Bortezomib Followed by High-Dose Melphalan and Bortezomib as Conditioning Regimen for Tandem Stem Cell Transplants
Condition: Multiple Myeloma; Plasma Cell Leukemia
MeSH terms: Leukemia; Multiple Myeloma; Neoplasms, Plasma Cell; Leukemia, Plasma Cell
Intervention: Bortezomib; Melphalan; PBSCT
Intervention description: the maximum tolerated dose (MTD) of bortezomib in combination with high-dose melphalan as a conditioning regimen for autologous stem cell transplant; Day -4 melphalan 100 mg/m2 intravenously over 30 minutes, Day -3 melphalan 100 mg/m2 intravenously over 30 minutes; PBSCT #1 Day 0 PBSCT #2 Day 0 (approx 90 days =/- 15 days after PBSCT #1)
Intervention MeSH terms: Bortezomib; Melphalan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The primary objectives of this study are to:

        -  To determine the maximum tolerated dose (MTD) of bortezomib in combination with
           high-dose melphalan as a conditioning regimen.

        -  To determine the safety, tolerability, and response rates of bortezomib given in
           combination with high-dose melphalan, as a conditioning regimen, for tandem transplants
           in patients with primary refractory multiple myeloma or plasma cell leukemia.

      The secondary objectives of this study are to:

        -  To determine gene expression profiles (pharmacogenomics) and perform RTPCR for Fanconi
           anemia pathway genes, prior to and after treatment with bortezomib, in patients with
           primary refractory multiple myeloma and plasma cell leukemia and correlate profiles with
           responses to treatment.

        -  To determine the time to disease progression and overall survival in patients with
           primary refractory multiple myeloma and plasma cell leukemia treated with bortezomib
           followed by tandem autologous transplantation

        -  To determine the response rates of 2 cycles of bortezomib in patients with primary
           refractory multiple myeloma or plasma cell leukemia
    

Eligibility criteria:

        Inclusion Criteria:

          -  Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the subject at any time without prejudice to future medical care.

          -  Female is either post-menopausal or surgically sterilized or willing to use an
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study.

          -  Male agrees to use an acceptable method for contraception for the duration of the
             study.

          -  Multiple Myeloma Criteria:

          -  Patients with primary refractory disease (those failing to achieve at least a partial
             response, as defined by the Bladé multiple myeloma response criteria, after first-line
             (induction) therapy). A partial response will be defined as the following: ≥50%
             reduction in the level of the serum monoclonal paraprotein, maintained for a minimum
             of 6 weeks, Reduction in 24-hour urinary light chain excretion either by ≥ 90% or to <
             200 mg, maintained for a minimum of 6 weeks. For patients with non-secretory myeloma
             only, ≥ 50% reduction in plasma cells in a bone marrow aspirate and biopsy, maintained
             for a minimum of 6 weeks, ≥ 50% reduction in the size of soft tissue plasmacytomas (by
             radiography or physical examination). No increase in the size or number of lytic bone
             lesions (development of a compression fracture does not exclude response).

          -  Patients with plasma cell leukemia, either newly diagnosed or previously treated.

          -  Patients greater than or equal to 18 years of age are eligible.

          -  Patients must have a histologically confirmed diagnosis by a pathologic review at the
             H. Lee Moffitt Cancer Center and Research Institute.

          -  Patients must have undergone a complete psychosocial evaluation and have been
             considered capable of compliance.

        Exclusion Criteria:

          -  Patient has a platelet count of <30× 10^9/L within 14 days before enrollment.

          -  Patient has an absolute neutrophil count of <1.0 × 10^9/L within 14 days before
             enrollment.

          -  Patient has a serum creatinine of greater than 2.0 mg/dL OR a creatinine clearance of
             less than 40 ml/minute within 14 days before enrollment. Creatinine clearance can be
             measured or calculated.

          -  Has >Grade 2 peripheral neuropathy within 14 days before enrollment.

          -  Myocardial infarction within 6 months prior to enrollment or has New York Hospital
             Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at screening has to be documented by the investigator as not medically
             relevant.

          -  Patient has hypersensitivity to bortezomib, boron or mannitol.

          -  Female is pregnant or breast-feeding. Confirmation that the subject is not pregnant
             must be established by a negative serum β-human chorionic gonadotropin (β-hCG)
             pregnancy test result obtained during screening. Pregnancy testing is not required for
             postmenopausal or surgically sterilized women.

          -  Patient has received other investigational drugs with 14 days before enrollment

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

          -  Patients with a DLCO less than 50% (adjusted) of normal or with symptomatic
             obstructive or restrictive lung disease are ineligible.

          -  Patients with renal dysfunction secondary to multiple myeloma may be enrolled at the
             discretion of the principal investigator. However, patients on hemodialysis or
             peritoneal dialysis are ineligible.

          -  Patients with a total bilirubin greater than 2.0 mg/dL and SGOT or SGPT greater than
             two and a half times normal (unless due to primary malignancy), or a history of severe
             hepatic dysfunction are ineligible.

          -  Patients with active infections are ineligible.

          -  Patients who are HIV positive are ineligible.

          -  Patients with active leptomeningeal involvement are ineligible. Patients with a
             history of previous CSF tumor involvement without symptoms or signs are eligible
             provided the CSF is now free of disease on lumbar puncture, and MRI of the brain shows
             no tumor involvement. Patients with severe symptomatic central nervous system (CNS)
             disease of any etiology are ineligible.

          -  Patients with uncontrolled insulin-dependent diabetes mellitus or uncompensated major
             thyroid or adrenal dysfunction are ineligible.

          -  Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2
             are ineligible.

          -  Patients with an ECOG performance status of 2 to 3, secondary to bone pain, may be
             enrolled at the discretion of the institutional investigator(s).