Bortezomib, Ascorbic Acid, and Melphalan in Treating Patients With Newly Diagnosed Multiple Myeloma

OBJECTIVES:

Primary

• Determine the overall response rate (combined complete response [CR], near CR, partial response [PR], and minimal response [MR]) and time to progression of disease in patients with newly diagnosed multiple myeloma treated with bortezomib, ascorbic acid, and melphalan.
• Assess the safety and tolerability of this regimen in these patients.

Secondary

• Assess the time to response in these patients.
• Determine progression-free and overall survival of these patients.
• Assess time to disease progression among subjects who continue to maintenance treatment with bortezomib.

OUTLINE: This is an open-label study.

• Induction therapy: Patients receive bortezomib IV on days 1, 4, 8, and 11 and oral melphalan and oral ascorbic acid on days 1-4. Treatment repeats every 28 days to maximum response [MR] or for at least 8 courses in the absence of disease progression or unacceptable toxicity. Patients with responding disease receive an additional 2 courses of induction therapy beyond MR and proceed to maintenance therapy. Patients with stable disease or without a maximum reduction in their paraprotein after 8 courses of induction therapy are eligible to receive maintenance therapy.
• Maintenance therapy: Patients receive bortezomib IV on days 1 and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Newly diagnosed symptomatic multiple myeloma based on the following criteria:

• Durie-Salmon staging
• Measurable disease, defined as a monoclonal immunoglobulin spike on serum electrophoresis of ≥ 1 g/dL and/or urine monoclonal immunoglobulin spike of ≥ 200 mg/24 hours
• Symptomatic disease
• No POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes)
• No plasma cell leukemia

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%
• Life expectancy > 3 months
• Platelet count ≥ 50,000/mm³ (30,000/mm³ if the bone marrow is extensively infiltrated)
• Hemoglobin ≥ 8.0 g/dL
• Absolute neutrophil count ≥ 1,000/mm³
• Creatinine ≤ 3 mg/dL
• Sodium > 130 mmol/L corrected
• AST and ALT ≤ 3 times upper limit of normal (ULN)
• Bilirubin ≤ 2 times ULN unless clearly related to the disease
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Any ECG abnormality has to be documented by the investigator as not medically relevant
• No electrocardiographic evidence of acute ischemia or new conduction system abnormalities
• No myocardial infarction or EKG evidence of infarction within the past 6 months
• No active infection
• No severe hypercalcemia (i.e., serum calcium ≥ 14 mg/dL [3.5 mmol/L])
• No New York Heart Association class III or IV heart failure
• No uncontrolled angina
• No severe uncontrolled ventricular arrhythmias
• No active conduction system abnormalities
• No poorly controlled hypertension
• No diabetes mellitus
• No known HIV infection
• No known active hepatitis B or C viral infection
• No history of grand mal seizures
• No history of allergic reaction to compounds of similar chemical or biological composition to melphalan, bortezomib, boron, or mannitol
• No peripheral neuropathy ≥ grade 2 within the past 14 days
• No other serious medical or psychiatric illness that could potentially interfere with the completion of study treatment

PRIOR CONCURRENT THERAPY:

• More than 4 weeks since prior immunotherapy, antibody therapy, or radiotherapy
• More than 4 weeks since prior major surgery
• No prior therapy for myeloma

• Prior prednisone at a total of 400mg over ≤ 4 days (or an equivalent potency of another steroid) allowed
• No concurrent corticosteroids (≥ 10 mg prednisone/day or equivalent)
• No other concurrent investigational agents
• No other concurrent antimyeloma therapy