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

Phase 2
18 Years
Not Enrolling
Multiple Myeloma

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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.

Inclusion Criteria:

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
neurological compromise.

- Prior radiation therapy will be allowed but radiation therapy must be completed prior
to registration.

Exclusion Criteria:

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
clinical study.

- 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).

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Andrzej J Jakubowiak, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

The University of Michigan Health System


United States: Institutional Review Board

Study ID:

UMCC 2004.047



Start Date:

June 2005

Completion Date:

December 2007

Related Keywords:

  • Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



University of Michigan Ann Arbor, Michigan  48109-0624