostat resulted in high incidences of diarrhea and fatigue in PANORAMA-1. These toxicities impact quality of life and pose a challenge to widespread implementation, comments Gertz. Exploratory trials are evaluating the combination of panobinostat with lenalidomide, or panobinostat with carfilzomib, another proteasome inhibitor. Neither regimen has reported significant gastrointestinal toxicity or fatigue, adds Gertz.

Bortezomib was administered intravenously twice weekly in PANORAMA-1. Today, it is commonly administered subcutaneously on a weekly basis, says Jatin J. Shah, MD. Changing the dosing schedule likely improved the tolerability, comments Shah.

Future studies should be evaluating HDAC inhibitors in combination with other drug classes, states Noopur Suresh Raje, MD. Rocilinostat is a more selective HDAC inhibitor that has been studied in combination with proteasome inhibitors and IMiDs. Epigenetic inhibitors may partner better with IMiDs, says Raje.
 
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Panobinostat is an orally available histone deacetylase (HDAC) inhibitor that was approved the FDA based on results from the PANORAMA-1 study, which showed that panobinostat in combination with the proteasome inhibitor, bortezomib, improved progression-free survival compared with placebo plus bortezomib in pretreated patients with multiple myeloma. 

A predefined subgroup analysis of PANORAMA-1 among patients with multiple myeloma who had received prior bortezomib in addition to an immunomodulatory drug (IMiD)—either lenalidomide or thalidomide—showed an overall response rate of 58.4% with panobinostat compared with 41.4% for the control, states Morie A. Gertz, MD. A separate analysis that evaluated the depth of response in the trial showed that patients with complete or near-complete responses had a progression-free survival of 16.5 months.

Combination therapy with bortezomib and panobinostat resulted in high incidences of diarrhea and fatigue in PANORAMA-1. These toxicities impact quality of life and pose a challenge to widespread implementation, comments Gertz. Exploratory trials are evaluating the combination of panobinostat with lenalidomide, or panobinostat with carfilzomib, another proteasome inhibitor. Neither regimen has reported significant gastrointestinal toxicity or fatigue, adds Gertz.

Bortezomib was administered intravenously twice weekly in PANORAMA-1. Today, it is commonly administered subcutaneously on a weekly basis, says Jatin J. Shah, MD. Changing the dosing schedule likely improved the tolerability, comments Shah.

Future studies should be evaluating HDAC inhibitors in combination with other drug classes, states Noopur Suresh Raje, MD. Rocilinostat is a more selective HDAC inhibitor that has been studied in combination with proteasome inhibitors and IMiDs. Epigenetic inhibitors may partner better with IMiDs, says Raje.
 
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