An American Society of Clinical Oncology (ASCO) meeting abstract, to be presented on June 1 at the ASCO Annual Meeting, describes a study on the combined effects of tanespimycin ^[1] and Velcade ^[2] (bortezomib) on patients with relapsed and refractory multiple myeloma. Researchers found that combining tanespimycin and Velcade strengthened the drugs' effects; thus, the combined treatment compared favorably to therapy involving Velcade alone.

Tanespimycin, an antibiotic, binds to and disrupts Hsp90 (Heat Shock Protein 90). Hsp90 is a “chaperone” protein; it helps in the production of other proteins that contribute to myeloma growth, survival, and drug resistance.

Velcade works by inhibiting proteasomes. Proteasomes are large protein complexes that break down other proteins inside cells so that the cells can continue to grow and function. When Velcade inhibits this process in the cells of myeloma patients, their myeloma cells are unable to grow and eventually die.

The trial abstract states that preclinical data showed anti-tumor synergy between tanespimycin and Velcade, which means that the effects of each drug are stronger when used together. Additionally, data show that tanespimycin may protect against nerve damage induced by Velcade. Finally, a previous Phase 1 study of tanespimycin showed favorable tolerability for and produced a modest response in relapsed and refractory myeloma patients.

In this study, 72 patients with relapsed and refractory myeloma received 0.7-1.3 mg/m² of Velcade, followed by an infusion of 100-340 mg/m² of tanespimycin, on specific days throughout the trial. Forty-two patients received the highest doses of both Velcade and tanespimycin as part of a Phase 2 expansion. Toxicity levels and responses were assessed after the treatment concluded.

More details on the patients involved in the study were provided, including that 72 percent had the IgG subtype of myeloma. These patients’ myeloma cells produce immunoglobulin G. Median age of the patients was 60 years old, median time since diagnosis was 50 months, and median number of prior treatment regimens was five. A list of prior therapies included thalidomide ^[3] (Thalomid) (74 percent), Velcade (69 percent), stem cell transplant (69 percent), Revlimid ^[4] (lenalidomide) (28 percent), and Hsp90 inhibitors (13 percent).

Researchers measured the following response rates to the tanespimycin and Velcade treatment: 41 percent in those who had not been previously treated by Velcade, 20 percent in pre-treated patients, and 14 percent in refractory patients. One particular subgroup, those who experienced one to three prior treatments and were not previously exposed to Velcade, had a particularly strong response rate of 56 percent. For all patients who responded to the treatment, the median duration of response was 10.7 months. Three refractory patients had a durable partial response through months 12, 22, and 28. Three other patients remain in response through 24 months.

Common side effects patients experienced during the trial included diarrhea, nausea, fatigue, platelet deficiency (thrombocytopenia), and raised AST levels (indicative of AST liver enzyme overproduction), which were handled through dose reduction and supportive care.

Overall, the treatment was well tolerated and provided a durable response all types of patients: those who had not been treated by Velcade before, pre-treated patients, and refractory patients. The median duration of response for Velcade plus tanespimycin compared favorably to the duration of response for therapy involving only Velcade. Additional findings supported tanespimycin’s neuroprotective effect.

A Phase 3 study of Velcade plus tanespimycin treatment compared to Velcade treatment is currently in progress.

For more information on the study, visit abstract 8503 ^[5] at the 2009 ASCO meeting ^[6] Web site.