Multiple myeloma remains a non-curable disease. Initial therapy with one of the commonly used regimens, such as thalidomide with dexamethasone, VAD, dexamethasone pulses, and melphalan with prednisone results in at least partial response (PR) in approximately 50-75% of patients. Complete responses (CRs) with any of these regimens are uncommon. A proportion of patients will have further improvement of response after autologous stem cell transplant, which usually follows initial therapy. However, virtually all patients will eventually relapse and will require re-treatment. Emerging data suggests that achieving CR or near CR after transplantation will result in a more durable remission and longer survival. It is not clear whether CR in response to initial therapy and prior to transplant may have similar impacts on overall outcomes.

Newer agents and their combinations appear to provide higher response rates and higher CR rates. One of the new active agents in multiple myeloma is Velcade (bortezomib, formerly known as PS-341). This molecule has a novel mechanism of action by specifically inhibiting the proteasome. In a reported phase II trial, Velcade as a single agent induced at least minimal responses (MR) in 35% of patients and CR in 4% of patients, and at least a stabilization of the disease in 59% of patients with heavily pretreated, relapsed/refractory multiple myeloma using strict SWOG criteria. Velcade alone is superior than dexamethasone pulses in a phase III randomized study in patients with at least one but no more than 3 lines of therapy. Preliminary reports indicate that combinations of Velcade with other active anti-myeloma agents appear to provide superior outcomes than Velcade alone. An additional 18% of patients responded when dexamethasone was combined with Velcade in a patient population refractory to Velcade alone. Velcade with Doxil was shown to produce high response rates in a phase I study with 60% PR rate and 20% CR rate and acceptable toxicity in patients with relapsed/refractory multiple myeloma. There is only limited data on the outcomes of treatment of newly diagnosed patients with myeloma with Velcade or its combinations. Velcade as a single agent has been shown to have impressive response rate in newly diagnosed patients with 55% percent of patients achieving at least PR and 77% of patients achieving at least MR as per preliminary report from a phase II study. Treatment with Velcade did not appear to affect stem cell collection.

Considering the high activity of Velcade alone in untreated patients and the superior activity of combinations of Velcade with either Doxil or dexamethasone, we propose combining all three agents as a VDd combination (i.e. Velcade, Doxil, and dexamethasone). We hypothesize that this combination will have similar or better efficacy compared to other commonly used combinations for initial therapy (i.e. thalidomide with dexamethasone, dexamethasone pulses, VAD or melphalan and prednisone) or Velcade alone and higher than these treatment regimens CR rate with acceptable toxicity.