Rajkumar's obituary to VAD (vincristine-doxorubicin-dexamethasone) as initial therapy in multiple myeloma (MM) is premature.1 Thalidomide-dexamethasone (Thal-Dex) is a promising regimen for upfront treatment of symptomatic myeloma prior to high-dose therapy and autologous stem cell transplantation (ASCT) with high response rates and convenience of oral administration, but has it done enough to usurp VAD and similar regimens?
We believe a change in clinical practice is mandated if Thal-Dex could demonstrate improved overall survival, reduced toxicity, or a significant reduction in cost without compromising clinical outcomes in comparison to VAD. However, we must be careful when drawing conclusions from surrogate outcomes such as response rate. While most studies have demonstrated the prognostic importance of achieving complete remission after ASCT, this has not been the case for the pre-ASCT response.2,3 In this regard, Cavo et al4 demonstrated that Thal-Dex resulted in higher response rate with induction therapy compared to VAD but did not show improved overall survival. A recent large prospective randomized trial evaluating the role of intensive chemotherapy with or without thalidomide in the initial therapy of MM demonstrated higher complete remission and event-free survival with thalidomide, but similar overall survival for the 2 groups.5
Few would argue that Thal-Dex is an innocuous regimen. Common adverse events of thalidomide include rash, sedation, neuropathy, deep venous thrombosis (DVT), and teratogenicity.6 These risks balance with higher rates of granulocytopenia in VAD, thus the overall toxicity of Thal-Dex is not significantly different from VAD.4
Finally, the cost savings of a purely oral regimen by avoiding hospitalization and central venous access are offset by the high cost of thalidomide, reflecting stringent monitoring and postmarketing surveillance. New agents such as lenalidomide or bortezomib also impose a heavy pharmaco-economic burden.
Thal-Dex remains a promising and useful initial regimen in MM prior to ASCT but falls well short of nailing the VAD coffin shut. It has not been demonstrated to improve overall survival or to reduce toxicity or costs. VAD remains useful and clinically relevant in the initial treatment of symptomatic MM.
VAD and initial therapy for multiple myeloma
Lane and colleagues state that vincristine-doxorubicin-dexamethasone (VAD) remains important as initial therapy for myeloma since Thal/Dex has not shown superiority in terms of overall survival, toxicity, or cost. However, this argument overlooks many of the other reasons I stated why VAD is not a good option in this setting that have little to do with its relative efficacy compared to Thal/Dex. Two of these reasons are worth emphasizing again. First, in newly diagnosed myeloma, VAD has not been shown to be superior to dexamethasone alone using the same type of standards that Lane and colleagues argue are essential when comparing VAD and Thal/Dex.1 Second, it is not wise to subject patients with newly diagnosed myeloma to the neurotoxicity of vincristine right up front when other alternatives are available. I share their concern about cost, toxicity, and lack of demonstrated overall survival benefit with Thal/Dex, but those should not be the reasons to continue using VAD. If data with Thal/Dex are not felt to be sufficient, dexamethasone alone should be preferred over VAD. This will be the most consistent option one can take based on the standards advocated by Lane and colleagues. In fact, it was precisely based on these standards, all of which I agree with, that dexamethasone alone, rather than VAD, was chosen by us as the standard arm in the treatment of newly diagnosed myeloma in a recent randomized trial conducted by the Eastern Cooperative Oncology Group (ECOG).2 The avoidance of VAD as initial therapy will allow patients to receive maximum duration of therapy with active drugs such as thalidomide and bortezomib later in their disease course without incurring clinical or subclinical neurotoxicity from vincristine, a drug with minimal single-agent activity in myeloma.
If not VAD, and if data with Thal/Dex are considered insufficient to advocate its use as standard induction therapy for all patients, what are the alternatives? Due to space constraints my article focused on the drawbacks of VAD but did not discuss alternatives to VAD or the current approach to the treatment of newly diagnosed myeloma. Clearly, enrollment in clinical trials evaluating induction therapy should be considered first. Two large randomized trials are ongoing in the United States using lenalidomide (a new safer and more active analog of thalidomide) as initial therapy; other trials are examining bortezomib-based induction. Outside a clinical trial setting, I actually agree with Lane and colleagues that Thal/Dex should not be used routinely as initial therapy.3 Based on preliminary results of an ECOG randomized trial comparing Thal/Dex versus dexamethasone alone,2 I have suggested that for patients with newly diagnosed myeloma in whom a delay of 1 to 2 months to assess response can be safely done, dexamethasone alone can be used as pretransplant induction therapy, with the plan of adding thalidomide if response is inadequate. Thal-Dex can be reserved for those patients with more aggressive disease with painful symptoms, large lytic lesions, impending cord compression, hypercalcemia or renal failure, in whom a more rapid response is desired.3 Other investigators are pursuing more intense strategies for induction combining bortezomib, thalidomide, and dexamethasone in an attempt to achieve superior complete response rates.4,5 VAD may have a role in relapsed disease but should be avoided as initial therapy for multiple myeloma.
Correspondence: S. Vincent Rajkumar, Division of Hematology, Mayo Clinic, Rochester, MN 55905; e-mail: rajkumar.vincent@mayo.edu.
