Dexamethasone and Cyclophosphamide: More Convenient and as Effective as VAD before High-Dose Melphalan and Autologous Transplantation in Newly Diagnosed Multiple Myeloma. Results of a Randomized NMSG Trial.

Background. High-dose melphalan with autologous stem cell transplantation (ASCT) is established in the first line treatment of myeloma patients. The initial tumour reducing therapy before high-dose treatment is usually VAD, i.e., vincristine and doxorubicin in continuous infusion plus high dose dexamethasone. The anti-myeloma effect of high dose corticosteroids is indisputable but the role of vincristine and doxorubicin is unclear, and never scrutinized in randomized studies. Both of these drugs do have well-known side effects and the administration of VAD is somewhat complicated. Melphalan is very effective in myeloma treatment but not suited for initial treatment because of the stem cell toxicity. However, another alkylating agent like cyclophosphamide is feasible to use before stem cell harvest and has well documented anti-myeloma effect. Trying to simplify initial treatment before ASCT, the Nordic Myeloma Study Group (NMSG) initiated a prospective, randomized multicentre study comparing conventional initial therapy of three 4-week courses of VAD with two 3-week courses of Cy-Dex.

Patients and methods. From Nov 2001 to Oct 2003, 315 patients younger than 65 years with symptomatic newly diagnosed myeloma were randomized to receive 3–4 courses of VAD or 2–3 cycles of Cy-Dex (cyclophosphamide 1000mg/sqm and dexamethasone 40mg/d days 1–4 and 9–12). Thereafter, both groups received cyclophosphamide 2g/sqm plus rhG-CSF (filgrastim) sc as mobilization therapy followed by stem cell harvest and subsequent high dose melfalan 200 mg/sqm supported by stem cell infusion. CR was defined as the disappearance of M-protein from serum and urine in agarose gel electrophoresis and < 5 % plasma cells in a bone marrow aspirate.

Results. Patients in the Cy-Dex group came quicker to ASCT, 3.2 months versus 4.5 for the VAD group. The study showed no significant difference in the proportion of patients undergoing ASCT, 137/158 pts (87 %) in the Cy-Dex group versus 133/157 pts (85 %) in the VAD group. Neither were there any significant differences in response rate. After the initial therapy there were 54 % major responses (7 % CR and 47 % PR) in the Cy-Dex group versus 55 % (11 % CR and 44 % PR) in the VAD-group. After ASCT the response rates were 76 % (32 % CR and 44 % PR) versus 72 % (34 % CR and 38 % PR) in the Cy-Dex and the VAD group respectively. Also, survival data were identical with a median event free survival time of 29 months and 75 % overall survival at three years, calculated from start of therapy for both groups.

Conclusion. This randomized trial indicates that Cy-Dex speeds up and simplifies initial treatment with an efficacy comparable to VAD. Cy-Dex can be recommended as a safe alternative for initial therapy in patients planned to undergo ASCT, and should be further studied in combination with novel agents, such as thalidomide, bortezomib and lenalidomide.