Role of VAD in the initial treatment of 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.