Throughout the past decade, dramatic advancements in treatment have improved overall survival for patients with multiple myeloma and particularly for those in older populations. Specifically, developments of new drugs that fall into two classes—proteasome inhibitors and immunomodulatory drugs (IMiDs)—contributed to better outcomes through lowered toxicity and a more rapid control of disease at the outset.
Despite the success of these agents in initial therapy, a number of patients still progress following treatment. A new subgroup analysis using data from the PANORAMA 1 clinical trial has found panobinostat, a potent pan-deacetylase inhibitor, in combination with bortezomib and dexamethasone, has the greatest benefit for patients who have received two or more prior regimens.
Progression-Free Survival Benefit
PANORAMA 1 consisted of a randomized, double-blind, phase III study of 768 patients with relapsed or relapsed and refractory multiple myeloma. The combination of panobinostat plus bortezomib and dexamethasone led to an increase in progression-free survival as compared to placebo plus bortezomib and dexamethasone.
This subgroup analysis compared patient outcomes in the trial according to prior treatment, either an IMiD, bortezomib plus an IMiD, or two or more regimens including bortezomib and an IMiD. When compared to the treatment with placebo in place of panobinostat, results indicated a clear progression-free survival benefit of 7.8 months among the latter group of patients who received two or more prior regimens.
The study, published online by the journal Blood (2015;127:713-21), suggests panobinostat could provide a much-needed option for a subset of patients with multiple myeloma who currently have limited treatment options and a poorer prognosis.
“The prognosis for relapsed and refractory disease once treatment with immunomodulatory drugs and proteasome inhibitors has failed our patients is dire,” said Paul G. Richardson, MD, Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and R. J. Corman Professor of Medicine at Harvard Medical School, Boston. “Thus, the 7.6 month progression-free survival we saw in this population is impressive.”
Panobinostat belongs to a novel class of compounds called deacetylase inhibitors and works by altering gene expression through epigenetic mechanisms as well as inhibiting protein degradation. On the basis of results from the PANORAMA 1 trial, the FDA granted accelerated approval to panobinostat plus bortezomib and dexamethasone for the treatment of patients with multiple myeloma who have received at least two prior regimens. The median progression-free survival for the panobinostat-containing arm was 10.6 months as compared to 5.8 months for the control arm.
“Panobinostat is among a new class of oral drugs known as histone deacetylase inhibitors, with next generation agents in the same class that are less toxic for patients and more targeted also in development,” said Richardson. “Current results show that this class of drug can combine well with not only proteasome inhibitors, but also with immunomodulatory drugs as well.”
PANORAMA 1 Trial Results
This new subgroup analysis of the PANORAMA 1 data included 485 patients who received prior IMiD, 193 who received prior bortezomib plus IMiD, and 147 received two or more prior regimens including bortezomib and an IMiD. In the trial, patients went through a maximum of 12 cycles of treatment across two treatment phases. The first consisted of eight three-week cycles of oral panobinostat or placebo administered three times per week for two out of three weeks, along with IV bortezomib administered twice weekly along with oral dexamethasone. For those who demonstrated clinical benefit, the second phase consisted of four additional six-week cycles.
Median progression-free survival showed improvement for patients in the panobinostat arm across all prior treatment groups. The benefit for patients who received prior IMiD and prior bortezomib plus IMiD was similar—4.9 months and 4.8 months, respectively. The greatest difference in median progression-free survival between treatment arms was seen in the group who received two or more prior regimens including bortezomib and an IMiD, 7.8 months.
Other endpoints of the study also improved among patients receiving panobinostat, such as complete response rate, time to response, duration of response, and time to progression. The rate of high-quality responses, defined as near complete responses or complete responses, showed a notable boost for patients with two or more prior regimens (21.9% for panobinostat arm versus 8.1% for placebo arm).
As for safety, common grade 3/4 adverse events and laboratory abnormalities associated with panobinostat included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. The safety profile was consistent across prior treatment groups and similar to those seen in the overall PANORAMA 1 population, which can be managed with dose interruptions or reductions and supportive measures for key toxicities.
Because panobinostat has a different mechanism of action as compared to proteasome inhibitors and IMiDs, Richardson believes it has promise as an agent for hard-to-treat patients who prove resistant to more common therapies.
“Panobinostat can possibly help this population overcome therapeutic resistance through its completely novel mechanism of action,” Richardson said. “We also now have next-generation histone deacetylase inhibitors coming which show great promise as well and better tolerability.”
Meeri Kim is a contributing writer.