The use of histone deacetylase (HDAC) inhibitors as human cancer therapy has focused on the impact of these agents on epigenetic regulation and gene transcription. However, the use of HDAC inhibitors in myeloma may be working through a different mechanism. Specifically, HDAC6 is known to regulate the aggresome/autophagy pathway, a secondary pathway for protein catabolism. When the proteasome is inhibited, the aggresome pathway becomes an accessory pathway through which protein homeostasis is maintained intracellularly.1,2
Early Trials
This concept of HDAC/proteasome inhibitor was first tested in earnest with the combination of vorinostat (Zolinza) and bortezomib (Velcade); the combination demonstrated efficacy,3 but at the doses and schedule used in the larger phase II and phase III clinical trials, the regimen was simply not tolerated well enough to support long-term use among a majority of patients. The studies did, however, provide proof of principle that the combination was able to overcome bortezomib resistance, and at certain doses, could be tolerated.
The use of panobinostat in a similar set of trials4,5 was based on early data again suggesting the potential to overcome bortezomib resistance.6 In the PANORAMA 2 trial,7 patients with known bortezomib-resistant myeloma were treated with the combination of panobinostat and bortezomib. Overall, the trial demonstrated that 30% of patients responded to the novel combination.
This encouraging early data gave rise to the phase III PANORAMA 1 trial, reported by San-Miguel and colleagues and reviewed in this issue of The ASCO Post.8 This trial is evaluating the benefit of adding panobinostat to bortezomib/dexamethasone vs bortezomib/dexamethasone alone. The primary endpoint of the study was met, with an improvement in progression-free survival from 8 months with bortezomib/dexamethasone to 12 months with panobinostat plus bortezomib/dexamethasone.
Overall survival data were not mature at the time of reporting. The difference in progression-free survival was, interestingly, not associated with an improvement in overall response rate, though the quality of response was better among those who received panobinostat. While the combination clearly demonstrated benefit, a significant fraction of patients were not able to continue on study due to the development of adverse events.
Interpreting PANORAMA Findings
So what are the challenges with interpretation of this study, and how do we as clinicians use the information to provide better care for our patients? The clinical benefit of the treatment is clear, with a significant improvement in progression-free survival. But what about the adverse events that were encountered by patients that limited the duration of therapy?
First, it should be recalled that at the time of study initiation, the routine use of subcutaneous administration of bortezomib had not yet become the standard. Thus, toxicity of the regimen overall may in part be related to the use of intravenous rather than subcutaneous bortezomib.
Second, the most common adverse events that occurred on study were gastrointestinal events (nausea and diarrhea) as well as fatigue. Gastrointestinal toxicity is likely in part due to the overlap with intravenous bortezomib but also directly related to panobinostat itself. Management requires some experience with the drug and may include modification of dose and schedule and use of antiemetics. Fatigue can often be reversed through the use of concomitant steroids or stimulants.
In terms of hematologic toxicity, there was a higher incidence of grade 4 thrombocytopenia seen with the combination, but given that thrombocytopenia is a common adverse event for both agents, this is not a surprise. In an in vivo murine model of thrombocytopenia, it was demonstrated that while the nadir of platelets was lower when panobinostat was combined with bortezomib, the time to platelet recovery (back to baseline) was the same as when either agent was given alone.9 Thus, patients may need support for hematologic toxicity during the initial therapy, but such toxicity should not be a reason to limit delivery of therapy.
Patient Selection
The question remains: Which patients are best suited for this treatment approach? From the outset, it is clear from the data that patients with high-risk myeloma and those who appear to be less sensitive to bortezomib should likely receive the combination. From the subset analyses, it was apparent that patients from these groups gained benefit vs those who received bortezomib/dexamethasone alone.
The larger question revolves around the patients with early relapse in general. Do we know that triplets are better than doublets in this setting? This has been nicely demonstrated among newly diagnosed myeloma patients, where there is near global consensus that a three-drug induction is superior to two-drug induction, and there are now hints that the same may apply to patients with early relapse (after one to three prior lines of therapy, the same population that was studied in the current study).
This concept began to take hold several years ago, when the MMVAR/IFM 2005-04 trial showed a significant improvement in progression-free survival and a trend toward improved overall survival with bortezomib/thalidomide (Thalomid)/dexamethasone vs thalidomide/dexamethasone.10 The ASPIRE trial comparing carfilzomib (Kyprolis)/lenalidomide (Revlimid)/dexamethasone vs lenalidomide/dexamethasone also suggests a similar benefit of triple-drug salvage, and now we have the PANORAMA 1 findings continuing the trend of three drugs being superior to two in the early relapse setting.
I suspect that in order to make the leap to three drugs being better than two in the relapsed disease setting, we will likely need to see an impact on overall survival. Nevertheless, the question is an interesting one, especially as we begin to delve into the importance of minimal residual disease and its impact on duration and durability of response.11-13 While attention to this issue has been focused on newly diagnosed myeloma, the issue is also likely to be relevant in the early relapse setting.
HDAC inhibitors would be a welcome addition to our treatment armamentarium—one that may be very helpful for those challenging patients with more aggressive myeloma. Careful attention to symptom management and supportive care will help to increase the duration of HDAC inhibitor–containing therapy, which will ultimately allow more patients to gain benefit from the new treatment. ■
Disclosure: Dr. Lonial reported no potential conflicts of interest.
References
1. McConkey DJ, White M, Yan W: HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer. Adv Cancer Res 116:131-163, 2012.
2. Simms-Waldrip T, Rodriguez-Gonzalez A, Lin T, et al: The aggresome pathway as a target for therapy in hematologic malignancies. Mol Genet Metab 94:283-286, 2008.
3. Dimopoulos M, Siegel DS, Lonial S, et al: Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study. Lancet Oncol 14:1129-1140, 2013.
4. Wolf JL, Siegel D, Goldschmidt H, et al: Phase II trial of the pan-deacetylase inhibitor panobinostat as a single agent in advanced relapsed/refractory multiple myeloma. Leuk Lymphoma 53:1820-1823, 2012.
5. Hideshima T, Richardson PG, Anderson KC: Mechanism of action of proteasome inhibitors and deacetylase inhibitors and the biological basis of synergy in multiple myeloma. Mol Cancer Ther 10:2034-2042, 2011.
6. Neri P, Bahlis NJ, Lonial S: Panobinostat for the treatment of multiple myeloma. Expert Opin Investig Drugs 21:733-747, 2012.
7. Richardson PG, Schlossman RL, Alsina M, et al: PANORAMA 2: Panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 122:2331-2337, 2013.
8. San-Miguel JF, Hungria VT, Yoon SS, et al: Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: A multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 15:1195-1206, 2014.
9. Giver CR, Jaye DL, Waller EK, et al: Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia 25:362-365, 2011.
10. Garderet L, Iacobelli S, Moreau P, et al: Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: The MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol 30:2475-2482, 2012.
11. Galimberti S, Benedetti E, Morabito F, et al: Prognostic role of minimal residual disease in multiple myeloma patients after non-myeloablative allogeneic transplantation. Leuk Res 29:961-966, 2005.
12. Martinez-Sanchez P, Montejano L, Sarasquete ME, et al: Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: The prognostic impact of achieving molecular response. Br J Haematol 142:766-774, 2008.
13. Paiva B, Vidriales MB, Cervero J, et al: Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 112:4017-4023, 2008.
Dr. Lonial is Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta.
