Phase II Study of Velcade, Decadron, and Doxil Followed by Cyclophosphamide in Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Bortezomib; dexamethasone; liposomal doxorubicin; cyclophoshamide; filgrastim
Intervention description: During Induction Phase (6 cycles): Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 During 21-day mobilization cycle (1 cycle): Bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; During Induction Phase (6 cycles): dexamethasone 40 mg on days 1-4, 8-11, and 15-18; If patients achieve less then a PR during the induction phase after 2 cycles, or less then a CR after 4 cycles: Liposomal doxorubicin was added at 30 mg/m2 on day 4 for the remaining cycles; During the 21 day mobilization phase (1 cycle): cyclophosphamide at 3 g/m2 on day 8; During the 21 day mobilization phase (1 cycle): 10 μg/kg/day for 10 consecutive days starting 24 hours after cyclophosphamide administration on day 9
Intervention MeSH terms: Dexamethasone; Doxorubicin; Liposomal doxorubicin; Bortezomib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: Consolidation: All patients will receive 2 cycles of bortezomib (VEL) and dexamethasone (DEX). Patients who achieve a complete response after 2 cycles will receive 4 additional cycles of VEL/DEX before mobilization.
Patients who do not achieve at least a partial response after 2 cycles will receive 4 more cycles of VEL/DEX plus DOXIL.
Patients who achieve a partial response after 2 cycles on VEL/DEX, will continue this combination for 2 more cycles. Patients who achieve a complete response after 4 cycles will receive 2 additional cycles of VEL/DEX before mobilization. Patients who remain with a partial response after 4 cycles of VEL/DEX will receive 2 additional cycles of the combination of VEL/DEX plus DOXIL.
Mobilization: Patients who complete 6 cycles of consolidation will proceed to mobilization. Patients will receive one cycle of VEL plus high dose CYTOXAN followed by G-CSF beginning 24 hours after CYTOXAN given for a total of 10 daily doses.
Masking: None (Open Label)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      PRIMARY STUDY OBJECTIVES

        -  To evaluate the efficacy of the combination of bortezomib, dexamethasone, with and
           without DOXIL, followed by high-dose cyclophosphamide as a therapy for two different
           subsets of multiple myeloma patients:

             1. Patients post first line therapy

             2. Patients with relapsed/refractory disease who are bortezomib-naïve

        -  To evaluate the safety of the combination of bortezomib and dexamethasone, with and
           without DOXIL, followed by high-dose cyclophosphamide as therapy for patients with
           multiple myeloma.

      SECONDARY STUDY OBJECTIVES

        -  To evaluate the role of the combination of bortezomib dexamethasone, with and without
           DOXIL, followed by high-dose cyclophosphamide on the ability to collect > 10 x 106 CD34+
           cells/kg in < 7 collections (for both subsets of multiple myeloma patients).

        -  To evaluate the survival of patients who receive the combination of bortezomib
           dexamethasone, with and without DOXIL, followed by high-dose cyclophosphamide (for both
           subsets of patients).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must voluntarily sign and understand written informed consent.

          -  Confirmed diagnosis of multiple myeloma as specified by the SWOG criteria and is
             detailed in Appendix I.

          -  Measurable disease as defined the following:

               1. For patients post induction therapy, any measurable paraprotein in the serum or
                  urine and/or any plasmacytoma present on physical exam or imaging.

               2. For patients with relapsed/refractory disease, > 0.5 g/dL serum monoclonal
                  protein, > 0.1 g/dL serum free light chains, > 0.2 g/24 hrs urinary M-protein
                  excretion, and/or measurable plasmacytoma(s).

          -  Age > or = than 18 years at the time of signing the informed consent form.

          -  Karnofsky performance status> or =70% (>60% if due to bony involvement of myeloma).

          -  Group A (post-induction therapy)- patients who have received only one prior treatment
             regimen (eg VAD, Thal/Dex, BLT-D, MP, BiRD, or DVd) with at least 20 patients having
             received a Revlimid based regimen or Group B(>1st line of therapy)- patients with
             relapsed/refractory multiple myeloma who have received two or more prior treatment
             regimens .

          -  If the patient is a woman of childbearing age, she must have a negative serum or urine
             pregnancy test within 7 days of starting study and must use effective contraception
             throughout the course of the study.

          -  Life expectancy > 12 weeks.

          -  Absolute neutrophil count (ANC)> or = 1500 cells/mm3 (> or = 1000 for patients with
             bone marrow biopsy displaying > 50% involvement by myeloma)

          -  Platelets count > or = 50,000/mm3 (> or = 30,000 for patients with bone marrow biopsy
             displaying > 50% involvement by myeloma)

          -  Hemoglobin > 9.0 g/dL

          -  Serum SGOT/AST <3.0 x upper limits of normal (ULN)

          -  Serum SGPT/ALT <3.0 x upper limits of normal (ULN)

          -  Serum creatinine < 2.5 mg/dL or creatinine clearance > 40ml/min

          -  Serum total bilirubin < 1.5 x ULN

          -  Patients must have a MUGA scan with LVEF >50%

        Exclusion Criteria:

          -  Patients with non-secretory MM (no measurable monoclonal protein, free light chains,
             and/or M-spike in blood or urine) unless measurable disease is available with imaging
             techniques such as MRI and PET scan.

          -  Prior treatment with bortezomib.

          -  Peripheral neuropathy of > Grade 2 as defined by CTCAE Version 3.0 (see Appendix II)

          -  History of allergic reactions to compounds containing mannitol, bortezomib,
             conventional formulation of doxorubicin HCL or the components of DOXIL.

          -  Prior history of other malignancies (except for basal cell or squamous cell carcinoma
             of the skin or carcinoma in situ of the cervix or breast) unless disease free for ³ 5
             years.

          -  NYHA Class III or IV heart disease. History of active unstable angina, congestive
             heart disease, serious uncontrolled cardiac arrhythmia or myocardial infarction within
             6 months.

          -  Female patients who are pregnant or breastfeeding. Women of childbearing potential and
             men must agree to use adequate contraception prior to study entry and for the duration
             of study participation.

          -  Known HIV or hepatitis A, B, or C positivity

          -  Active viral or bacterial infections or any coexisting medical problem that would
             significantly increase the risks of this treatment program.

          -  Any concurrent, uncontrolled medical condition, laboratory abnormality, or psychiatric
             illness which could place him/her at unacceptable risk, including, but not limited to,
             uncontrolled hypertension, uncontrolled diabetes, active uncontrolled infection,
             and/or acute chronic liver disease (i.e., hepatitis, cirrhosis).

          -  No prior anti-myeloma therapy within 2 weeks of treatment initiation.