Histone deacetylase (HDAC) inhibitors are among the emerging classes of drugs for the treatment of multiple myeloma. Value-Based Care in Myeloma (VBCM) asked Paul G. Richardson, MD, Director, Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer Center, and Associate Professor of Medicine, Harvard Medical School, who has led clinical studies with some of these agents, to describe where the research in this area is heading.
VBCM: Why are HDAC inhibitors of interest in multiple myeloma?
Dr Richardson: Gene expression and epigenetic changes, such as acetylation of histone or nonhistone proteins, are recognized as important factors in cancer development. Aggresome upregulation is a mechanism by which myeloma cells can bypass the antimyeloma effect of proteasome inhibition. When the proteasome pathway is blocked by drugs such as bortezomib, HDAC inhibitors can potentially inhibit the aggresome pathway that is compensating for this.
Therefore, when we combine an HDAC inhibitor with a proteasome inhibitor such as bortezomib, this produces a very potent and toxic proapoptotic signal for tumor cells, at least in the laboratory. This is why we are so interested in combining HDAC inhibitors with proteasome inhibitors as a treatment strategy.
VBCM: Vorinostat and panobinostat are being studied for the treatment of myeloma. How are these drugs different?
Dr Richardson: Vorinostat and panobinostat are in the same drug class, but they have important pharmacokinetic differences and different tolerability profiles. Vorinostat is dosed daily, whereas panobinostat is dosed more intermittently. They are both pan inhibitors, at least in theory, but panobinostat appears to be more potent at targeting HDAC-6, which is a particularly important target.
Another drug is romidepsin, which is used in cutaneous T-cell lymphoma and is approved by the US Food and Drug Administration for this indication. Romidepsin hits different HDACs and appears very promising in preclinical studies of myeloma in the laboratory and in an early, dose-finding trial of patients with advanced myeloma. Specifically, in a recent study of 25 patients with relapsed and refractory myeloma, romidepsin, in combination with bortezomib, produced a 72% response rate, including complete remissions in 8% of patients (Harrison SJ, et al. Blood. 2011;118:6274-6283).
VBCM: How well do these agents partner with other important antimyeloma drugs?
Dr Richardson: Panobinostat and bortezomib partner well together. Conversely, vorinostat and lenalidomide partner well together. Vorinostat and bortezomib can also be combined; however, in phase 3 trials, the benefit of this combination was not as impressive as we had hoped, perhaps because of schedule and dosing issues.
In VANTAGE 088, patients receiving the combination had a median progression-free survival of 7.6 months versus 6.8 months with placebo for an overall difference of <1 month (Dimopoulos MA, et al. Blood. 2011;18:Abstract 811). This was a statistically significant difference, but it was not as clinically meaningful as one would have expected. The intense dosing led to higher response rates (56% vs 41%, respectively), but toxicity was excessive. Therefore, dose and schedule changes may improve the ability to tolerate this drug combination, which is why many of us feel that vorinostat still has considerable promise for the treatment of myeloma. The issue is that the dose and schedule will need careful thought; for example, the combination of lenalidomide and vorinostat (with the latter given 1 week on and 1 week off, and lenalidomide with dexamethasone given according to the classic schedule) has been especially successful. However, at present the overall direction of vorinostat in myeloma is still unclear.
VBCM: Are the outcomes more encouraging with panobinostat?
Dr Richardson: It seems that some of the problems facing the VANTAGE trials have not been seen in the panobinostat trials. The dose and schedule of panobinostat, in combination with bortezomib, was carefully developed as part of a phase 1 program led by Jésus F. San Miguel, MD, PhD. In the phase 2 PANORAMA 2 study, we gave oral panobinostat 20 mg on days 1, 3, and 5 for 2 weeks, with 1 week off, for the first 8 cycles (Richardson PG, et al. Blood. 2011;118:Abstract 814). Responders could continue to receive the drug for another 6 weeks.
The reality seems to be that this particular schedule, with intermittent dosing, is proved more feasible. We do see thrombocytopenia, but with dose reduction it is manageable. Moreover, for a study in patients with relapsed/refractory myeloma, a 49% clinical benefit rate is impressive. I say this carefully, but I am hopeful that the panobinostat trials will be successful.