S0417 Bortezomib, Thalidomide, and Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as thalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. It may also stop the growth of cancer by blocking blood flow to the cancer. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with thalidomide and dexamethasone may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving bortezomib together with thalidomide and dexamethasone works in treating patients with relapsed or refractory multiple myeloma.

Detailed Description
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OBJECTIVES: Determine the confirmed overall response rate (complete remission, remission, and partial remission) in patients with relapsed or refractory multiple myeloma treated with bortezomib, thalidomide, and dexamethasone. Determine overall and progression-free survival of patients treated with this regimen. Determine the qualitative and quantitative toxic effects of this regimen in these patients. Correlate, preliminarily, treatment with bortezomib with the activation of osteoblasts in these patients. OUTLINE: This is a multicenter study. Induction therapy: Patients receive bortezomib IV on days 1, 4, 8, and 11, oral thalidomide once daily on days 1-21, and oral dexamethasone once daily on days 1, 2, 4, 5, 8, 9, 11, and 12. Treatment repeats every 21 days until achievement of confirmed complete remission (CR), remission (R), or partial remission (PR) OR for up to 8 courses in the absence of disease progression or unacceptable toxicity. Patients achieving confirmed CR, R, or PR who reach a plateau prior to receiving the maximum 8 courses of induction therapy OR who achieve confirmed CR, R, or PR after receiving the maximum 8 courses of induction therapy proceed to maintenance therapy. Patients achieving stable disease after receiving the maximum 8 courses of induction therapy either proceed to maintenance therapy or receive further treatment with bortezomib, thalidomide, and dexamethasone off-study. Maintenance therapy: Patients receive oral dexamethasone on days 1-4. Courses repeat every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed within 30 days and then every 6 months for up to 5 years. PROJECTED ACCRUAL: A total of 90 patients will be accrued for this study within 18 months.

Official Title
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S0417 A Phase II Study of Bortezomib (Velcade™, PS-341), Thalidomide, and Dexamethasone in Patients With Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: bortezomib
* Drug: dexamethasone
* Drug: thalidomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of multiple myeloma (MM) Active disease Relapsed or refractory disease after ≥ 1 prior therapy for MM, that may have included autologous or allogeneic stem cell transplantation Relapse is defined as the occurrence of any of the following during or after prior treatment: Myeloma protein level increase by > 100% from the lowest previously recorded level Myeloma protein level increase above the defined response criteria for partial remission Reappearance of any myeloma peak that had disappeared during the prior treatment Increase in the size and number of lytic bone lesions and/or focal lesions by x-ray, MRI, positron emission tomography, and/or CT scan Refractory disease is defined as no response (i.e., not achieving complete remission, remission, or partial remission) to prior therapy Measurable disease No evidence of POEMS (polyneuropathy, organomegaly, endocrinopathy, presence of M-protein, and skin changes) syndrome Must be registered on protocol SWOG-S0334 PATIENT CHARACTERISTICS: Age 18 and over Performance status Zubrod 0-2 (unless due to bone pain) Life expectancy Not specified Hematopoietic Absolute neutrophil count > 1,000/mm^3 Platelet count > 50,000/mm^3 Hepatic AST or ALT ≤ 3 times upper limit of normal (ULN) Bilirubin ≤ 3 times ULN Renal Creatinine clearance > 30 mL/min Cardiovascular No New York Heart Association class III or IV congestive heart failure No myocardial infarction within the past 6 months No poorly controlled hypertension Other Not pregnant or nursing Negative pregnancy test Fertile female patients must use effective double method contraception for ≥ 4 weeks before, during, and for ≥ 4 weeks after completion of study treatment (during and for 4 weeks after completion of study treatment for male patients) No blood, ova, or sperm donation during study treatment No active infection requiring antibiotics No neurotoxicity ≥ grade 2 No diabetes mellitus No other serious medical or psychiatric illness that would preclude study treatment No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy See Disease Characteristics Chemotherapy At least 14 days since prior chemotherapy (28 days for nitrosoureas) and recovered Endocrine therapy Not specified Radiotherapy At least 14 days since prior radiotherapy and recovered Surgery Not specified Other No prior bortezomib alone or combined with thalidomide Concurrent participation on protocol SWOG-S0309 allowed

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bortezomib with thalidomide and dexamethasone<br>bortezomib with thalidomide and dexamethasone | Drug: bortezomib<br>* induction: 1 mg/m2 IV push days 1, 4, 8, 11 every 21 days<br>Drug: dexamethasone<br>* induction: 20 mg/d PO days 1, 2, 4, 5, 8, 9, 11, 12 every 21 days maintenance: 40 mg days 1-4 every 28 days until progression<br>Drug: thalidomide<br>* 100 mg/d PO days 1-21 every 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Complete Remission (CR), Remission (R), and Partial Remission (PR). | Responses are defined as follows: Complete Remission: Absence of bone marrow or blood findings of multiple myeloma. This includes disappearance of all evidence of serum and urine M-proteins on immunofixation electrophoresis studies. Normalization of serum concentrations of normal immunoglobulins is not required for CR. There must also be no evidence of increasing anemia. Bone marrow cellularity must be ≥ 20% with plasma cells ≤ 5%. Remission: A ≥ 75% reduction in the serum M-protein, and if a urine M-protein (Bence-Jones protein) is present, either a ≥ 90% reduction in this protein, or a urine M-protein < 0.2gm/day. Bone marrow plasma cells must be ≤ 5%. Partial Remission: A ≥ 50% reduction in the serum M-protein, and if present, a ≥ 50% reduction in the urine M-protein (Bence-Jones protein). Bone marrow plasma cells must not be increased from baseline level. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Evaluation | To evaluate the qualitative and quantitative toxicities associated with this regimen. | From date of protocol therapy start to date of protocol therapy end, i.e., up to about 3.5 years | 
| Progression-Free Survival | From date of initial registration to date of progression/relapse of disease (> 25% increase from baseline in myeloma protein production or other signs of disease progression such as hypercalcemia, etc.) or death from any cause, whichever came first, up to 5 years | about 12-18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma