At the 2005 annual meeting of the American Society of Hematology, Dr. Jesús F. San Miguel presented interim data on the ongoing GEM/PETHEMA study of VELCADE® (bortezomib) plus melphalan and prednisone (V-MP) in elderly, previously untreated myeloma patients. The national, multi-center, open-label study comprises 60 patients, with a median age of 74 years.
To date, melphalan and prednisone has remained the gold standard for elderly myeloma patients. Therefore new treatment strategies are needed for these patients. VELCADE, a proteasome inhibitor, has shown significant activity in refractory and relapsed myeloma patients. Moreover, in vitro synergy has been reported when VELCADE is combined with cytotoxic agents such as melphalan.
The goal of the PETHEMA study is to define the appropriate dose of VELCADE in combination with melphalan and prednisone (MP), and to analyze the response and toxicity of the V-MP combination therapy in untreated myeloma patients aged 65 years and older.
The V-MP treatment schedule consists of four 6-week cycles followed by five 5-week cycles. In Phase I, two sequential dose levels of VELCADE (1.0 and 1.3 mg/m2) were explored, administered on days 1,4,8,11,22,25,29 and 32 in combination with oral melphalan, 9 mg/m2 and prednisone, 60mg/m2 once daily on days 1 to 4. No dose limiting toxicity (DLT) was observed in Phase I.
When maximum tolerated dose (MTD) of VELCADE in combination with MP was defined, the cohort of patients at the MTD was expanded to further refine estimates of efficacy and toxicity during Phase II of the PETHEMA study. The recommended dose for Phase II was 1.3 mg/m2 of VELCADE in combination with MP. Analysis of response after cycle 1 revealed a Response Rate (RR) of 72%. Analysis of best response after a median of 5 cycles revealed a RR of 85%; including 30% Complete Response (CR) by immunofixation, plus 14% by electrophoresis. The toxicity was manageable.
In conclusion, the most significant finding of the PETHEMA V-MP study thus far is the high rate of response to treatment, with more than one third of patients achieving CR – and this was irrespective of chromosomal abnormalities. Longer follow-up is needed to assess the duration of response and the overall survival data, and to determine if V-MP could replace MP as the standard of care for elderly myeloma patients. An international Phase III randomized trial is currently underway.
Note: IMF Scientific Advisor Dr. San-Miguel is Professor of Hematology at the University of Salamanca, head of the Department of Hematology of the University Hospital of Salamanca, and Principal Investigator of different research projects supported by the Cancer Research Foundation and the Spanish Goverment (FIS & CICYT).