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.

First‐line therapy with thalidomide, dexamethasone and zoledronic acid decreases bone resorption markers in patients with multiple myeloma

“…These data are not unexpected, as dexamethasone is known to suppress osteoblastogenesis, to induce osteoblast apoptosis, and to downregulate osteoprotegerin, thus allowing the interaction of receptor activator of NFkB ligand (RANK‐L), with its own receptor, RANK, that is subsequently activated and promotes the proliferation of pre‐osteoclasts, and activation of mature osteoclasts (33). Dexamethasone, however, is highly effective in MM, and shows a synergistic activity in combination with thalidomide, ultimately resulting in 40–50% partial response rates in pre‐treated patients (8, 34) and 65–75% responses in patients with newly diagnosed MM (9–11). Little is known about the effects of thalidomide on cells implicated in bone metabolism as osteoblasts or osteoclasts.…”

“…The median age of the patients was 53.5 yr (range 34–65), and none of them had abnormal renal function or hypercalcaemia. After informed consent, patients were enrolled in the ‘Bologna 2002’ clinical trial (11). Consequently, they received 4 months of combined oral thalidomide (100 mg/d for 2 wk and 200 mg/d thereafter) and dexamethasone (40 mg/d on days 1–4, 9–11, 17–20/28 on odd cycles and on days 1–4 on even cycles) as remission induction treatment prior to peripheral blood stem cell collection and subsequent double autologous transplant.…”

“…The introduction of novel therapeutic agents such as thalidomide, thalidomide analogues and bortezomib, that target both the myeloma clone and its microenvironment, has widened the scope of treating this disease (7). In particular, thalidomide, after having shown remarkable activity in relapsed or refractory MM (8), is now being used in newly diagnosed patients, and encouraging results have been obtained so far, in terms of response and tolerance (9–11).…”

Hemostatic complications of angiogenesis inhibitors in cancer patients

“…The incidence of VTE was 10% without a significant increase in the incidence of bleeding complications [102]. In contrast to the experience of Weber and colleagues and Zangari et al with 1.0 mg of warfarin [53,101], Cavo et al and Ikhlaque et al reported that fixed, low-dose warfarin (1.25 mg/d or 1-2 mg) resulted in effective thromboprophylaxis for newly diagnosed patients treated with thalidomide and dexamethasone [103,104]. It is controversial whether this dose of warfarin can be safely used without the added burden to the patient of INR monitoring.…”

Vincristine, doxorubicin, and dexamethasone or thalidomide plus dexamethasone for newly diagnosed patients with multiple myeloma?

“…However, VAD have several disadvantages including the need for an intravenous indwelling catheter, which predisposes patients to catheter related sepsis and thrombosis; most of the activity of VAD was from high‐dose dexamethasone component (5). Recently the combination of thalidomide plus dexamethasone (Thal/Dex) has emerged as an alternative to VAD in newly diagnosed MM patients based on three phase II clinical trials and one case–control study (6–9). Response rates with Thal/Dex varied from 64% to 76%, which are comparable or better than those obtained with VAD (9, 10).…”