HDAC Inhibitor Active in Myeloma Maintenance Setting

A phase I study has found that combination treatment with lenalidomide and vorinostat, a histone deacetylase inhibitor (HDAC-I), may be effective as a maintenance therapy in patients with multiple myeloma who have undergone autologous transplant.

“Our trial is the first to investigate HDAC-I’s in the maintenance setting, but this phase I study only sets the stage to compare multidrug regimens in the randomized setting against lenalidomide monotherapy,” wrote Douglas W. Sborov, MD, of the Ohio State University, and colleagues in the British Journal of Hematology. “Additionally, pan HDAC-I’s may not be the most effective therapy, and more selective HDAC-I’s are being actively investigated.”

Lenalidomide is currently the standard post-transplant therapy used to treat patients with multiple myeloma.

According to the study, “In recent years, the importance of epigenetic modification in the initiation, proliferation, survival and progression of tumor cells has risen to the forefront” and “a novel class of agents, the HDAC-I’s, inhibit HDAC enzymes, effectively targeting epigenetic silencing mechanism(s) that can reverse crucial steps involved in carcinogenesis.”

Therefore, in this study, Sborov and colleagues sought to test vorinostat, a drug used to treat cutaneous T-cell lymphoma, in combination with lenalidomide in patients who had undergone transplant for myeloma. Sixteen patients were given vorinostat beginning day +90 post-hematopoietic stem cell transplantation for days 1 to 7 and 15 to 21, and lenalidomide was started at 10 mg days 1 to 21, both on a 28-day cycle.

According to the researchers, this combination treatment was well tolerated in all 16 patients. After 12 months, the median dose of lenalidomide was 5 mg and vorinostat was 200 mg.

“Considering that the majority of patients required dose reductions and that the median dose of vorinostat and lenalidomide at 1 year were 200 mg and 5 mg, respectively, it is likely that the most well-tolerated dose of vorinostat includes vorinostat 200 mg days 1 to 7 and 15 to 21 of a 28-day cycle,” the researchers wrote. “In fact, in those patients treated at the 200-mg dose (Cohort 1), all three patients had an improvement in their post-transplant response, two of whom achieved stringent complete response.”

During the first cycle of treatment, the most commonly occurring toxicities were cytopenias, gastrointestinal complaints, and fatigue. Overall, the most common toxicities were neutropenia (14.4% of total patients), fatigue (13.5%), leucopenia (12.7%), thrombocytopenia (11.9%), lymphopenia (11.0%), diarrhea (9.3%), anemia (8.5%), hypokalemia (7.6%), rash (5.9%), and nausea (5.1%).

After transplant, three patients had stable disease, two had partial responses, seven had very good partial responses, two had complete responses, and two had stringent complete responses. The use of combination maintenance therapy resulted in an improved response in seven study patients, and this improvement occurred with ≤ 5 cycles of therapy in four of these patients.

At a median follow-up of 38.4 months, median progression-free or overall survival have not yet been reached.