This is a research study for patients with newly diagnosed multiple myeloma. Multiple
myeloma remains a non-curable disease however, newer medications and their combinations
appear to provide higher response rates and higher complete response rates than current
treatment options. One of the new medications in multiple myeloma is Velcade. Preliminary
results from a study using a combination of Velcade with Doxil have shown high response
rates (disease reduction). Preliminary results also show that an addition of dexamethasone
to Velcade in patients not responding to Velcade alone showed improved response rates. This
study involves treatment with a new combination of three standard medications: Velcade,
Doxil, and dexamethasone (VDd combination). The proposed combination of all three drugs may
improve efficacy and response.
Velcade is approved by the Food and Drug Administration (FDA) for treatment in multiple
myeloma patients who have received at least two prior therapies and have demonstrated
disease progression on the last therapy. Velcade is still currently under investigation for
other indications. Doxil is not approved for use in multiple myeloma but is an approved drug
for use in patients with some other cancers. Several published clinical trials provide
evidence that Doxil is an active agent in multiple myeloma and it is used in treatment
combinations for multiple myeloma in general practice. Dexamethasone is a standard therapy
for multiple myeloma, but is not approved by the FDA for that use. The combination of all
three drugs is experimental (not FDA approved).
The goals of this study are to determine if this new combination therapy with Velcade, Doxil
and dexamethasone is an effective treatment and also to determine the side effects that
occur when this combination treatment is given.
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.
Each patient must meet all of the following inclusion criteria to be enrolled in the
- Histologic confirmation of multiple myeloma
- Patients must have active multiple myeloma requiring first line treatment
- At least 18 years of age
- Female patient is either postmenopausal or surgically sterilized or willing to use an
acceptable method of birth control (i.e. hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study and for 3 months after completing treatment.
- Male patient agrees to use an acceptable method of contraception for the duration of
the study and for 3 months after completing treatment.
- Expected survival of at least 6 months
- Patients with abnormal kidney function, including patients on dialysis, are eligible
if kidney insufficiency is secondary to multiple myeloma.
- Patients must have adequate liver functions
- Patients may have received up to 2 weeks of high dose steroids. Prior steroid
treatment for more than 2 weeks is allowed provided the treatment was given for
- Prior radiation therapy will be allowed but radiation therapy must be completed prior
Patients meeting any of the following exclusion criteria are not to be enrolled in the
- Serious medical or psychiatric illness likely to interfere with participation in this
- Patient had a myocardial infarction within 6 months of enrollment, history of cardiac
disease, or clinical evidence of congestive heart failure.
- Patient previously received 250 mg/m2 or more of doxorubicin (or equivalent for other
- Patient is known to be human immunodeficiency virus (HIV)-positive (patients assessed
to be at risk should be tested).
- Patient is known to be hepatitis B surface antigen-positive or has known active
hepatitis C infection (patients assessed by the investigator to be at risk should be
- Patient has Grade 2 or greater peripheral neuropathy within 14 days before
- Patient has hypersensitivity to bortezomib, boron or mannitol, conventional
doxorubicin HCL or the components of Doxil, or other study drugs.
- Female subject is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum pregnancy test result obtained
during screening. Pregnancy testing is not required for post-menopausal or
surgically sterilized women.
- Patient is currently receiving other investigational drug(s).