Velcade, Doxil, and Dexamethasone (VDd) as First Line Therapy for Multiple Myeloma
Velcade, Doxil, and Dexamethasone (VDd) as First Line Therapy for Multiple Myeloma
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.
Inclusion Criteria:

 Each patient must meet all of the following inclusion criteria to be enrolled in the study:

 -  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
 study:

 -  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
 anthracyclines).

 -  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
 tested)

 -  Patient has Grade 2 or greater peripheral neuropathy within 14 days before enrollment.

 -  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).