Multiple Myeloma First-Line Treatment Study at CORT
Treatment options for multiple myeloma have significantly expanded over the past decade with the development of several new, effective combination drug therapy regimens. These agents have been employed as stand-alone therapy for patients who are not candidates for high-dose melphalan and autologous bone marrow transplant (HD-BMT), as induction therapy (before HD-BMT), or for salvage treatment of patients who have failed HD-BMT. Treatment response rates have approached or exceeded 90% in treatment-naive patients, and disease control and survival of patients receiving these therapies has significantly improved.
Velcade (bortezomib) is a proteosome inhibitor with significant activity in myeloma therapy. It has been FDA-approved for treatment of patients who have received at least one prior therapy, based on a large phase III study of Velcade with Dexamethasone. In that study, patients received Velcade at 1.3 mg/m2 on day 1,4,8, and 11 every 21 days, with Dexamethasone 40 mg/d on days 1-4, 9-12 every 21 days. After 8 three-week cycles, responding patients continued to receive Velcade weekly for 3 thiry-five day cycles. The control group received high-dose Dexamethasone (HD-Dex) alone. Cross-over was allowed in this study. Velcade-Dexamethasone (VD) improved response compared to HD-Dex, 38% versus 18%. Even with cross-over from HD-Dex to VD, the survival of patients who had initial VD versus HD-Dex was higher, with one-year survival of 80% versus 66%. This was a 43% reduction in the risk of death at 1year.
A subsequent study of VD versus HD-Dex (SUMMIT) confirmed these findings.
Velcade has been under extensive investigation as part of other drug therapy combinations for myeloma, both in the initial and salvage therapy treatment settings. In the VISTA study presented at the American Society of Hematology meeting in 2007, the Velcade, Melphalan (oral), and prednisone (VMP) combination was compared to standard MP therapy for first-line treatment of myeloma. MP therapy produced complete response (CR) in 4%, and partial response (PR) in 31%. The median duration of response (DOR) and of CR was 13 months each, the median time to progression (TTP) was 16.6 months, and the 2-year survival was 70%. For VMP, the CR was 30%, PR 40%, median DOR 20 months, median duration of CR 24 months, median TTP 24 months, and 2-year survival 83%. Treatment related death occurred in 1% of MP and 2% of VMP patients. Most common toxicities included myelosuppression, fatigue, insomnia, infection, diarrhea, neuropathy, and nausea/vomiting, somewhat greater in the VMP treatment arm.
Thalidomide (Thalomid) is an oral drug with significant activity in myeloma. The mechanism of action of Thalomid is not completely understood. Thalomid and Dexamethasone may increase the risk of thrombosis in myeloma patients. Anticoagulation strategies may reduce that risk. Velcade, Thalomid, and Dexamethasone (VTD) has been compared to TD in a randomized study, the GIMEMA MMY-3006 Study reported at ASH in 2007. The VTD regimen produced CR in 38% (versus 7% for TD) and PR in 63% (versus 25% for TD).
Therefore, for newly diagnosed patients, the inclusion of first-line Velcade with either TD or MP appears to offer significant promise. In the national US study UPFRONT, being conducted at CORT, first-line treatment with VD, VTD, or VMP are being randomly compared for efficacy and long-term outcomes. For further information about this study, please visit the CORT website (www.CORTPA.com) or call to speak with a research coordinator at 972-566-5588.
Tags: Bortezomib, Myeloma, Thalidomide, Thalomid, UPFRONT Study, Velcade
