Panobinostat to revert bortezomib resistance

In this issue of Blood, Richardson et al present convincing results demonstrating that panobinostat, an oral pan-deacetylase inhibitor, in combination with bortezomib and dexamethasone, can recapture responses in bortezomib-refractory multiple myeloma (MM).¹ 

Providing proof of concept is important to drive progress in any discipline and, as hematologists, we are excited to see evidence for new advances in treatments, particularly for challenging diseases. For example, the superiority of pomalidomide over lenalidomide was recently demonstrated for patients with relapsed MM when Lacy et al reported a partial response rate of 32% and an overall response rate of 47% (including 15% minimal responses) with pomalidomide in lenalidomide-refractory patients.² 

In the phase 2 trial that Richardson et al report, 55 patients with relapsed MM who were bortezomib-refractory were treated with a triple combination consisting of bortezomib, low-dose dexamethasone, and oral panobinostat 20 mg 3 times per week, for 2 weeks on and 1 week off. Notably, the partial response rate was 26% in patients with refractory disease who had received bortezomib (plus dexamethasone in the majority of cases) as the last line of therapy before study entry, and half of the patients achieved at least minimal response to the triple combination.

Why is this phase 2 (Panorama 2) study important? First, the results confirm preclinical evidence for a role of histone deacetylase (HDAC) inhibitors in MM. In vitro data indicated that the combination of proteasome and HDAC inhibition produces synergistic antitumor activity.³  The current trial clearly demonstrates in vivo that panobinostat is able to revert bortezomib resistance and that new responses can be induced in refractory patients. Of note, in the single-agent setting, panobinostat had shown only modest clinical activity.⁴  Nevertheless, we must be cautious when assessing and interpreting the current data because higher response rates do not always translate into improved outcome in terms of progression-free survival. Indeed, although vorinostat, another pan-deacetylase inhibitor, was able to revert bortezomib resistance in refractory patients treated in the phase 2 Vantage 095 trial,⁵  the results of a subsequent phase 3 trial were disappointing. Despite an improved response rate with bortezomib plus vorinostat compared with bortezomib alone in the randomized, double-blind phase 3 Vantage 088 trial (54% vs 41%, P < .0001), the benefit of progression-free survival was only marginal (7.6 vs 6.8 months), and there was no difference in overall survival.⁶ 

The Panorama 2 study reported by Richardson et al is the basis for the randomized phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in patients with relapsed MM (Panorama 1 trial). This pivotal study designed to gain regulatory approval for panobinostat in myeloma is now completed, and the results are eagerly awaited.

The report of the Panorama 2 study also allows for a discussion on the role of HDACs and HDAC inhibitors in MM. HDACs are enzymes specialized in the removal of acetyl groups and are therefore critically involved in the regulation of the transcription of various genes, particularly those involved in the control of the cell cycle. Importantly, they are known to regulate the activity of tumor-suppressor genes and oncogenes. HDACs are overexpressed in MM and may favor tumor progression by modifying gene transcription, cellular differentiation, cell cycle progression, or apoptosis.^3,7,8  Four classes of HDACs have been described: class I (HDAC1, 2, 3, 8), class IIA (HDAC4, 5, 7, 9), class IIb (HDAC6, 10), class III (SIRT1-7), and class IV (HDAC11).^3,7,8  The main HDAC inhibitors currently in clinical development in MM, including panobinostat and vorinostat, are nonselective, targeting classes I, II, and IV HDACs. This broad spectrum of inhibition is associated with significant toxicity and side effects, especially fatigue, gastrointestinal symptoms, and thrombocytopenia, as described in the current report of panobinostat by Richardson et al,²  as well as what was observed in the Vantage 095 trial with vorinostat. The reduction of such toxicity that can substantially limit the prolonged exposure to these agents might be achieved in the near future by a more selective inhibition of HDACs, as was recently reported with isoform selective HDAC6⁹  or HDAC3¹⁰  inhibitors.

Despite much progress in the treatment of MM, new classes of agents are still needed to improve the outcome of this incurable disease. HDAC inhibitors are not approved for MM, and panobinostat may be the first in class available in combination with bortezomib and low-dose dexamethasone in the relapse setting, after reviewing the results of the Panorama 1 and 2 studies. More selective inhibition of HDACs appears to be promising, and new drugs specifically targeting HDAC3 and HDAC6 are currently in development.