Bortezomib, Arsenic Trioxide, and Melphalan in Treating Patients Undergoing an Autologous Stem Cell Transplant For Multiple Myeloma
Bortezomib, Arsenic Trioxide, and Melphalan in Treating Patients Undergoing an Autologous Stem Cell Transplant For Multiple Myeloma
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes
 needed for cell growth. Drugs used in chemotherapy, such as arsenic trioxide and melphalan,
 work in different ways to stop the growth of cancer cells, either by killing the cells or by
 stopping them from dividing. Giving high-dose combination chemotherapy together with
 bortezomib may kill more cancer cells.

 PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when
 given together with arsenic trioxide and melphalan in treating patients undergoing an
 autologous stem cell transplant for multiple myeloma.
OBJECTIVES:

 Primary

 -  Evaluate toxicity of a conditioning treatment regimen comprising bortezomib, arsenic
 trioxide, and melphalan.

 Secondary

 -  Evaluate response and overall survival.

 -  Determine what correlative laboratory and clinical parameters, if any, are associated
 with efficacy (e.g., serum arsenic trioxide intracellular glutathione depletion, gene
 profiling of myeloma cells).

 OUTLINE: This is a dose-escalation study of bortezomib.

 -  Conditioning regimen: Bortezomib will be given on days -6, -4, and -2, arsenic trioxide
 will be given on days -6, -5, -4, -3, and -2 (total of 5 doses), and melphalan will be
 given on day -2.

 -  Stem cell infusion: On day 0 a minimum of autologous 2 x 10^6 CD34 cells/kg will be
 infused by central catheter.

 After completion of study therapy, patients are followed periodically for at least 5 years.
DISEASE CHARACTERISTICS:

 Inclusion criteria:

 -  Confirmed diagnosis of multiple myeloma (M-protein by serum protein electrophoresis or
 urine protein electrophoresis) and either bone marrow biopsy and aspirate
 demonstrating a plasma cell count > 10% or biopsy of a bone or soft tissue mass
 demonstrating a plasmacytoma

 -  Demonstration of an indication for therapy based on symptoms (e.g., boney pain),
 hypercalcemia, anemia, renal insufficiency, symptomatic plasmacytomas, multiple
 boney lytic lesions, etc

 -  Stable disease or has achieved a partial remission or complete remission to
 pre-transplant cyto-reductive therapy

 -  Primary refractory disease (no response to therapy but stable) is permitted

 -  Candidate for high-dose chemotherapy with autologous stem cell transplantation based
 on stabilization of disease with preparative chemotherapy (regardless of the specific
 agents)

 -  A minimum of 2 x 10^6 CD34+ cells/kg must be collected prior to proceeding to
 transplant

 Exclusion criteria:

 -  Evidence of active plasma cell leukemia

 -  Relapsed refractory disease (patients who have achieved at least a partial response
 [PR] to previous therapy and are now refractory [have not achieved a PR to subsequent
 therapy])

 -  Progressive disease on their last therapy

 PATIENT CHARACTERISTICS:

 Inclusion criteria:

 -  Karnofsky performance status 60-100%

 -  Creatinine < 3.0 mg/dL

 -  AST and ALT <2.5 times upper limit of normal

 -  Total bilirubin < 3 mg/dL

 -  WBC ≥ 2,000/mm³

 -  Platelet count ≥ 50,000/mm³

 -  If abnormal hematologic function is attributable to bone marrow infiltration by
 multiple myeloma, the principal investigator will decide on a case-by-case basis if
 the patient's bone marrow reserve is appropriate for this study

 -  Females of childbearing potential must have a negative serum pregnancy test prior to
 enrollment on the study and must use an effective barrier method while on the study

 -  Ejection fraction > 40% and no history of uncontrolled ischemic heart disease or
 congestive heart failure

 -  No evidence of cardiac amyloidosis by echocardiogram

 -  DLCO and FEV_1 ≥ 50%

 Exclusion criteria:

 -  Active peripheral neuropathy ≥ grade 2

 -  Recurrent supraventricular arrhythmia or any type of sustained ventricular arrhythmia
 or conduction block (e.g., A-V block grade II or III, left bundle branch block)

 -  Known HIV infection

 -  Pregnant or lactating women

 -  Underlying medical condition that could be aggravated by the treatment or
 life-threatening disease unrelated to myeloma as evaluated by the enrolling physician

 -  History of second malignancy within the past 3 years and not in complete remission
 from that malignancy, excluding adequately treated basal or squamous cell carcinoma of
 the skin, carcinoma in situ of the cervix, or local prostate cancer

 -  History of preexisting neurological disorders (grade 2 or higher by the NCI Common
 Toxicity Criteria, in particular seizure disorders)

 PRIOR CONCURRENT THERAPY:

 Inclusion criteria:

 -  Previous radiation therapy for palliation of cord compression or pathologic fractures
 is permitted provided last dose is given 14 days prior to initiation of chemotherapy

 -  Subjects with radiographic evidence of lytic bone disease receiving concomitant
 bisphosphonate therapy may be enrolled

 -  Bisphosphonates should be held at least 1 week prior to the transplant but
 continuing bisphosphonates after day +60 is at the discretion of the treating
 physician

 Exclusion criteria:

 -  Previous autologous or allogeneic transplantation

 -  Other investigational or experimental drug or therapy while on the study