Safety and Efficacy Study of Single Weekly Bortezomib in Newly Diagnosed Multiple Myeloma

Phase II Study to Evaluate Efficacy and Safety of Single Weekly Administration of Bortezomib in Newly Diagnosed Multiple Myeloma

This is a research study to see if a new drug called bortezomib is useful to treat multiple myeloma in people who are newly diagnosed, and have not yet received treatment for their disease. VELCADE® (bortezomib) for Injection is a drug under development by Millennium Pharmaceuticals, Inc.

This study is a multi-site study which will enroll up to 50 patients with multiple myeloma who have not had prior treatment.

Prior to starting treatment individuals will be evaluated to determine if they are eligible to participate in the study. There are certain prestudy test that are required: physical exam, blood tests, ECG, chest x-ray, skeletal survey, bone marrow aspirate and biopsy to confirm the diagnosis of multiple myeloma and to determine baseline health status.

Before beginning each treatment cycle and at the end of the study, patients will have protein studies (including blood and urine) to see if they are responding to the treatment. Before each weekly treatment cycle patients will also have blood tests for red and white blood cells and platelets, and blood chemistry tests for electrolytes, kidney and liver function, calcium and blood sugar.

Patients may receive up to 6 cycles of treatment. At the end of the study, individuals who have responded to treatment will be seen every two months to check for disease progression.

Inclusion Criteria:

1. Diagnosis of multiple myeloma based on standard criteria.

2. Measurable disease, defined as a monoclonal immunoglobulin spike on serum electrophoresis of > 1Gm/dL and/or urine monoclonal immunoglobulin spike of > 200mg/24 hours.

3. Non-secretors must have measurable protein by Freelite or measurable disease such as plasmacytoma to be eligible.

4. Patient must not have been previously treated with chemotherapy. Prior treatment of hypercalcemia with corticosteroids, or bisphosphonates does not disqualify the patient.

5. Patient must be ineligible for autologous stem cell transplant due to one or more of the following reasons:

   • Age>65

   • Impaired renal function (creatinine≥2.0 mg/dL)

   • Impaired pulmonary function (DLCO≤50%)

   • Poor performance status (KPS≤80)

   • Other prohibitive comorbid disorder

     • 5b. Patients≥60 who decline autologous stem cell transplant are eligible for this study.
     • 5c. Patients who are eligible but wish to postpone autologous stem cell transplant are eligible for this study.

6. Karnofsky performance status>50

7. Patients treated with local radiotherapy with or without a brief exposure to steroids are eligible. Patients who require concurrent radiotherapy should have entry to the protocol deferred until the radiotherapy is completed, followed by a four week wash out period Spot RT to ≤3 vertebrae acceptable prior to entry.

8. Meets the following pretreatment laboratory criteria at Baseline (Within 14 days prior to study drug administration):

   1. Platelet count>50x10^9/L or, if the bone marrow is extensively infiltrated,>30x10^9/L
   2. Hemoglobin>8.0G/dL
   3. Absolute neutrophil count >1.0x10^9/L or, if the bone marrow is extensively infiltrated, >0.5x10^9/L

9. Meets the following pretreatment laboratory criteria for liver function tests at the screening visit conducted within 14 days of registration

   1. AST (SGOT): <3 times the upper limit of institutional laboratory normal
   2. ALT (SGPT): <3 times the upper limit of institutional laboratory normal
   3. Total bilirubin: <2 times the upper limit of institutional laboratory normal, unless clearly related to the disease

10. Women with child-bearing potential should be practicing an adequate form of contraception, as judged by the investigator (i.e. birth control pills, double barrier method, abstinence, etc.) or be surgically sterile or 12 months post-menopausal. Male subject agrees to use an acceptable method for contraception for the duration of the study.

11. Age 18 years or older

12. Has given voluntary written informed consent.

Exclusion Criteria:

1. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes)
2. Plasma cell leukemia
3. Impaired kidney function requiring dialysis, patients on hemodialysis are excluded
4. Receiving steroids >the equivalent of 10mg prednisone daily for other medical conditions, e.g., asthma, systemic lupus erythematosis, rheumatoid arthritis
5. Infection not controlled by antibiotics
6. HIV infection. Patients should provide consent for HIV testing according to the institution's standard practice
7. Known active hepatitis B or C
8. Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
9. Second malignancy requiring concurrent treatment
10. Other serious medical or psychiatric illness that could potentially interfere with the completion of treatment according to this protocol
11. Positive pregnancy test in women of childbearing potential
12. Patient has hypersensitivity to boron or mannitol.
13. Patient has ≥Grade 2 peripheral neuropathy within 14 days before enrollment.
14. Patient has received other investigational drugs with 14 days before enrollment