Histone deacetylase (HDAC) inhibitors may become a promising component of the treatment of multiple myeloma, based their unique mechanism of action and cytotoxic synergy with other agents. Several studies presented at the 2014 American Society of Hematology meeting evaluated the safety and efficacy of panobinostat in combination with established agents.
At the meeting, Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston, discussed the use of HDAC inhibitors in myeloma during an educational session at the meeting. He pointed out that HDAC inhibitors have strong rationale for combining with the proteasome inhibitor bortezomib (Velcade). Simply put, the dual inhibition of the proteasome pathway plus the aggresome pathway of HDAC inhibitors ultimately leads to enhanced apoptosis, or killing, of the myeloma cell. The PANORAMA-2 trial, which Dr Richardson led, has shown this combination to be very efficacious in relapsed or refractory disease.
In PANORAMA-2, the median progression-free survival was 11.99 months with panobinostat plus bortezomib versus 8.08 months with bortezomib (P <.001), and the 2-year progression-free survival rates were 20.6% and 8.4%, respectively. Toxicity was generally manageable with supportive measures and dose reductions, he said.
Bortezomib, Lenalidomide, and Dexamethasone
“We have preclinical data demonstrating synergy, and these support the combination of panobinostat with both proteasome inhibitors and immunomodulatory drugs by affecting multiple protein metabolism pathways,” said Jatin J. Shah, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.
Dr Shah presented data for panobinostat in combination not only with bortezomib but also with the combination of bortezomib, lenalidomide (Revlimid), and dexamethasone (Decadron), a regimen known as RVD. The study in 31 newly diagnosed transplant-eligible patients was the first experience of panobinostat in combination with these 3 drugs.
“The combination was highly active, with high depth of response and rapid disease control after 4 cycles,” he said. The maximum tolerated doses were determined to be panobinostat 10 mg, lenalidomide 15 mg, and bortezomib 1 mg/m2.
Of the 22 patients who completed 4 cycles at the time of analysis, the overall response rate was 95%, of which 50% were complete responses or near-complete responses. This is much higher than the historic complete response rates of 10% to 20% for RVD alone, according to Dr Shah. The combination was “very well-tolerated,” with limited grade 3/4 toxicity; the rate of grade 3/4 diarrhea and constipation was 6%.
Panobinostat plus Carfilzomib
Jonathan Kaufman, MD, of Emory University, presented results from a multicenter, phase 1 clinical trial. In 28 heavily pretreated patients with relapsed or refractory myeloma, panobinostat was combined with the proteasome inhibitor carfilzomib (Kyprolis). The maximum tolerated dose was determined to be carfilzomib 36 mg/m2 and panobinostat 20 mg 3 times weekly for 3 of 4 weeks.
The overall response rate was 46%, and 4% of patients achieved complete responses, Dr Kaufman reported. Of note, 44% of patients with disease refractory to previous treatment with bortezomib also responded, indicating that this more difficult group may respond to this combination as well as other patients. The study confirmed that patients could tolerate this dose of panobinostat for 3 of 4 weeks. The relative dose intensities were 98% for carfilzomib and 93% for panobinostat, he added.
“We are very happy to note that at the maximum tolerated dose, patients have been able to tolerate more than 90% of the planned dose, and we saw no unexpected toxicities,” Dr Kaufman said.
Two patients are still responding past 18 months. The median progression-free survival was 11.4 months. Of 28 patients, 8 (31%) are still in the study.
Panobinostat, Bortezomib, and Dexamethasone
Dr Richardson presented a comparison of the combination of panobinostat, bortezomib, and dexamethasone versus other treatments for relapsed and/or refractory myeloma using a fixed-effects model to analyze 5 relevant trials involving 3005 patients altogether.
“To our knowledge, this is the first study that has compared the efficacy of commonly used agents in terms of progression-free survival, time to progression, and response rates,” Dr Richardson indicated.
The numerical trends of the analyses suggested that the combination of panobinostat, bortezomib, and dexamethasone is at least as effective as other treatments in patients with relapsed and/or refractory myeloma and has significant advantage versus most comparators. The progression-free survival comparison indicated that the combination of panobinostat, bortezomib, and dexamethasone had the lowest associated risk of progression or death. Similarly, response rates were highest with this regimen, Dr Richardson reported.
“The presented results may be directly used as clinical input data in economic evaluations, such as cost-effectiveness analyses,” he said.
Additional HDAC Inhibitors in Development
Other HDAC inhibitors are also on the horizon and may be even more effective in the treatment of patients with myeloma. One of these treatments is ricolinostat, an orally bioavailable, very potent, selective inhibitor of HDAC6.
“This drug has synergistic multiple myeloma cytotoxicity with bortezomib and lenalidomide in vitro and in vivo and a favorable pharmacokinetic and pharmacodynamics profile,” Dr Richardson noted.
Phase 1 and 2 studies are ongoing with ricolinostat, alone and with bortezomib, and with the combination of lenalidomide and dexamethasone. Trials with pomalidomide plus dexamethasone should begin this year, Dr Richardson said.