Bortezomib and Thalidomide May Benefit Elderly with Multiple Myeloma
NEW YORK NOV 27, 2006 (Reuters Health) - The addition of bortezomib or thalidomide to conventional chemotherapy to treat elderly patients with multiple myeloma improves response rates and prolongs survival, according to results of two prospective trials reported in the October issue of Blood. In both studies, side effects were "predictable and manageable," and serious adverse events were rare.
The majority of patients with multiple myeloma are over the age of 65, but most are not candidates for high-dose therapy followed by stem cell transplantation, and many chemotherapeutic regimens are too toxic for frail patients, the authors of one of the studies notes.
The Italian research team, led by Dr. Massimo Offidani, from Ospedali Riuniti Ancona, conducted a phase 2 trial of thalidomide added to pegylated liposomal doxorubicin, and dexamethasone (ThaDD) in patients over the age of 65.
The regimen included IV doxorubicin 40 mg/m² every 28 days, dexamethasone 40 mg on days 1-4 and 9-12, and thalidomide 100 mg each evening. The 50 patients, median age 71.5, had untreated multiple myeloma and underwent 5 or 6 cycles of ThaDD. Median follow-up was 18 months (range 6-36 months).
After four cycles, the overall response rate was 98%, with complete or near complete remission documented in 54%. Grades 3 and 4 neutropenia occurred in 12%, and venous thromboembolisms occurred in 14%. Projected event-free survival at 3 years was 57%, and overall survival was 74%.
For those with at least a "very good partial remission" (defined as a greater than 90% reduction in serum paraprotein), survival was significantly greater than among patients with less successful treatment. Event-free survival was 78% versus 37% (p = 0.021), and overall survival was 84% versus 61% (p = 0.053).
Dr. Offidani's team concludes: "The response to thalidomide combined with chemotherapy is not dose dependent; high-dose dexamethasone proves to be crucial; and liposomal-pegylated doxorubicin seems more effective than both epirubicin and low-dose melphalan."
Moreover, they add, "the toxicity (of ThaDD) was manageable in older fragile patients, and complications such as infections and DVT can be prevented with adequate antibiotic and antithrombotic prophylaxes."
In a phase 1/2 trial conducted in Spain, Dr. Jesus-F. San Miguel, from Grupo Espanol de MM, and associates evaluated melphalan and prednisone with bortezomib (VMP).
Bortezomib (Velcade, Millennium Pharmaceuticals, Cambridge, Massachusetts and Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium) is an inhibitor of the 26S proteasome, which is "an enzyme involved in the catabolic pathway for numerous intracellular regulatory proteins," Dr. San Miguel and his associates explain.
In vitro studies suggested a synergistic relationship between bortezomib and cytotoxic agents, thus permitting lower doses than required with monotherapy.
The current study included 60 patients age 65 and older with untreated multiple myeloma. In the dose-escalation phase of the trial, no dose-limiting toxicities were observed, so a 2.3 mg/m² bortezomib dose was used in the second phase.
During four 6-week treatment cycles, bortezomib was administered eight times by day 32, along with melphalan 9 mg/m² and prednisone 60 mg/m² on days 1-4. A shorter maintenance phase followed. The entire duration of treatment was 49 weeks, and median time to response was 2.7 months.
"Results from the present study compare favorably with our historical control data for MP," Dr. San Miguel and his associates report. At 16 months, progression-free survival was 91% versus 66% (p = 0.002); overall survival was 90% versus 62% (p < 0.001).
Based on these encouraging findings, the authors add, an international phase 3 randomized trial is underway.
The trial by Dr. San Miguel's group was supported by Millenium and Johnson & Johnson.
SOURCE:
* Blood 2006:108:2165-2172. |
