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

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.

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)