BY MARK FUERST
CHICAGO -- Adding panobinostat to the standard-care combination of bortezomib and dexamethasone significantly improves progression-free survival (PFS) in patients with multiple myeloma, according to the results of a randomized, double-blind, placebo-controlled, Phase III trial reported here at the ASCO Annual Meeting (Abstract 8510)
“Panobinostat is a significant advance in the treatment of patients with relapsed or relapsed and refractory multiple myeloma,” said the study’s lead author, Paul Richardson, MD, Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.
“These are the first Phase III results to show meaningful clinical benefit and provide scientific support for adding panobinostat to bortezomib-based treatment for patients with relapsed or relapsed and refractory multiple myeloma and provide a strong rationale for the use of histone deacetylase inhibitors as part of the therapeutic armamentarium in this setting.”
Asked for his opinion for this article, Sagar Lonial, MD, Professor and Vice Chair of Clinical Affairs and Director of Translational Research for the B-cell Malignancy Program at Emory University School of Medicine, called the results exciting and said they may “allow a new mechanism to treat relapsed multiple myeloma, and move treatment to an earlier setting to debulk the disease and get to better outcomes.”
Also commenting, Mikkael Sekeres, MD, Associate Professor of Medicine and Director of the Leukemia Program at Cleveland Clinic, said, “This is another combination that seems to do better than what we had before in multiple myeloma with a promising new agent, panobinostat. … “We have so many options for multiple myeloma and so many combination therapies. What is the best combination for relapsed/refractory multiple myeloma? Does this change that? What about sequencing?”
Almost all patients with multiple myeloma ultimately relapse and become resistant to treatment, so new therapies are critical for continuing to manage the disease and improve outcomes, said Richardson, who is also Professor of Medicine at Harvard Medical School.
Panobinostat is an oral pan-histone deacetylase (HDAC) inhibitor that has been shown to modulate the acetylation of proteins involved in multiple oncogenic pathways, ultimately inducing cell cycle arrest and apoptosis. Richardson noted that one of the targets is HDAC6, an enzyme that has been identified as an important target in multiple myeloma.
In preclinical studies, panobinostat was synergistic in combination with bortezomib and dexamethasone.
Panobinostat inhibits the aggresome pathway of protein degradation, which is upregulated when the proteasome pathway is inhibited by bortezomib, he said. A three-drug combination of panobinostat, bortezomib, and dexamethasone has shown substantial clinical activity in patients with relapsed or refractory multiple myeloma, inducing durable responses even in patients with disease that is refractory to bortezomib.
The PANORAMA 1 (PANobinostat ORAl in Multiple MyelomA) trial, conducted at 215 centers in 34 countries, enrolled 768 patients, median age of 63, with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy and were not bortezomib-refractory. About two-thirds of patients had relapsed disease and one-third had relapsed and refractory disease.
About 48 percent of the patients had received at least two prior regimens. Previous treatments included bortezomib (43% of patients), thalidomide (51%), and lenalidomide (20%). One-quarter had received both bortezomib and immunomodulatory agents. Slightly more than half had autologous stem cell transplantation.
Patients were stratified based on the number of prior lines of therapy and prior bortezomib therapy. They were randomly assigned to receive either panobinostat (387 patients) or placebo (381 patients) in combination with intravenous bortezomib and dexamethasone. For cycles 1 to 8, patients received 20 mg of oral panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; 1.3 mg/m2 of intravenous bortezomib on days 1, 4, 8, and 11; and 20 mg oral dexamethasone on days 1-2, 4-5, 8-9, and 11-12 of every 21-day cycle.
Patients with clinical benefit after the first eight cycles proceeded to the second treatment phase. In this phase, which consisted of four 42-day cycles, the panobinostat regimen remained constant and bortezomib administration was reduced to days 1 and 8 and dexamethasone administration was reduced to days 1-2 and 8-9.
The primary endpoint of the trial was progression-free survival; secondary endpoints included overall survival (OS), overall response rate (ORR), complete response/near complete (CR/nCR) rate, duration of response (DOR), and safety. An independent review committee confirmed PFS and ORR.
After a median follow up of 28 months, the three-drug combination led to a significant improvement over the two-drug combination, with median PFS of 12.0 months versus 8.1 months, respectively, which represents a 37 percent improvement.
“The primary endpoint was met, with a clinically relevant increase in median PFS of 3.9 months in the panobinostat-bortezomib-dexamethasone arm,” Richardson said. The PFS benefit was maintained regardless of baseline characteristics and regardless of prior treatment history.
The final overall survival data are not yet mature, but an interim analysis shows no difference in median OS in the panobinostat arm (33.64 months) and the placebo arm (30.39 months), he reported.
The findings also showed that adding panobinostat to bortezomib and dexamethasone led to a significant increase in higher-quality responses compared with use of standard-of-care therapy alone, with a nearly two-fold increase in CR/nCR response rates (28% vs. 16%, respectively).
The overall response rate was also higher in the panobinostat arm versus the placebo arms -- 60.7 vs. 54.6 percent. The median duration of response, time to response, and time to progression also favored the panobinostat arm.
Side effects were consistent with those previously seen in previous panobinostat studies, he said. The most common Grade 3/4 adverse events in the panobinostat-combination arm were thrombocytopenia (67% vs. 31% with placebo), lymphopenia (53% vs. 40% with placebo), neutropenia (35% vs. 11% with placebo), diarrhea (26% vs. 8% with placebo), and asthenia/fatigue (23.9% vs. 11.9%). Adverse events were generally manageable through supportive care and dose reductions, he said.
In an analysis of platelet kinetics, “following an initial decrease in platelet median levels during the first two weeks of treatment, platelet levels rebounded to baseline by day 1 of each cycle. Thrombocytopenia is reversible and not cumulative.”
Toxicity resulted in treatment discontinuation in 36 and 20 percent of patients in the panobinostat and placebo arms, respectively. The all-cause death rates were similar (8% in the panobinostat arm and 5% in the placebo arm).
In conclusion, Richardson said, “these results confirm the efficacy of panobinostat, bortezomib, and dexamethasone previously observed in the PANORAMA 2 trial with patients who were heavily pretreated and bortezomib-refractory. It shows the superiority of a triple-drug combination versus a dual-drug combination. This is a new option with an HDAC inhibitor as a novel mechanism of action. The activity in high-risk populations is promising.”
He said that in the future, the use of subcutaneous bortezomib may improve tolerability. Other panobinostat-containing combinations are under evaluation in multiple myeloma, and additional HDAC inhibitors are also under study. Trials of panobinostat in myelodysplastic syndromes and myelofibrosis are also underway.
In May panobinostat was granted priority review by the Food and Drug Administration, and additional global regulatory submissions are underway.
“If approved, panobinostat will be first in its class of anticancer agents available to this population,” Lonial said. “It will be a new option with a novel mechanism of action in multiple myeloma.”
He noted that because overall survival for multiple myeloma patients has about doubled in the last decade, the prevalence of the disease is going up. Among those with relapsed/refractory multiple myeloma, the median OS is six to nine months. “Most patients relapse. It’s not uncommon to see patients who have had 10 to 12 lines of prior therapy before entering a relapsed/refractory trial. And there is decreasing durability of response with each additional line of therapy. New treatment options are needed in this patient population.”
As for the PANORAMA 1 study, he noted that although the difference in overall response rate between the panobinostat and placebo arms was only six percent, “CR and near CR were almost twice as high. Getting depth of response is important.”
Lonial pointed out that of course, the incidence of adverse events was higher with three drugs versus two drugs. “However, toxicity was early, and with appropriate management, mitigated or reduced.” Earlier multiple myeloma trials with another HDAC inhibitor, vorinostat, saw a lot of gastrointestinal toxicity, which was not seen with panobinostat. “Hematologic toxicity with panobinostat was more neutropenia, which should not impact the ability to give this combination therapy,” he said.
The debate among oncologists comes down to using three or two drugs in the early-relapse setting. “Would you rather use bortezomib as single agent or along with dexamethasone, or add in panobinostat and double the CR rate, which is an important endpoint in patients with early relapse?” Lonial asked.
The Discussant for the study, Robert Z. Orlowski, MD, PhD, of the University of Texas MD Anderson Cancer Center, noted that the “activity in high-risk patients seemed comparable, although this subgroup was small and not stratified.” He also pointed out that 43 percent of patients had received prior bortezomib. “But if they had to be sensitive, did this select patients more likely to respond?” Orlowski asked. “A better hazard ratio was seen in patients who had prior bortezomib.”
A lower dose intensity was given to the panobinostat-bortezomib-dexamethasone group of patients, which meant that “panobinostat had to work harder to overcome this. Perhaps a lower dose or schedule could have been better,” he said.