Study of DOXIL/CAELYX (Pegylated Liposomal Doxorubicin) and VELCADE (Bortezomib) or VELCADE Monotherapy for the Treatment of Relapsed Multiple Myeloma

This is a randomized (study drug assigned by chance), parallel-group, open-label (all
involved people know the identity of the intervention), multicenter study in 18 countries. A
total of 646 patients with multiple myeloma whose disease has progressed after an initial
response to at least 1 line of prior therapy or was refractory to initial treatment will be
enrolled. The primary endpoint is time to progression (the interval between the date of
randomization and the date of disease progression); secondary endpoints are overall survival
(the interval between the date of randomization and the patient's death from any cause),
response rate (the proportion of patients in the evaluable population who achieved a
complete or partial response), and safety. Other study endpoints include patient reported
outcomes and exploratory pharmacogenics (to identify genetic markers of response). Patients
are assessed for efficacy and safety every 3 weeks until disease progression is documented
or for up to 42 weeks from the start of the first dose of study drug. Patients, who do not
progress after the 42-week period, are assessed every 6 weeks until disease progression is
documented. Efficacy evaluations includes: serum protein electrophoresis, 24-hour urine
collection for protein electrophoresis, skeletal survey (plain films), bone marrow biopsy
and aspirate, clinical or radiologic assessment of plasmacytomas, and serum calcium.
Responses and progressions are assessed objectively by a computer algorithm based on the
EBMT criteria. Safety evaluations include adverse event reports, changes in clinical
laboratory findings, and tests for cardiac function (multiple gated acquisition
scan/echocardiogram and electrocardiogram). Group A: VELCADE monotherapy: VELCADE 1.3
milligram per meter square (mg/m^2) to be administered by i.v. bolus on Days 1, 4, 8, and 11
of each 21-day cycle. Group B: DOXIL/VELCADE combination: treated with VELCADE at the same
dose and schedule as specified in Group A. DOXIL/CAELYX 30 mg/m^2 by intravenous infusion
given on Day 4 of every 21-day cycle following the administration of VELCADE.

Inclusion Criteria:

- Patients with multiple myeloma who have received at least 1 prior therapy and who
have either responded and later had progressive disease or have progressed during
their first therapy (primary refractory) are eligible for the study

- Patients who may have received prior doxorubicin but not more than a cumulative dose
of 240 milligram per meter square (mg/m^2) doxorubicin, DOXIL, or the equivalent
amount of another anthracycline (i.e., 1 mg doxorubicin = 1 mg DOXIL/CAELYX = 1.8 mg
epirubicin = 0.3 mg mitoxantrone = 0.25 mg idarubicin)

- Must have normal cardiac function, as evidenced by a left LVEF within institutional
normal limits.

Exclusion Criteria:

- History of treatment with VELCADE or progressive disease while receiving an
anthracycline-containing regimen

- No change in disease status during initial therapy

- No treatment for malignancy within past 5 yrs (other than multiple myeloma) or
progressive disease while receiving anthracycline-containing regimen

- Non-secretory disease

- Myocardial infarct within past 6 months

- No major surgery in past 30 days.