The results of a recent Phase 2 clinical trial indicate that the new drug Istodax, administered alone, is unlikely to achieve a significant response rate in therapy-resistant multiple myeloma patients. However, the results indicate that that Istodax may help stabilize M-protein production, resolve high calcium levels, or reduce bone pain in some multiple myeloma patients.

Istodax (romidepsin) is a cyclic peptide that inhibits an enzyme in cancer cells known as histone deacetylase (HDAC). By inhibiting HDAC, Istodax disrupts the cell cycle and causes cancer cell death. Istodax is marketed by Celgene Corporation and was approved by the FDA in November 2009 as a treatment for cutaneous T-cell lymphoma.

The clinical efficacy of HDAC inhibitors as single treatment agents for multiple myeloma has not been very promising so far. Dr. Ruben Niesvizky, the lead investigator of the Phase 2 Istodax trial, noted in email correspondence with The Myeloma Beacon that no HDAC inhibitor has previously shown clinical activity as a single agent.

This Phase 2 trial sought to evaluate the safety and efficacy of Istodax as a single agent therapy. It was also designed to provide a basis for Istodax’s integration into standard multiple myeloma therapies, such as Velcade (bortezomib), in the future.

Thirteen patients with recurrent and therapy-resistant (refractory) multiple myeloma were enrolled in the study.  Each had received at least two prior lines of therapy, including stem cell transplantation, Velcade, and thalidomide. 

Patients received 13 mg/m² of Istodax on days 1, 8, and 15 of a 28-day cycle. After one cycle, patients with progressive disease were excluded from the study while the remaining patients proceeded to the next treatment cycle.

The researchers found that Istodax did not produce any anti-cancer responses.

However, four patients (31 percent) exhibited stabilization of monoclonal (M) protein production during treatment. In multiple myeloma, the M-protein is overproduced by plasma cells and cannot effectively fight infections.

Istodax treatment also resolved high calcium levels in five patients and improved bone pain in two others. 

The only severe side effect caused by Istodax treatment was lowered platelet levels, experienced by 23 percent of patients. Other commonly experienced side effects were mild and included nausea and fatigue. 

While HDAC inhibitors may not be clinically effective on their own, previous studies have shown that other HDAC inhibitors enhance the effectiveness of standard multiple myeloma therapies, including Velcade and thalidomide (Thalomid).

Further studies are currently underway to evaluate the combination of HDAC inhibitors and Velcade for multiple myeloma.

“We are anxiously awaiting the results of the first randomized trial of [the HDAC inhibitor] Zolinza (vorinostat) and Velcade,” said Dr. Niesvizky. “This will dictate approval and future usage of the drug. Currently, these drugs are seldom used in relapsed and refractory patients, with mixed results.”

A Phase 1/2 trial evaluating the combination of Velcade and Istodax in relapsed multiple myeloma is currently recruiting patients. For more information, please see the clinical trial description. 

For more information on the Istodax single agent study, please refer to the journal Cancer (abstract) and the clinical trial description.