VAD-doxil vs.VAD-doxil Plus Thalidomide as Initial Treatment in Patients with Multiple Myeloma: A Multicenter Randomized Trial of the Greek Myeloma Study Group.

Introduction: VAD-doxil and VAD-doxil plus thalidomide have already been separately evaluated, as initial cytoreductive treatment in multiple myeloma, in two previous clinical trials of our study group. Both regimens proved effective yielding overall (complete and partial) response rates of 61.3% and 74% respectively, while toxicity was acceptable in both studies. Aim of the study was to compare the efficacy and toxicity of these two regimens in the context of a multicenter randomized clinical trial.

Patients and Methods: Patients randomized in arm A received vincristine 2mg IV, liposomal doxorubicin 40mg/m2 IV in a single dose on day 1, and dexamethasone 40mg PO daily for 4 days. The regimen was repeated every 4 weeks. Dexamethasone was also administered on days 15–18 of the first cycle. Patients randomized in arm B received VAD-doxil with continuous thalidomide 200 mg PO daily at bedtime. Response to treatment was the primary objective of the study and was evaluated after the completion of 4 cycles. Subsequently, patients were allowed to proceed to high dose chemotherapy or to receive two additional cycles of the same regimen. Response and toxicity were evaluated according to EBMT and NCI criteria respectively. Patients’ characteristics, response and toxicity rates were compared using two-independent- samples tests and x2 tests.

Results: Between June 2002 and December 2005, 200 patients entered the study. Patients and disease features were equally balanced among the two groups. As of June 2006, 198 patients are evaluable for toxicity and 160, 80 in each arm, for efficacy. On an intention- to- treat basis, overall response rate was 66.3% and 81.3% in arms A and B respectively (p = 0.048). Neutropenia, thrombocytopenia, infections, mucositis, palmar-plantar erythrodysesthesia, deep venous thrombosis (DVT) and early mortality were not significantly different (p > 0.05) between arms A and B (13% vs. 15%, 8.5% vs. 10%, 7.5% vs. 5%, 5% vs. 4%, 6.3% vs. 5%, 3.8% vs. 9.5% and 6.3% vs. 5% respectively). Constipation, peripheral neuropathy, dizziness/somnolence, skin rash and edema were significantly higher (p < 0.05) in arm B compared to arm A (57% vs. 10%, 46% vs. 13.8%, 54% vs. 0%, 13% vs. 0%, 10% vs. 2% respectively).

Conclusions: We added thalidomide to VAD-doxil which, at the time of trial design was considered the gold standard induction regimen in our Group for symptomatic patients with MM. VAD-doxil plus thalidomide compared to VAD-doxil alone, resulted in a higher response rate. The addition of thalidomide to VAD-doxil resulted in a higher rate of constipation, neuropathy and skin rash while the incidence of DVT was similar in both arms. The final analysis of this study will be performed in October 2006.