Speakers debate role of HDAC inhibitors in myeloma treatment

NEW YORK — Two speakers at Lymphoma & Myeloma 2015 debated how significant a role histone deacetylase inhibitors will play in the treatment of myeloma.

There is currently a substantial unmet need for new drugs in the setting of relapsed or refractory myeloma, according to 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 HemOnc Today’s myeloma section editor.

Joseph R. Mikhael

“These are very exciting times, particularly with the advent of monoclonal antibody therapy,” Richardson said during his presentation. “But for anyone who has used these new monoclonal antibodies … we recognize that a proportion of patients benefit, but over time a substantial proportion of patients progress. We therefore have an urgent unmet medical need for newer drugs and newer mechanisms of action.”

Relapsed, refractory disease

Richardson took the stance that histone deacetylase (HDAC) inhibition may move the field forward due to their capacity to inhibit growth and promote death of multiple myeloma cells.

Richardson referred to the phase 3 VANTAGE 088 study to provide data on the benefits of HDAC inhibitors. In that study, the addition of vorinostat (Zolinza, Merck) to bortezomib (Velcade; Takeda Oncology, Millennium) conferred a statistically significantly — although not clinically meaningful — PFS improvement (HR = 0.77; 95% CI, 0.64-0.94).

Paul G. Richardson

The PANORAMA 1 trial showed a statistically significant and clinically meaningful benefit with the addition of panobinostat (Farydak, Novartis) to bortezomib and dexamethasone (HR = 0.63; 95% CI, 0.52-0.76). The clinical benefit was more pronounced in subsets of patients, particularly those with high-risk cytogenetics, Richardson said.

Patients previously treated with bortezomib or immunomodulatory drugs, as well as patients with relapsed or refractory disease, also experienced a clinically meaningful benefit from the panobinostat combination. The median PFS improvement among patients who had received bortezomib or an immunomodulatory drug was 7.8 months (12.5 vs. 4.7 months; HR = 0.47; 95% CI, 0.31-0.72).

Based in part on these data and others, panobinostat was approved for patients with relapsed or refractory disease.

“That group provides compelling evidence that this class of drug clinically can be exploited in patients with an unmet medical need,” Richardson said.

However, OS and the overall response rate did not appear significantly improved with panobinostat in the total patient population, Joseph R. Mikhael, MD, associate professor of medicine at Mayo Clinic in Scottsdale, Arizona, said during a counterargument. Further, panobinostat has no single-agent activity in this setting, he said.

“Yes, we are living in an era where we, generally speaking, treat myeloma with combinations, but we would want every partner in that combination to make a very significant contribution,” Mikhael said.

Toxicity

Toxicity may also be a concern. Data from PANORAMA 1 showed 67.4% of patients who received the panobinostat combination experienced grade 3 to grade 4 thrombocytopenia and 34.5% experienced grade 3 to grade 4 neutropenia. However, only 1.6% of patients in that cohort discontinued treatment due to thrombocytopenia.

Dose optimization — through subcutaneous bortezomib administration, weekly vs. biweekly bortezomib dosing, and dose reductions of bortezomib and panobinostat — will be crucial to determining the optimal administration of the regimen, Richardson said. Next-generation drugs in this class also may offer benefits in terms of reduced toxicity.

“HDAC inhibitors provide clinically meaningful benefit to a patient population with an exquisitely unmet medical need,” Richardson said. “Obviously there are challenges, but I would propose to you that with the appropriate optimization and adaptation of current regimens, we can make this a more effective and more favorable platform for our patients.”

However, it is also important to consider the financial toxicity, Mikhael said. The average cost of panobinostat is about $100,000 per gram, or approximately $7,000 to $8,000 for six pills.

The four standards of treatment for myeloma may include alkylators, immunomodulatory agents, monoclonal antibodies and proteasome inhibitors, Mikhael said. Panobinostat — along with steroids, conventional chemotherapies and doxorubicin — may be considered an “add on” to these four central treatments, he said.

“Panobinostat is an FDA-approved agent that will help patients with myeloma,” Mikhael said. “But I cannot with a clear conscious say that it is a major advance, but that it is a minor advance that comes with substantial clinical and financial toxicity.”

Richardson and Mikhael both agreed they look forward to more data on panobinostat in different combinations, as well as on the efficacy of next-generation drugs. – by Alexandra Todak

For more information:

Richardson PG and Mikhael JR. Are HDAC inhibitors a real advance in myeloma treatment or simply more toxic therapy? Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies; Oct. 22-24, 2015; New York, New York.

Disclosure: Mikhael reports grant/research support from AbbVie, Celgene, Genentech and Janssen. Richardson reports advisory roles with Genmab, Millennium, Onyx and Takeda.