Vorinostat Shows Activity as Salvage in Multiple Myeloma

Zosia Chustecka

December 14, 2011

December 14, 2011 — Although there have been great strides in the treatment of multiple myeloma over the past decade, most patients will eventually relapse or become resistant to treatment. What to do then is a pressing clinical issue, and several new drugs are being tested in this setting.

One of them is vorinostat (Zolinza, Merck & Co), a histone deacetylase inhibitor, which is the first of this class of drugs to have reached the market. It was approved by the US Food and Drug Administration (FDA) in 2006 for cutaneous T cell lymphoma.

Results in the setting of relapsed/refractory multiple myeloma — a potential new indication for the drug — were presented here at the American Society of Hematology 53rd Annual Meeting.

Updated results from a phase 2b study showed that adding vorinostat to bortezomib (Velcade, Millennium) in patients who had failed on all therapies could recapture some responses, and new data from a phase 3 registration trial showed that adding vorinostat to bortezomib significantly improved progression-free survival.

"We are encouraged by the results...in this difficult-to-treat population," said the lead author of the phase 3 study, Meletious Dimopoulos, MD, professor of clinical therapeutics at the University of Athens School of Medicine in Greece.

However, although the results were statistically significant, an expert not involved in the study questioned whether they were clinically important. Adding vorinostat to the treatment improved progression-free survival by only 25 days, noted Noopur Raje, MD, director of the center for multiple myeloma at Massachusetts General Hospital, and associated professor of medicine at Harvard Medical School in Boston.

"Most of us the field were disappointed with these results," she told Medscape Medical News, and wondered if the data would be sufficient for approval of this new indication.

Recapturing Responses

The phase 2b study, known as the VANTAGE (Vantage in Combination with Bortezomib in Salvage Multiple Myeloma Patients) 095 trial, addressed an unmet need, said lead author David Siegel, MD, MD, PhD, chief of multiple myeloma at the John Theurer Cancer Center, Hackensack University Medical Center, New Jersey. These are patients who have failed all therapies, including alkylating agents, thalidomide, lenalidomide, and bortezomib, and in whom there are no good alternatives, he told Medscape Medical News.

In this study, vorinostat (which does not have activity in multiple myeloma when used alone) was added to bortezomib to see if any responses could be recaptured. The results show that they were, Dr. Siegel said. Of the 143 patients treated, 17% had a partial or better response and 77% had stable disease or better. "The majority of patients had benefit, and the responses were of some durability — around 7 months," he said.

Progression-free survival was 3.1 months and overall survival was 11.2 months, which is "very good in this patient population," he noted. There was a delay of around 4 months between patients becoming refractory to treatment and enrolling in the study, so in total, the medial overall survival was about 15 months from becoming refractory, which is about "twice what would be expected in a patient population that is premorbid."

Dr. Siegel said he is "very excited" about the potential for vorinostat in relapsed/refractory multiple myeloma. "We have significant experience with this drug, and it clearly demonstrates activity and sustained activity in patients for whom there are no reasonable alternatives."

Larger Study Disappointment

The larger phase 3 study (known as VANTAGE 088), presented at the meeting by Dr. Dimopoulos, had a slightly different population — patients had relapsed but they were not refractory to bortezomib. They were receiving bortezomib but were progressing, or they had never used bortezomib.

The trial involved 637 patients randomized to bortezomib or bortezomib plus vorinostat. Response rates were higher with combination therapy than with bortezomib alone (56% vs 41%; P < .0001). The primary end point was met, and there was a statistically significant improvement in progression-free survival with the combination, compared with bortezomib alone (7.6 vs 6.8 months; hazard ratio, 0.774; P = .01).

"But there was disappointment that this amounted to barely a month," Dr. Raje told Medscape Medical News. "We were hoping to see better results."

In addition, there was a "fair amount of toxicity," including gastrointestinal problems and thrombocytopenia, she said. Overall, 50% of the patients treated with the combination withdrew from the study or had a dose reduction, compared with 25% of patients treated with bortezomib alone.

Dr. Raje wondered whether the dosing was too high; in this phase 3 trial, vorinostat 40 mg/day was used for 14 days of each 21-day bortezomib cycle. She noted that ongoing studies with another histone deacetylase inhibitor, panobinostat (under development by Novartis), are looking to modify the dosing and are exploring giving the drug every other day or for a week on and then a week off, but these are early studies, she said.

Other Approaches to Salvage

Dr. Raje noted that there are several other approaches to salvage therapy in multiple myeloma being studied, including pomalidomide (under development by Celgene) and carfilzomib (under development by Onyx).

Pomalidomide is the newest immunomodulator in the same class as thalidomide and lenalidomide. Dr. Raje explained that in patients who had become refractory to lenalidomide, this new agent showed responses in about 30% of patients, and the responses lasted for about 8 months, which is "pretty significant."

Carfilzomib is a new protease inhibitor, in the same class as bortezomib, but carfilzomib is an irreversible inhibitor, whereas bortezomib is reversible. Dr. Raje noted that this drug has shown responses in 18% of patients who were relapsed on bortezomib and in 24% of patients who were refractory to bortezomib, with a duration of response of around 8 or 9 months.

Data from phase 2 studies with carfilzomib were submitted to the FDA with a request for accelerated review, but Onyx announced on December 11 that this was not granted, and the drug will need to undergo the standard review process. Two phase 3 trials in relapsed/refractory multiple myeloma patients are ongoing in the United States and Europe.

Both VANTAGE trials were sponsored by Merck & Co, the manufacturer of vorinostat (Zolinza).

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 811 and abstract 480. Presented December 12, 2011.

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