Comment on Cavo et al, page 35

In a matched case-control study of 200 patients, Cavo and colleagues show that thalidomide plus dexamethasone (Thal-Dex) yields significantly higher response rates compared with VAD as pretransplant induction therapy for multiple myeloma.

In recent years, the treatment of myeloma has undergone dramatic changes. After some 4 decades of mainly alkylator and corticosteroid-based therapy, we now have something to talk about in the form of new, active agents.1  This includes thalidomide, an old drug with a notorious past reborn as an anti-neoplastic agent; bortezomib, a novel proteasome inhibitor; and lenalidomide (CC-5013), a potentially safer and more effective analogue of thalidomide. These discoveries have been associated with a better understanding of the bone marrow microenvironment, and assisted by a good dose of serendipity. The task at hand is to determine the best way of incorporating these active agents into the overall therapeutic strategy for myeloma.

Over the years, the paucity of effective drugs led to a dependence on autologous stem cell transplantation as the mainstay of therapy for myeloma patients considered eligible for the procedure. Since its introduction in the 1980s,2  the vincristine-doxorubicin (Adriamycin)-dexamethasone (VAD) regimen quickly became one of the most commonly used treatments for myeloma in preparation for stem cell transplantation. Patients with newly diagnosed myeloma deemed as candidates for a transplant would receive VAD for 4 to 6 cycles and then proceed to transplantation. VAD stood the test of time, and became the standard induction regimen for myeloma in major randomized trials. All this changed with the arrival of thalidomide.3 

Despite its efficacy, VAD was plagued by the need for a central venous line and continuous intravenous infusion for 4 days every 4 to 5 weeks. This meant an increased risk of catheter-related sepsis and thrombosis. There were also substantial questions about the value of vincristine and doxorubicin in the VAD regimen, 2 drugs with negligible single-agent activity in myeloma. Was VAD merely a glorified and more toxic version of dexamethasone? Many thought so. Thus when thalidomide showed promising activity in relapsed myeloma, it was quickly combined with dexamethasone in an attempt to develop an oral alternative to the cumbersome VAD regimen. Three phase-2 trials established that the combination of thalidomide and dexamethasone (Thal-Dex) can achieve similar or better response rates compared with VAD as initial therapy for myeloma.4  As a result, the use of VAD as initial therapy has declined substantially.

In this issue of Blood, Cavo and colleagues appear to have placed the final nail in the coffin for VAD. In a matched case-control study of 200 patients, they show a significantly higher response rate with oral Thal-Dex therapy compared with intravenous VAD; 76% versus 52%, respectively. This difference in response rate is almost identical to the difference in response rate between Thal-Dex and dexamethasone alone observed in a recent randomized trial,5  confirming earlier suggestions that most of VAD's efficacy was due to dexamethasone. But Thal-Dex is not without issues either; deep vein thrombosis occurs in over 15% of patients, necessitating prophylactic anti-coagulation.

Are we prematurely writing the obituary for VAD? I think not. Given the neurotoxicity of vincristine and its questionable activity in myeloma, it would be inappropriate to subject patients to such toxicity up front, thus potentially limiting the future use of thalidomide and bortezomib, both of which also have neurotoxic potential. Similarly, there is little reason to subject patients to the cumulative cardiotoxicity of doxorubicin when other alternatives are available. The paper by Cavo and colleagues adds more substance to this reasoning by demonstrating that VAD is simply less effective than Thal-Dex. As a testament to this, none of the 4 large randomized trials in newly diagnosed myeloma currently ongoing in the United States use VAD as the initial regimen. In fact, the fight is now on for the successor to Thal-Dex, with lenalidomide plus dexamethasone (Rev-Dex) and several bortezomib-based regimens vying to prevail.

Yes, it is time to finally say goodbye to VAD, at least as initial therapy for myeloma. ▪

1
Kyle RA, Rajkumar SV. Multiple myeloma.
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2004
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Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents.
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Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma.
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Dimopoulos MA, Anagnostopoulos A, Weber D. Treatment of plasma cell dyscrasias with thalidomide and its derivatives.
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Rajkumar SV, Blood E, Vesole DH, Shepard R, Greipp PR. Thalidomide plus dexamethasone versus dexamethasone alone in newly diagnosed multiple myeloma (E1A00): results of a phase III trial coordinated by the Eastern Cooperative Oncology Group [abstract].
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. Abstract 205.