Results of a small, Phase 1/2 Australian study indicate that a combination of Istodax, Velcade, and dexamethasone may be effective in relapsed and refractory multiple myeloma patients.

According to the study authors, patients who participated in the study achieved durable responses and experienced manageable treatment-related side effects with the Istodax combination treatment.

Based on their findings, the study authors concluded that the Istodax combination treatment warrants further evaluation.

“We continue to examine this combination on a [21-day] schedule. We are also planning a study of Revlimid and [Istodax] in a number of advanced hematologic malignancies including multiple myeloma,” said Dr. Simon Harrison of the Peter MacCallum Cancer Center in East Melbourne, Australia, and lead author of the study.

Istodax (romidepsin) belongs to a class of drugs called HDAC inhibitors, which cause cancer cell death by inhibiting an enzyme known as histone deacetylase (HDAC) and disrupting the cell cycle in cancer cells. Istodax is approved in the United States as a treatment for cutaneous T-cell lymphoma and is currently being investigated as a potential therapy for multiple myeloma.

A study conducted in the U.S. last year showed that Istodax as a single agent achieved little response in relapsed or refractory myeloma patients (see related Beacon news).

“It appears that none of the HDAC inhibitors have substantial anti-myeloma activity as single agents, and yet when they are combined with [Velcade] or [Revlimid or thalidomide], the activity is enhanced,” said Dr. Ruben Niesvizky of Weill Cornell Medical College in New York who led the single-agent study.

As a result, Dr. Harrison and his colleagues investigated the efficacy and safety of Istodax in combination with Velcade (bortezomib) and dexamethasone (Decadron) in patients with relapsed or refractory myeloma. They also sought to establish the maximum tolerated dose of Istodax when used in this combination.

The study included 25 relapsed or refractory multiple myeloma patients with a median age of 58 years who had received a median of two prior therapies.

Patients started treatment with 8 mg/m² of Istodax on days 1, 8, and 15 of each 28-day cycle. The Istodax dose was gradually increased to a maximum of 14 mg/m² if the number of side effects were low and manageable for previous doses.

Patients also received 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 of each 28-day cycle, and 20 mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle.

Patients had the option to receive maintenance therapy with Istodax if they had stable disease or better after eight cycles of therapy. Istodax was administered on days 1 and 8 of each 28-day cycle for the first 12 months and then every two months until disease progression.

Patients received a median of eight cycles of therapy. Those who did not receive maintenance therapy received a median of 7.5 cycles of the Istodax-Velcade-dexamethasone combination.

After a median follow-up time of 22 months, 72 percent of patients responded to treatment. Eight percent of patients achieved a complete response, 52 percent achieved a very good partial response, and 12 percent achieved a partial response.

The median time to disease progression was 7.2 months. Seventy-six percent of patients were still alive after 12 months, and the median overall survival has not been reached yet.

The researchers determined the maximum tolerated dose of Istodax to be 10 mg/m² when used in combination with Velcade and dexamethasone, which is lower than the approved dose of 14 mg/m² for cutaneous T-cell lymphoma. Of the 25 patients included in the study, 60 percent of patients received the maximum tolerated dose of Istodax.

All patients experienced at least one treatment-related side effect. Seventy-two percent of patients experienced at least one blood-related side effect, most commonly low platelet counts. Sixty percent of patients experienced at least one non-blood related side effect, most commonly fatigue.

Seventy-six percent of patients experienced peripheral neuropathy, a common Velcade-related side effect characterized by pain and tingling sensations in the extremities.

Of the patients who received the maximum tolerated dose of Istodax, 84 percent had severe side effects, most commonly fever or infection, and 58 percent had severe low platelet counts.

The Istodax dose had to be reduced in 12 percent of patients, and 48 percent of patients either discontinued or received a reduced dose of Velcade.

According to Dr. Harrison, the side effects associated with Istodax-Velcade-dexamethasone in this study were not worse than those associated with other regimens. However, he stated that his team is also investigating whether reducing the dose of Istodax may help to mitigate these side effects.

“Overall, we felt this was a well-tolerated regimen. Notwithstanding, we are exploring a different schedule giving one less dose of [Istodax] on a 21-day cycle, and we will compare [the side effects],” said Dr. Harrison.

“We are actively exploring the mechanisms of action of [Istodax], as well as how they cause toxicity in order to better understand how they may be used in the future,” he added.

For more information, please see the article in the journal Blood (abstract).