Busulfan, Melphalan, Fludarabine and T-Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation Followed by Post Transplantation Donor Lymphocyte Infusions
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: busulfan, melphalan and fludarabine; busulfan, melphalan and fludarabine
Intervention description: Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be adjusted if patient is > 125% ideal body weight and should be calculated on adjusted ideal body weight.; Patients will be cytoreduced with IV busulfan, melphalan and fludarabine. Busulfan will be administered at a dose of 0.8mg/Kg q6hrs for 10 doses on days -9, -8, -7. Doses for busulfan should be adjusted according to pharmacokinetic studies. Melphalan will be administered at a dose of 70 mg/m2/day for 2 days on days -7, -6. Fludarabine will be administered at a dose of 25 mg/m2/day for 5 days on days -6, -5, -4, -3, -2. Patients will also receive rabbit anti-thymocyte globulin (ATG) to prevent immune mediated graft rejection. The ATG will be administered at a dose of 2.5 mg/Kg/day IV on days -3 and -2. Doses for busulfan, melphalan and ATG should be adjusted if patient is > 125% ideal body weight and should be calculated on adjusted ideal body weight.
Intervention MeSH terms: Vidarabine; Fludarabine; Fludarabine phosphate; Melphalan; Busulfan; Lenograstim
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 66.0
Sex: All
Minimum age: 21 Years
Maximum age: 72 Years
Healthy volunteers: No
Keywords: Myeloma; Busulfan; Melphalan; Fludarabine; T-Cell; Stem Cell Transplantation; 10-051

Summary:

      The patients are being offered a stem cell transplant. Stem cells are very early blood cells.
      They have not yet matured to become red or white blood cells or platelets. They have already
      received the standard treatment of chemotherapy and an autologous stem cell transplant. An
      autologous stem cell transplant is when the patient receives their infusion of their own
      cells. Thi will give the patient a better chance of curing the disease, this protocol
      includes an infusion of stem cells from the blood (or the bone marrow) of another person.
      This is called an allogeneic stem cell transplant. The stem cells will begin to grow in the
      bone marrow and produce new blood cells.

      Allogeneic stem cell transplants can cause a condition called graft-versus-host disease or
      GVHD. In GVHD, a kind of white blood cell from the donor (graft) begins to attack the body
      (host). That blood cell is called a T-cell. It is a cell that normally helps to protects
      against things like bacteria and viruses. In this case, the donor's T-cells see the body as
      foreign in the same way they would see bacteria as foreign. GVHD can be fatal. In order to
      lower the chance that the patient will get GVHD this protocol treatment will remove the
      T-cells from the donor's cells. This is called T-cell depletion. The T cells are removed by a
      system called "Clinimacs". This method is still being evaluated through clinical trials and
      not been approved by the Federal Drug Administration (FDA) at this time.

      Before the transplant, the physician will treat the bone marrow to get rid of the cancer. The
      physician uses three chemotherapy drugs plus ATG. The chemotherapy drugs (Busulfan, Melphalan
      and Fludarabine) kills the cancer. ATG gets rid of any of the patients T cells that survive
      the chemotherapy. This ensures that the donor stem cells are not rejected. The patient will
      also receive additional white blood cells called lymphocytes from the donor. This is called a
      donor lymphocyte infusion or DLI. These additional infusions will help cause a
      graft-versus-myeloma effect and can help the donor stem cells grow.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patient must have multiple myeloma that has either relapsed or has high risk
             cytogenetics.

          -  Patients with relapsed multiple myeloma following autologous stem cell transplantation
             must have achieved at least partial response following additional chemotherapy (cohort
             1):

          -  Patients are eligible if relapse occurs with complex/high-risk cytogenetics or occurs
             with normal cytogenetics but within 15 months following the autologous transplant.

          -  Patients with high risk cytogenetics at diagnosis must have achieved at least very
             good partial response following autologous stem cell transplantation (cohort 2):

               -  Patients must have complex karyotype, 1q25, del17p, t4;14 and/or t14;16 by FISH
                  and/or del13 by karyotyping.

        DONOR: Patients must have a healthy HLA matched or mismatched related or unrelated donor
        who is willing to receive G-CSF injections and undergo apheresis for PBSC collection, or
        undergo a marrow harvesting procedure.

          1. HLA-matched related and unrelated donors Patients who have an HLA-matched related or
             unrelated donor are eligible for entry on this protocol. This will include a healthy
             donor who is genotypically matched at all A, B, C, DRB1 and DQB1 locus, loci, as
             tested by DNA analysis.

          2. HLA- mismatched related and unrelated donors Patients who do not have an HLA-matched
             donor but have a related or unrelated donor who have one antigen or one allele
             mismatch at the HLA A, B, C, DRB1 or DQB1 loci; or who have two mismatches, at
             HLA-DQB1 and at one other locus, will be eligible for entry on this protocol.

        The following inclusion criteria are also required:

          -  Patients should be ≥ 21, < 73 years old.

          -  Patients may be of either gender or any ethnic background.

          -  Patients must have a Karnofsky (adult) or Performance Status ≥ 70%

          -  Patients must have adequate organ function measured by:

        Cardiac: asymptomatic or if symptomatic then LVEF at rest must be ≥ 50% and must improve
        with exercise. Hepatic: < 3x ULN ALT and ≤ 1.5 total serum bilirubin, unless there is
        congenital benign hyperbilirubinemia.

        Renal: serum creatinine <1.2 mg/dl or if serum creatinine is outside the normal range, then
        CrCl > 40 ml/min (measured or calculated/estimated) with dose adjustment of Fludarabine for
        <70ml/min.

        Pulmonary: asymptomatic or if symptomatic, DLCO > 50% of predicted (corrected for
        hemoglobin)

          -  Each patient must be willing to participate as a research subject and must sign an
             informed consent form.

        Exclusion Criteria:

          -  Patients achieving < Partial Response following preceding chemotherapy (cohort 1) or <
             Very Good Partial Response following autologous stem cell transplantation (cohort 2).

          -  Patients with Plasma Cell Leukemia.

          -  Female patients who are pregnant or breast-feeding

          -  Active viral, bacterial or fungal infection

          -  Patient seropositive for HIV-I/II; HTLV -I/II

          -  Patients who have undergone prior allogeneic hematopoietic stem cell transplantation.

          -  Patients who have had a previous malignancy that is not in remission.

          -  Patients with known hypersensitivity to mouse proteins (murine antibodies in ISOLEX)
             if receiving SBA-E- bone marrow, or chicken egg products.