A Phase II Dose-Response Study of Velcade® and Bone Formation in Patients With Relapsed/Refractory Multiple Myeloma

Inclusion Criteria:

- History of histologically documented MM with relapsed or progressive disease after at
least one line of prior therapy.

- Patient has measurable disease in which to capture response, defined as one or more
of the following:

- Serum M-protein level > 1.0 gm/dl (10.0 g/L) measured by serum protein
electrophoresis or immunoglobulin electrophoresis; or

- Urinary M-protein excretion > 1000 mg/24 hours; or

- Bone marrow plasmacytosis of > 30% by bone marrow aspirate and/or biopsy; or

- Serum free light chains (by the Freelite test) > 2 X the upper limit of normal,
in the absence of renal failure.

- Evidence of active disease by radiographic techniques

- Performance status (PS) of <= 2 as per Southwest Oncology Group scale, unless PS of
3-4 based solely on bone pain.

- Patients must have a platelet count >= 50,000/mm3, and an absolute neutrophil count
of at least 1,000/μl.

- Patients must have adequate renal function defined as creatinine clearance >
30ml/min.

- Patients must have adequate hepatic function defined as serum transaminases and
direct bilirubin < 2 X the upper limit of normal.

- Pregnant or nursing women may not participate. Women of childbearing potential must
have a negative pregnancy test documented within one week of registration. Women of
reproductive potential may not participate unless they have agreed to use an
effective contraceptive method.

- Male or female adults of at least 18 years of age.

- Patients must have signed and Institutional Review Board approved written informed
consent form and demonstrate willingness to meet follow-up schedule and study
procedure obligations

Exclusion Criteria:

- Chemotherapy or radiotherapy received within the previous 4 weeks.

- Has received previous bortezomib therapy

- Significant neurotoxicity, defined as grade > 2 neurotoxicity per National Cancer
Institute Common Toxicity Criteria.

- Platelet count < 50,000/mm3, or ANC < 1,000/μl

- Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes
syndrome.

- Patient has hypersensitivity to bortezomib, boron, or mannitol

- Clinically significant hepatic dysfunction as noted by bilirubin or AST >3 times the
upper normal limit or clinically significant concurrent hepatitis.

- New York Hospital Association Class III or Class IV heart failure.

- Myocardial infarction within the last 6 months.

- Non-secretory multiple myeloma, unless the patient has measurable lesions on computed
tomography, magnetic resonance imaging and/or positron emission tomography.

- Uncontrolled, active infection.

- Patients with a history of treatment for clinically significant ventricular cardiac
arrhythmias.

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

- Pregnant or potential for pregnancy. Women of childbearing potential will have a
pregnancy [beta-HCG] test at screening, and will be required to use a medically
approved contraceptive method. Pregnancy testing will be performed prior to
administration of each cycle of study drug.

- Breast-feeding women may not participate.