NEW YORK—Histone deacetylase (HDAC) inhibitors may provide a new mechanism of action in myeloma, but they have yet to prove to be a real advance in myeloma treatment. That was the winning argument in a recent debate at the 2015 Lymphoma & Myeloma meeting here about the pros and cons of the efficacy and toxicity of HDAC inhibitors in myeloma.
Both debaters agreed there is an unmet need in relapsed/refractory multiple myeloma for new therapies and drugs with new mechanisms of action. Patients who are refractory to bortezomib and immunomodulatory drugs (IMiDs) have a poor prognosis. While many of the attendees at first believed HDAC inhibitors were a therapeutic advance, after hearing the debate most were convinced these drugs are, at the moment, simply more toxic therapy.
Paul Richardson, MD: HDAC Inhibitors Important New Direction
The first debater, Paul Richardson, MD, Professor of Medicine at Harvard Medical School, took up the cause of HDAC inhibitors in myeloma.
“Checkpoint inhibitors failed as a new strategy to go forward. With monoclonal antibodies, we recognize that a proportion of patients benefit, but a substantial portion progress. HDAC inhibitors are an important new direction and provide a meaningful plateau from which to build upon,” he said.
Pan deacetylase inhibitors inhibit a broad range of enzymes. “What I like about pan deacetylase inhibitors is their multiple effects downstream,” he added.
The rationale for the combination of deacetylase inhibitors and bortezomib is the inhibition of both aggresome and proteasome pathways. This causes a buildup of intracellular misfolded cytotoxic proteins, leading to multiple myeloma cell apoptosis.
Richardson noted that the HDAC inhibitor, vorinostat, showed promise in a study in combination with immunotherapy, which may be an important partnership. A clinical trial of bortezomib plus vorinostat versus bortezomib alone, with no steroids, found statistically significant improvement in progression-free survival (PFS) for two drugs over one drug. However, the side effects profile precluded clinical benefit.
Another HDAC inhibitor, panobinostat, is generally well-tolerated and has a promising signal of durable, consistent response rate, he said. Richardson presented details of the PANORAMA 1 study, an international trial of 768 patients. This trial showed a significant and clinically relevant increase in median PFS of 3.9 months in the panobinostat-bortezomib-dexamethasone arm.
An analysis of a subgroup with genetic risks showed a more pronounced benefit. For patients with more than two prior regimens, including bortezomib and IMiDs, the median PFS benefit was 7.8 months. “The benefit was maintained regardless of prior treatment,” he said. “The benefit appears the greatest in the most heavily pretreated subgroup.”
PANORAMA 2, a similar trial in the U.S. of 55 patients, showed “a solid 35 percent response rate,” said Richardson. In a high-risk cytogenetic group, the median PFS was 5.4 months in relapsed/refractory patients.
“We believe there is compelling evidence that this class of drugs (HDAC inhibitors) can be exploited in patients with unmet need,” he said.
He believes that toxicity can be managed to provide optimal benefits for patients on deacetylase therapy. In PANORAMA 1, high rates of grade 3 or 4 hematologic adverse events were observed, but “they were generally predictable and manageable, leading to few discontinuations,” he said. Thrombocytopenia was generally reversible and not cumulative. “With dose reduction, we can make an impact,” he said. Non-hematologic adverse events were also predictable and manageable with supportive measures.
There are opportunities to reduce toxicity with dose optimization and novel combinations. Trials are now examining using subcutaneous bortezomib or once-weekly (instead of twice-weekly) intravenous bortezomib in combination with panobinostat and dexamethasone. A reduced dose of bortezomib appears to be beneficial, although a reduced dose of panobinostat appears to be preferable, he noted.
The unique mechanisms of action make these two drugs ideal partners. “Synergy with agents from several classes could provide greater efficacy benefit and improved tolerability,” he said. Ongoing trials in multidrug combinations in both the relapsed/refractory and front-line settings include lenalidomide-bortezomib-dexamethasone plus panobinostat and carfilzomib-dexamethasone-panobinostat.
Successful combinations can be accomplished with other drugs as well. “Combinations with lenalidomide show manageable adverse effect rates. New HDAC 6 selective inhibitors, such as ricolinostat, when combined with proteazome inhibitors and IMiDs, show an even more manageable side effects profile. Pomalidomide response rate shows this platform is promising and well-tolerated,” Richardson said.
In summary, Richardson said: “Deacetylase inhibitors provide clinically meaningful benefit to a patient population with unmet need. Other combinations and next-generation drugs show great promise. The safety profile is predictable and generally manageable, and efforts are ongoing to optimize treatment to improve tolerability and patient quality of life. Next-generation agents appear to have a highly favorable profile.”
Joseph R. Mikhael, MD: HDAC Inhibitors a Toxic Therapy
Taking the opposing view, Joseph Mikhael, MD, MEd, FRCPC, FACP, Professor of Medicine, Mayo College of Medicine; Associate Dean, Mayo School of Graduate Medical Education; Deputy Director - Education, Mayo Clinic Cancer Center; and Associate Medical Director, Department of Development Mayo Clinic in Arizona, said HDAC inhibitors are a minor, not a major, advance forward, and are just a toxic therapy.
“The rationale behind combining HDAC inhibitors and proteasome inhibitors in multiple myeloma makes sense, with therapeutics of varying abilities combined to inhibit multiple pathways. Yes, this is the era of treating myeloma with combinations, but we want to develop partners to make a contribution. Panobinostat has minimal activity,” said Mikhael, who noted that the Oncology Drugs Advisory Committee voted against accelerated approval of panobinostat.
Mikhael pointed out that in the PANORAMA 1 trial, the overall response rate (ORR) was not statistically different between the two arms, and there was no difference in overall survival. “Are we really overcoming proteasome inhibitor resistance, which is the goal of a new mechanism of action?” he asked. The reality in myeloma clinics is that “patients are resistant to all drugs we use.”
In terms of clinical toxicity in the PANORAMA 1 trial, overall severe adverse events, as well as the rate of diarrhea, arrhythmias, and deaths due to progression, were all higher in the treatment as compared to the control arm. He added that a Black Box warning was issued for cardiac toxicity and diarrhea with the use of panobinostat.
“We are treating sick patients with drugs that have significant toxicity,” he said.
Mikhael also highlighted the financial toxicity of panobinostat. “The average cost of the drug is $7,000 to $8,000 for six pills, or $100,000 per gram,” he said, wryly comparing that to the price of gold at $36 per gram. In Britain, the National Institute for Health and Care Excellence ruled out covering panobinostat, he noted.
“Yes, panobinostat has a novel mechanism of action, the first in 15 years since IMiDs and proteasome inhibitors. However, the data with HDAC inhibitors shows they are not as effective as we would want. We are not on the cusp of bringing in a new treatment for myeloma. HDAC 6 inhibitors have not shown genuine promise,” Mikhael said.
It may be true that immunotherapeutic agents may have a different response curve, but “the net effect here is weak with only minimal improvement in PFS. Is this really immunotherapy?” he asked.
“Panobinostat used with twice weekly bortezomib has yet to be proven. The agent still has minimal single agent activity and significant toxicity,” he stated.
Mikhael believes real advances in multiple myeloma can be found with elotuzumab and anti-CD 38 agents. “Elotuzumab shows a 15 percent increase in ORR, PFS improvement of five months, and minimal toxicity. Anti-CD 38 agents, daratuzumab, and isatuximab are the most exciting. They show a 30 percent increase in ORR, more than four months prolongation of PFS in heavily pretreated patients, and minimal toxicity.”
Currently, the standard of care for myeloma, he said, is the “big three” classes of IMiDs, proteasome inhibitors, and monoclonal antibodies, plus steroids immediately and alkylators immediately or later. Add-on agents include doxorubicin and panobinostat. “Panobinostat is like an oral version of doxorubicin, and is similar to doxorubicin in late-stage disease,” he said.
In baseball terms, Mikhael likened panobinostat to a single, which still helps the team, but is not a home run. He believes the role of panobinostat is as an add-on, not a centerpiece, and it should be used in similar ways to doxorubicin for late-stage patients who likely had at least three lines of therapy, who are still proteasome inhibitor sensitive, and to boost the effect of bortezomib in combination.
In conclusion, Mikhael said: “Panobinostat is an FDA-approved agent that will help patients with myeloma, but I cannot say it is a major advance and it comes with significant clinical and financial toxicity. HDAC inhibition will function as an adjunct therapy to the major therapeutic classes we have now. We look forward to more combinations and evidence of its anti-myeloma activity.”
The results of the debate show Mikhael successfully made his argument. He convinced more than half the audience (58 percent) to agree with him, whereas only 12 percent did beforehand. About one-third of the audience had favorable views of HDAC inhibitors in the pre-debate vote, but only one-quarter of them shared the same views afterward.