Superiority of First-Line Thalidomide-Dexamethasone over Vincristine-Doxorubicin-Dexamethasone in Preparation for Autologous Stem Cell Transplantation for Multiple Myeloma.

Abstract

The aim of the present study was to compare thalidomide-dexamethasone (THAL-DEX) and vincristine-doxorubicin-dexamethasone (VAD) as primary therapy for newly diagnosed multiple myeloma (MM). For this purpose, we performed a retrospective matched case-control analysis of 200 patients who were treated with THAL-DEX (n=100) or VAD (n=100) on two consecutive studies from 1996 to 2003. Thalidomide was given orally at the daily dose of 200 mg, while VAD was administered by continuous infusion. Pulsed dexamethasone combined with thalidomide or vincristine-doxorubicin was given at the monthly dose of 40 mg/d for 4 days (1 to 4), with courses repeated on days 9 to 12 and 17 to 20 on odd cycles. By design of both studies, THAL-DEX and VAD were planned to be given for 4 months in an attempt to reduce tumor cell mass before collection of peripheral blood stem cells (PBSC) and subsequent autologous transplantation. Matching criteria were age (within 2 years), clinical stage and serum β2-microglobulin (within 1 mg/l). In addition to the above mentioned criteria, all other relevant baseline patient characteristics were comparable between the two groups. Response to therapy was evaluated using an intent-to-treat approach and stringently defined criteria (EBMT). In comparison with VAD, THAL-DEX resulted in a significantly higher ≥ partial response rate (76% versus 52%, respectively; P=0.0004) and effected more profound reduction in serum IgG (P=0.002) and IgA (P=0.01) M protein levels. Nine patients treated with THAL-DEX and 9 patients who received VAD did not proceeded to PBSC mobilization, mainly because of death while on study treatment (THAL-DEX=5 patients; VAD=6 patients) or nonfatal toxicity (THAL-DEX=3 patients; VAD=2 patients). The median number of CD34+ cells collected following high dose cyclophosphamide 7 g/m2 was 7.85 x 106/kg in the THAL-DEX group and 10.5 x 106/kg in the VAD group. Considering 4 x 106 CD 34+/kg as the minimum number of stem cells required to safely perform double autologous transplantation, adequate cell yields were obtained in 83% of patients with prior exposure to THAL-DEX and in 88% of patients treated with VAD (P=0.3). In conclusion, results of the present study (to the best of our knowledge, the first comparing THAL-DEX with VAD as initial cytoreductive therapy in preparation for autologous transplantation) extend and confirm prior observations by our group and others showing that THAL-DEX is an effective and relatively well tolerated induction regimen for previously untreated patients with MM. In comparison with VAD, THAL-DEX significantly augmented tumor cytoreduction without increasing the toxicity or interfering with subsequent collection of PBSC. Based on these data, thalidomide-dexamethasone may be considered an oral, and easy to administer, alternative to the more complex, and cumbersome to administer, combination of vincristine-doxorubicin-dexamethasone as front-line therapy for MM patients who are candidates to subsequent autologous transplantation.