An International, Multi-Center, Randomized, Open-Label Study of PS-341 (VELCADE™) Versus High-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Inclusion Criteria

Inclusion Criteria

- Patient is of a legally consenting age, as defined by local regulations.

- Patient is, in the investigator's opinion, willing and able to comply with the
protocol requirements.

- Patient has given voluntary written informed consent before performance of any
study-related procedure not part of normal medical care, with the understanding that
consent may be withdrawn by the patient at any time without prejudice to their future
medical care.

- Female patient is either post-menopausal or surgically sterilized or willing to use
an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
duration of the study.

- Male patient agrees to use an acceptable method for contraception for the duration of
the study.

- Patient was previously diagnosed with multiple myeloma based on standard criteria and
currently requires second-, third-, or fourth-line therapy because of PD, defined as
a 25% increase in M-protein, development of new or worsening of existing lytic bone
lesions or soft tissue plasmacytomas, or hypercalcemia (serum calcium >11.5 mg/dL),
or relapse from CR.

- Patient has measurable disease, defined as follows:

- For secretory multiple myeloma, measurable disease is defined as any quantifiable
serum monoclonal protein value (generally, but not exclusively, greater than 1 g/dL
of IgG M-Protein and greater than 0.5g/dL IgA) and, where applicable, urine
light-chain excretion of ≥200 mg/24 hours.

- For oligo- or non-secretory multiple myeloma, measurable disease is defined by the
presence of soft tissue (not bone) plasmacytomas as determined by clinical
examination or applicable radiographs (i.e. MRI, CT-Scan). In patients with
oligosecretory multiple myeloma, the serum and/or urine M-protein measurements are
very low and difficult to follow for response assessments. Therefore, other disease
sites (bone marrow; extramedullary mass) must be assessed and followed. In patients
with non-secretory multiple myeloma, there is no M-protein in serum or urine by
immunofixation.

- Patient has a Karnofsky performance status ≥60%.

- Patient has a life-expectancy >3 months.

- Patient has the following laboratory values at and within 14 days before Baseline
(Day 1 of Cycle 1, before study drug administration):

- Platelet count ≥50 x 10E+9/L without transfusion support within 7 days before the
laboratory test.

- Hemoglobin ≥7.5 g/dL, without transfusion support within 7 days before the laboratory
test.

- Absolute neutrophil count (ANC) ≥0.75 x 10E+9/L without the use of colony stimulating
factors.

- Corrected serum calcium <14 mg/dL (3.5 mmol/L).

- Aspartate transaminase (AST): ≤2.5 x the upper limit of normal (ULN).

- Alanine transaminase (ALT): ≤2.5 x the ULN.

- Total bilirubin: ≤1.5 x the ULN.

- Calculated or measured creatinine clearance: ≥20 mL/minute.

Exclusion Criteria

- Patient previously received treatment with VELCADE.

- Patient previously was refractory to treatment with high-dose dexamethasone, as
experiencing less than a partial response to or PD within 6 months after
discontinuing dexamethasone, or discontinued dexamethasone because of ≥Grade 3
dexamethasone-related toxicity.

- Previous high-dose dexamethasone therapy is defined as >500 mg dexamethasone or
equivalent over a 10-week period, whether administered alone or as part of the VAD
regimen.

- Patient received nitrosoureas within 6 weeks or any other chemotherapy, including
thalidomide or clarithromycin, or radiation therapy within 3 weeks before enrollment.

- Patient received corticosteroids (>10 mg/day prednisone or equivalent) within 3 weeks
before enrollment.

- Patient received immunotherapy or antibody therapy within 8 weeks before enrollment.

- Patient received plasmapheresis within 4 weeks before enrollment.

- Patient had major surgery within 4 weeks before enrollment. (Kyphoplasty is not
considered major surgery.)

- Patient has a history of allergic reaction attributable to compounds containing boron
or mannitol.

- Patient has peripheral neuropathy of Grade 2 or greater intensity, as defined by the
NCI Common Toxicity Criteria (NCI CTC):

- Grade 2: Objective sensory loss or paresthesia (including tingling), interfering
with function, but not interfering with activities of daily living (ADLs).

- Grade 3: Sensory loss or paresthesia interfering with ADLs.

- Grade 4: Permanent sensory loss that interferes with function.

- Patient had a myocardial infarction within 6 months of enrollment or has New York
Heart Association (NYHA) Class III or IV heart failure uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities.

- Patient was treated for a cancer other than multiple myeloma within 5 years before
enrollment, with the exception of basal cell carcinoma or cervical cancer in situ.

- Patient has cardiac amyloidosis.

- Patient has poorly controlled hypertension, diabetes mellitus, or other serious
medical or psychiatric illness that could potentially interfere with the completion
of treatment according to this protocol.

- Patient is known to be human immunodeficiency virus (HIV)-positive. (Patients
assessed by the investigator to be at risk for HIV infection should be tested in
accordance with local regulations.)

- Patient is known to be hepatitis B surface antigen-positive or has known active
hepatitis C infection.

- Patient has an active systemic infection requiring treatment.

- Female patient is pregnant or breast-feeding.

- Patient currently is enrolled in another clinical research study and/or is receiving
an investigational agent for any reason.