Samarium 153 and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Radioactive substances, such as samarium 153, may release radiation as it breaks down and kill cancer cells. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bortezomib may also make tumor cells more sensitive to radiation. Giving samarium 153 together with bortezomib may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best dose of samarium 153 when given together with bortezomib in treating patients with relapsed or refractory multiple myeloma.

Detailed Description
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OBJECTIVES: Primary Assess the safety and tolerability (maximum tolerated dose and dose-limiting toxicity) of samarium Sm 153 lexidronam pentasodium and bortezomib in patients with relapsed or refractory multiple myeloma. Secondary Determine the response rate (combined complete response, partial response, and minimal response) in patients treated with this regimen. Determine the time to response and the time to progression of disease in patients treated with this regimen. Determine the progression-free survival and overall survival of patients treated with this regimen. Assess the antitumor effects of this regimen in these patients. OUTLINE: This is an open-label, dose-escalation study of samarium Sm 153 lexidronam pentasodium. Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and samarium Sm 153 lexidronam pentasodium IV on day 3. Treatment repeats every 8 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of samarium Sm 153 lexidronam pentasodium until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. The MTD of samarium Sm 153 lexidronam pentasodium is determined with 2 different doses of bortezomib. After completion of study treatment, patients are followed every 3 months. PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.

Official Title
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A Phase I Study of Samarium Sm-153 Lexidronam Combined With Bortezomib for Patients With Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
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* Drug: bortezomib
* Radiation: samarium Sm 153 lexidronam pentasodium


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosed with multiple myeloma by 1 of the following criteria: Meets any 2 of the following major criteria: Plasmacytomas on tissue biopsy Bone marrow plasmacytosis (i.e., > 30% plasma cells) Monoclonal immunoglobulin spike IgG > 3.5 g/dL or IgA > 2.0 g/dL by serum electrophoresis; kappa or lambda light chain excretion > 1 g by 24-hour urine protein electrophoresis Plasmacytomas on tissue biopsy AND meets any 1 of the following minor criteria: Presence of monoclonal immunoglobulin at a lesser magnitude than given under above major criteria Lytic bone lesions Normal IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL Monoclonal immunoglobulin spike IgG > 3.5 g/dL or IgA > 2.0 g/dL by serum electrophoresis; kappa or lambda light chain excretion > 1 g by 24-hour urine protein electrophoresis AND meets 1 of the following minor criteria: Bone marrow plasmacytosis (i.e., 10-30% plasma cells) Lytic bone lesions Presence of monoclonal immunoglobulin at a lesser magnitude than given under major criteria with bone marrow plasmacytosis (i.e., 10-30% plasma cells) AND meets 1 of the following minor criteria: Lytic bone lesions Normal IgM < 50 mg/dL, IgA < 100 mg/dL, or IgG < 600 mg/dL Measurable disease, defined as a monoclonal immunoglobulin spike of ≥ 1 gm/dL by serum electrophoresis and/or a immunoglobulin spike of ≥ 200 mg by 24-hour urine protein electrophoresis or evidence of lytic bone disease OR Nonmeasurable disease (i.e., patients with nonsecretory or oligosecretory multiple myeloma) Relapsed or refractory disease Relapsed disease following a response or stable disease after prior chemotherapy (e.g., single-agent steroids, vincristine, doxorubicin, and dexamethasone [VAD], or melphalan and prednisone [MP]) or high-dose chemotherapy Refractory (i.e., failure to achieve at least complete or partial response or stable disease) to the most recent chemotherapy with or without systemic corticosteroids No plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein), and skin changes (POEMS syndrome) No extramedullary myeloma PATIENT CHARACTERISTICS: Karnofsky performance status 60-100% Life expectancy > 3 months Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 75,000/mm³ AST and ALT ≤ 3 times upper limit of normal (ULN) Bilirubin ≤ 2 times ULN (unless clearly related to disease) Creatinine clearance ≥ 30 mL/min Creatinine clearance > 15 mL/min and < 30 mL/min due to significant myelomatous involvement of kidneys allowed at discretion of investigator Sodium > 130 mmol/L No ECG evidence of acute ischemia or new conduction system abnormalities No myocardial infarction within the past 6 months Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active infection No severe hypercalcemia (i.e., serum calcium ≥ 14 mg/dL) No New York Hospital Association class III or IV heart failure No poorly controlled hypertension, diabetes mellitus, or other serious medical or psychiatric illness that would preclude study treatment No known HIV history No known active hepatitis B or C viral infection No history of allergic reaction attributable to compounds of similar chemical or biological composition to bortezomib, boron, mannitol, ethylenediaminetetramethylenephosphonic acid (EDTMP), or phosphonates No peripheral neuropathy > grade 1 PRIOR CONCURRENT THERAPY: At least 12 weeks since prior samarium Sm 153 lexidronam pentasodium No more than 1 prior treatment At least 24 weeks since prior strontium chloride Sr 89 No more than 1 prior treatment No major surgery within the past 4 weeks No chemotherapy within the past 3 weeks (6 weeks for nitrosoureas) No corticosteroids (> 10 mg/day prednisone or equivalent) within the past 3 weeks No immunotherapy, antibody therapy, or radiotherapy (except localized radiotherapy) within the past 4 weeks No other concurrent investigational agents No concurrent corticosteroids (≥ 10 mg prednisone or equivalent)

Ages Eligible for Study
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Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: bortezomib|nan|
|Radiation: samarium Sm 153 lexidronam pentasodium|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose and dose-limiting toxicity |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate (complete, partial, and minimal response) |  |  | 
| Time to disease progression and time to response |  |  | 
| Progression-free and overall survival |  |  | 
| Antitumor effects |  |  | 

 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