Pioneering studies of histone deacetylase inhibitors in myeloma: signals of activity set the stage for combination therapy trials

In this issue of the journal, Wolf and colleagues present a phase II clinical trial of the oral pan-histone deacetylase inhibitor (HDACi) panobinostat as a single-agent therapy in patients with relapsed/refractory myeloma [1]. This study was initiated as part of a suite of phase II clinical trials of panobinostat in hematological malignancies at a time when very little was known about the clinical spectrum of activity of the HDACi as a class. Indeed, it is now the third study reported of a single-agent HDACi in such a population of relapsed/refractory myeloma; all three studies have demonstrated modest single-agent clinical activity but insufficient efficacy to move single-agent HDACi further along the drug development pipeline [2,3]. Of note, this panobinostat study by Wolf and colleagues was in particularly heavily pre-treated patients and, unlike the other two studies using romidepsin and vorinostat, required that patients must have been treated with bortezomib and lenalidomide and be refractory (progressed on, or within 60 days) to their most recent anti-myeloma therapy. Despite these very stringent criteria, they report two patients who achieved deep and prolonged responses. Pharmacokinetics and toxicity profile were consistent with previously described reports, the most common toxicities being gastrointestinal, fatigue and reversible thrombocytopenia, all manageable with appropriate dose-adjustment.

So how is HDACi drug development moving forward in the broader setting of lymphoid malignancies? Vorinostat and romidepsin are already approved in the United States for cutaneous T-cell non-Hodgkin lymphoma (NHL), with response rates (RRs) of approximately 25–35%. Romidepsin is also approved for peripheral T-cell NHL based on two large phase II studies (RRs of 34–38%) [4,5]. Vorinostat has recently demonstrated promising activity in low-grade B-cell NHL [6], and panobinostat is clearly active in Hodgkin lymphoma [7] with a 27% RR in heavily pre-treated patients. It is likely that further development will take place in these indications using combination therapy either with chemotherapy, monoclonal antibodies or biological agents.

Further development of the HDACi in the context of myeloma is somewhat more challenging, as the single-agent RRs are consistently less than 10% [1–3]. The most obvious partners, based on sound pre-clinical evidence, are the proteasome inhibitors such as bortezomib (refer to reviews [8,9]). Harrison and colleagues were the first to demonstrate that intravenous romidepsin, a class I HDACi, dexamethasone and bortezomib could be combined safely; this combination had a manageable safety profile but required a relatively lower dose of romidepsin (10 mg/m²) compared to its single-agent recommended dose (14 mg/m²). Moreover, the response rate and progression-free survival (PFS) were promising [10,11]. Nonetheless, a randomized study of this triplet compared to a bortezomib/dexamethasone control arm will be required to confirm clinically meaningful activity of romidepsin in myeloma. Indeed, a similar such comparison has recently been completed with vorinostat and bortezomib. This placebo controlled phase III study (Vantage 088), recently presented in preliminary form, involved over 600 heavily pre-treated patients and demonstrated a 25% relative risk reduction for progression in the vorinostat-containing arm [12]. Although the absolute improvement in PFS was only approximately 1 month, the study confirms that this class of drugs has activity in myeloma and deserves further development in myeloma – one would predict that the benefit is likely to be more impressive when used earlier in the course of the disease. With respect to panobinostat, a similar phase III study (Panorama 1) is under way based on the very promising phase II results [13,14]. One intriguing difference between the Vantage 088 and Panorama 1 studies is that the latter incorporates dexamethasone in both arms; this has the potential to enhance the pro-apoptotic effects of panobinostat. Indeed, it is somewhat surprising that the value of steroid combinations with HDACi has not really been explored, and it is a pity that Wolf and colleagues did not take the opportunity to address this issue in their early trial. Nonetheless, this group of investigators needs to be congratulated on their rigorous pioneering efforts in HDACi in myeloma – it should not be forgotten that they designed and commenced this study at a time when we had very little evidence about HDACi in myeloma. They should be very pleased to see how this class of drugs has come such a long way in such a short period of time.

Potential conflict of interest

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