FDA Approves New Agent for Multiple Myeloma

In February, the U.S. Food and Drug Administration (FDA) approved a new drug, panobinostat, for multiple myeloma. A histone deacetylase (HDAC) inhibitor, panobinostat is for patients who have relapsed and no longer respond to one of the most effective treatments for multiple myeloma: the proteasome inhibitor bortezomib. Although panobinostat is the first FDA-approved HDAC inhibitor for this disease, the approval comes with a caveat. Under accelerated approval—which gives patients faster access to promising new drugs—no trials to confirm their clinical benefit more robustly have yet been completed. Novartis, the manufacturer, must conduct those trials. As the drug makes its way to market, some clinicians express concerns about its toxic side effects, which could outweigh the benefits. Nonetheless, many experts expect that these challenges will be overcome and that panobinostat will prove effective for some patients. HDAC inhibitors target epigenetics: They change only the pattern of genes that the cell expresses—not the genes themselves. Specifically, these drugs act on chemical tags called the acetyl group, which helps determine what genes are expressed by which cell type, and when. HDAC inhibitors block the removal of acetyl groups from histone proteins, thereby reactivating silenced genes. Panobinostat acts on proteins other than histones as well. According to Gareth Morgan, M.D., Ph.D., professor of medicine and director of the Myeloma Institute at the University of Arkansas for Medical Sciences in Little Rock, “it’s unclear exactly how these drugs work.” Some evidence indicates that HDAC inhibitors work differently in multiple myeloma. Treatment that combines panobinostat with a proteasome inhibitor such as bortezomib inhibits both the aggresome and proteasome pathways. Blocking these pathways prevents myeloma cells from disposing of misfolded proteins, a by-product of antibody synthesis. Overloaded by misfolded proteins, myeloma cells self-destruct. Researchers first investigated this idea by combining bortezomib with a drug called vorinostat. This endeavor, called the VANTAGE program, compared progression-free survival between those receiving the combination and those receiving only bortezomib. During the phase III clinical trial among 173 patients, investigators found only a minimal, non–statistically significant difference in progression-free survival (7.6 months vs. 6.8 months), with no difference in overall survival. With the arduous dosage and treatment schedule, many patients could not tolerate the medicine. As a result, the program was suspended. Yet many researchers remained intrigued with the concept of adding HDAC inhibitors to proteasome inhibitors. Work continued with another drug in this class—panobinostat—in new combinations. A phase II study, PANORAMA 2 (Blood 2013;122:2331–7; doi:10.1182/blood-2013-01-481325), looked at outcomes for 55 patients treated with oral panobinostat, bortezomib, and the corticosteroid dexamethasone. These patients all had had at least two previous lines of therapy that included an immunomodulatory drug (often lenalidomide) and had relapsed on or within 60 days of the last bortezomib-based therapy. The results were promising. The overall response rate was close to 36%, with one near-complete response, 18 partial responses, and 10 minimal responses. Median progression-free survival was 5.4 months, and median duration of response was 6 months. Most patients experienced side effects, with diarrhea the most common (70.9%), followed by fatigue (69%), thrombocytopenia (65%), nausea (60%), and anemia (47.3%). In this study, however, no patients withdrew because of the side effects. Kenneth C. Anderson, M.D., director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at the Dana–Farber Cancer Institute in Boston, pointed out that “the combination of panobinostat and bortezomib offered the opportunity to extend the duration of progression-free survival and overcome potential bortezomib resistance.” Kenneth C. Anderson, M.D. Building on these results, a phase III PANORAMA trial was recently completed (Lancet Oncol 2014;15:1195–206; doi:10.1016/S1470-2045(14)70440–1). A randomized, double-blind trial, this study included 768 patients from 215 centers in 34 countries who had relapsed or had relapsed and had refractory multiple myeloma. All patients had received one to three previous treatments. The study compared patients receiving panobinostat, bortezomib, and dexamethasone (387 patients) with those receiving a placebo, bortezomib, and dexamethasone (381 patients). Findings from this larger study showed the efficacy of the combination. Median progression-free survival for the panobinostat group and placebo group, respectively, was 12 months, compared with 8 months. Two-year progression-free survival was 20.6% versus 8.4%. Although overall survival data are not yet available, median overall survival was 33.64 versus 30.39 months, and median duration of response was 13.14 versus 10.87 months. Among patients with a near-complete response, median progression-free survival was 19.38 versus 15.21 months. As in PANORAMA 2, patients in the phase III study had many side effects. Serious adverse events occurred in 60% of the panobinostat group, compared with 42% in the control group. Furthermore, treatment was discontinued among 36% of patients in the panobinostat group, compared with 20% in the placebo group. Also, dose modifications were made in both groups. For the treatment group, adjustments were made for panobinostat in 51% of patients; for bortezomib, in 61%; and for dexamethasone, in 17%. In the placebo group, 23% of patients had adjustments for the placebo: 42% for bortezomib, and 17% for dexamethasone. With the data still being analyzed, finding an appropriate way to use panobinostat presents some challenges. According to some clinicians, however, its place is starting to emerge. Frederic Reu, M.D., associate staff physician at the Cleveland Clinic in Ohio, notes that the drug may be more helpful for some patients than others. The translocation 4;14 [t(4;14)], which increases expression of a histone-modifying enzyme, is one mutation that a routine test can already assess; patients with this mutation may respond to drugs such as panobinostat. Studies have also suggested that patients with high-risk cytogenetics, defined as having at least one of the following mutations—t(4;14), t(14;16), or deletion of 17p—may be more likely to benefit from this treatment. This finding could indicate that cytogenetically high-risk myeloma depends more on epigenetic-silencing mechanisms, making it more responsive to panobinostat. Data are preliminary, however, and nonepigenetic mechanisms of panobinostat may also play important roles. Researchers are exploring ways to modify doses and treatment schedules. Paul G. Richardson, M.D., is clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at the Dana–Farber Cancer Institute and lead author of PANORAMA 2. He points out that at the time of the study, subcutaneous bortezomib, which is less toxic than intravenous transmission, was not yet being used. “Modifying dosing regimens and schedules may solve the problems with this drug,” Reu said, encouraged by preliminary analysis of his ongoing study that combines the oral proteasome inhibitor ixazomib with panobinostat and dexamethasone. “A recently published study further supports this notion,” Reu said. “Investigators saw a lower incidence of severe diarrhea and thrombocytopenia with an every-other-week panobinostat-dosing regimen, instead of 2 weeks on, 1 week off, as was done in the pivotal trial, PANORAMA 2. They found this improvement even though a higher panobinostat dose was used in combination with carfilzomib, another proteasome inhibitor.” But Jan S. Moreb, M.D., professor of medicine and director of the hematological malignancies stem cell transplantation program at the College of Medicine at the University of Florida in Gainesville, has another perspective on panobinostat. “I view it as a drug of last resort,” he said. “It’s always good to have another option, but I don’t see this one as a blockbuster.” Nonetheless, Anderson said he believes that panobinostat could be the beginning of a new wave of treatment options, especially since more selective-acting HDACs, with fewer side effects, are already in clinical trials. “They are showing promise and are better tolerated,” he said. “We’re excited about the addition of another class of drugs to the armamentarium of treatments for multiple myeloma,” Anderson concluded. “There’s cause for optimism here.”