VELCADE® (bortezomib) for Injection is currently approved in the United States and more than 50 countries worldwide for the treatment of patients with relapsed and refractory multiple myeloma. The timetable for clinical development and approval of VELCADE was unusually rapid; the FDA granted approval for U.S. marketing just over four and a half years after the first patient received VELCADE in a clinical trial. VELCADE is the first treatment in more than a decade to be approved for patients with myeloma.
VELCADE is proteasome inhibitor. The proteasome is an enzyme complex found within all cells. Many of the processes that rely on proteasome function can contribute to the growth and survival of cancer cells. VELCADE appears to induce myeloma cell death and to inhibit myeloma cell growth and survival by acting on the bone microenvironment. Due to the reversibility of proteasome inhibition with VELCADE, normal cells can recover from its effects, whereas cancer cells are more likely to undergo cell death.
The results of the phase III APEX clinical trial demonstrated a statistically significant survival advantage of VELCADE versus a standard therapy (high-dose dexamethasone). Early closure was recommended by an independent data monitoring committee at interim analysis of time to progression (50% of progressive
disease events). At termination, a final statistical analysis was performed. Survival advantage maintained despite at least 44% of dexamethasone patients crossing over to VELCADE prior to early study closure.
Of 333 patients on the VELCADE arm, 315 were evaluable for response. Of 336 patients on the dexamethasone arm, 312 were evaluable for response. Complete response (CR) required 100% disappearance of the original myeloma protein from blood and urine on at least 2 determinations 6 weeks apart by immunofixation, less than 5% plasma cells in the bone marrow, stable bone disease, and normal calcium. Near complete response (nCR) required that all CR criteria be met except that immunofixation was positive. Partial response (PR) required greater than or equal to 50% reduction in serum myeloma protein and greater than or equal to 90% reduction in urine myeloma protein on at least 2 determinations 6 weeks apart, stable bone disease, and normal calcium.
Several Phase III clinical trials of VELCADE are currently underway. In January 2005, Millennium Pharmaceuticals, Inc. announced the initiation of VISTA (VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone), an open-label, randomized, multicenter, international clinical trial of VELCADE in combination with melphalan and prednisone versus melphalan and prednisone in patients with newly diagnosed multiple myeloma who are not transplant candidates.
The VISTA study is designed to assess efficacy, overall safety, and tolerability of the combination regimen compared with melphalan and prednisone alone. "The frontline data seen to date have been very promising, and we are eager to explore the potential of VELCADE in combination with other therapies so that we may be able to offer new options for patients in need," said David Schenkein, MD, vice president, clinical oncology development, Millennium.
The primary study objective is to determine whether the addition of VELCADE to standard melphalan and prednisone therapy improves the time to disease progression in patients with previously untreated myeloma. The secondary study objectives are to determine overall survival, progression-free survival, time to response, CR rate and overall response rate, duration of response, and safety. Approximately 680 patients will be enrolled in 21 countries.
Millennium is also conducting a multicenter Phase IV clinical trial known as EVEREST (Evaluation of VELCADE Employed as Retreatment for Efficacy, Safety, and Tolerability). This study is designed to assess M-protein response in patients who have previously responded to VELCADE and relapsed following a treatment-free remission. Because there is no known mechanism of resistance to VELCADE and no new cumulative toxicity with extended therapy, it is hoped that retreatment with VELCADE will be beneficial.
NOTE: For more information about VELCADEï¿½ (bortezomib) for Injection clinical trials, patients and physicians can visit www.millennium.com or call the Millennium Medical Product Information Department at 866-VELCADE.