Study of Velcade® and Bone Formation in Patients With Relapsed/Refractory Multiple Myeloma

Velcade (bortezomib, PS-341) has recently been approved by the Food and Drug Administration (FDA) for the treatment of multiple myeloma for patients who have received at least one prior therapy. Velcade is a unique compound developed by scientists at Millennium Pharmaceuticals, Inc. Velcade enters cells and affects the way they divide. Cancer cells are particularly sensitive. Velcade interferes with the enzyme "proteasome" which is responsible for allowing cells to divide. When cancer cells cannot divide, they die. Velcade falls into the class of drugs known as "proteasome inhibitors."

Studies at the Myeloma Institute for Research \& Therapy have shown that Velcade is very effective in treating patients who are relapsing after having been treated with at least two lines of prior therapy.

One key factor in multiple myeloma is bone destruction caused by the myeloma cells. Most patients with multiple myeloma (80%) will develop skeletal lesions, despite treatment. These lesions are rarely repaired, even when the myeloma is in remission.

Experience at MIRT has suggested that Velcade may increase osteoblast (bone cells that cause bone growth) activity. One goal of this study is to identify if Velcade's effect on myeloma is due to its ability to increase osteoblasts.

This study also has the following goals:

* To find out the lowest dose of Velcade that has an effect on myeloma and also increases bone activation;
* To identify ways to predict if Velcade will increase bone activation.

Time periods are:

According to cohort assignment, you will receive three cycles of Velcade®™ (1.3 mg/m2, 1.0 mg/m2 or 0.7 mg/m2) on days 1, 4, 8, and 11, on a 21-day cycle.

During the first two cycles of Velcade®™, bone markers (tests on your bones) will be measured Days 1, 4, 8, 11: Pre-dose, post-dose, and every 2 to 4 hours for 8 hours.

Days 2-3, 5-7, 9-10, 12-21: every 24 hours, beginning with the immediate post-dose sample (+/- 2 hours)

During the third cycle of Velcade®™, bone markers will be measured Days 1 and 11: Pre-dose and post-dose, and then again on Day 21.

Eligibility Criteria:
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.