Trial Information

A Phase II Study of Combination of Velcade, Doxil, and Dexamethasone (VDd) as First Line Therapy for Multiple Myeloma

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.