Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Myeloma Immunoglobulin Idiotype Vaccine; Bortezomib; Cyclophosphamide; Cyclosporine; Doxorubicin hydrochloride; Etoposide; Fludarabine phosphate; Prednisone; Vincristine Sulfate; Methotrexate; GMCSF (granulocyte macrophage colony stimulating factor); GCSF (granulocyte colony stimulating factor)
Intervention description: 3 subcutaneous (SC) injections of myeloma protein within 10 weeks before stem cell collection the first (week 0), second (week 2), and third injection (week 6) with Id-KLH (0.5 mg SC day 1); Induction chemotherapy: 1.3 mg/m^2 bolus intravenous injection twice weekly for 2 weeks (days 1, 4, 8, 11) followed by 10 day rest period (day 12-21); Induction chemotherapy: 600 mg/m^2 day 4 Transplant: 1200 mg/m^2 intravenous x 4 days (days -6, -5, -4, -3); Transplant: 2 mg/kg intravenous every 12 hours continuous intravenous or by mouth (PO) until day + 180; Induction chemotherapy: 10 mg/m^2 day continuous intravenous (CIV) days 1-3; Induction chemotherapy: 50 mg/m^2 day continuous intravenous days 1-3; Induction chemotherapy: 25 mg/m^2 day intravenous days 1-3 Transplant: 30 mg/m^2 day x 4 days (days -6, -5, -4, -3 ); 60 mg/m^2 day 1-4; Induction chemotherapy: 0.5 mg/m^2 day continuous intravenous days 1-3; Transplant: 5 mg/m^2 intravenous on days +1, +3, +6, +11; 250 mcg/m^2 subcutaneously every day, days 1-4; 10 mcg/kg per day subcutaneously daily from day 5 until absolute neutrophil count (ANC) > 1000/ul x 2 days
Intervention MeSH terms: Cyclosporine; Prednisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Fludarabine; Fludarabine phosphate; Etoposide; Vincristine; Bortezomib; Molgramostim; Cyclosporins; Immunoglobulins; Lenograstim; Sargramostim; Immunoglobulin Idiotypes
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Immunoablative; Mobilization; Apheresis; Multiple Myeloma; IgG Multiple Myeloma; IgA Multiple Myeloma

Summary:

      Background:

      The mainstay of therapy for newly diagnosed multiple myeloma patients remains systemic
      chemotherapy. Although partial remissions of up to 60% are obtained with conventional
      regimens, multiple myeloma is essentially an incurable disease with a median survival of
      approximately 30 months.

      Allogeneic stem cell transplantation (SCT) results in a high percentage of complete
      remissions, but it can be associated with significant treatment-related mortality, which has
      been primarily attributed to conventional myeloablative transplant regimens.

      Recent clinical studies have shown that highly immunosuppressive yet non-myeloablative doses
      of fludarabine-based chemotherapy can result in alloengraftment. Even with a reduction in
      treatment related mortality, success with allogeneic SCT is limited by a significant risk of
      relapse.

      Donor immunization with myeloma Id in the setting of a non-myeloablative allogeneic SCT may
      represent a novel strategy for the treatment of multiple myeloma.

      Objectives:

      Primary Objectives:

      To induce cellular and humoral immunity in allogeneic stem cell donors and recipients against
      the unique idiotype expressed by the recipient's myeloma.

      To determine whether antigen-specific immunity, induced in the stem cell donor, can be
      passively transferred to the allogeneic SCT recipient in the setting of a non-myeloablative
      conditioning regimen.

      Secondary Objectives:

      To evaluate the effect of the Fludarabine-(etoposide, doxorubicin, vincristine, prednisone,
      cyclophosphamide) EPOCH regimen on host T cell depletion and myeloid depletion prior to
      allogeneic SCT.

      To determine the efficacy of a novel conventional chemotherapy regimen (Fludarabine-EPOCH) in
      the setting multiple myeloma.

      To determine the treatment-related morbidity and mortality of allogeneic stem cell
      transplantation using a non-myeloablative conditioning regimen in multiple myeloma.

      To determine if the re-vaccination of allogeneic stem cell donors with the unique idiotype
      expressed by the recipient's myeloma will enhance cellular and humoral immunity to patient
      specific-idiotype prior to lymphocyte donation for the treatment of patients with recurrent
      or progressive disease after transplantation.

      Eligibility:

      Patients 18-75 years of age with Immunoglobulin G (IgG) or Immunoglobulin A (IgA) multiple
      myeloma.

      Patients must have achieved at least a partial remission following initial conventional
      chemotherapy regimen or after autologous stem cell transplantation.

      Consenting first degree relative matched at 6/6 or 5/6 human leukocyte antigen (HLA)
      antigens.

      Design:

      Phase 2 trial using a non-myeloablative conditioning regimen to reduce treatment-related
      toxicity.

      Recipient will undergo a plasmapheresis to obtain starting material for the isolation of
      idiotype

      protein. Donors would be immunized with an Id vaccine prepared from the patient.

      Prior to transplantation patients would receive a conventional chemotherapy regimen which
      contains agents active in myeloma and is T cell depleting. The allogeneic SCT would be
      performed with a conditioning regimen consisting of cyclophosphamide and fludarabine. The
      stem cell source would be blood mobilized with filgrastim. Recipients will be immunized with
      the Id vaccine following transplantation.
    

Eligibility criteria:

        -  INCLUSION CRITERIA: Collection of plasma in recipient:

        Patients with Immunoglobulin G (IgG) or Immunoglobulin A (IgA) multiple myeloma.

        Patients have siblings.

        Human leukocyte antigen (HLA) typing of recipient and donor(s) initiated.

        Viral antibody screening initiated.

        INCLUSION CRITERIA: Recipient:

        Patients with IgG or IgA multiple myeloma.

        Patients must have achieved at least a partial remission following initial conventional
        chemotherapy regimen or after autologous stem cell transplantation. Patients who have
        undergone tandem autologous stem transplants are eligible if they meet all other
        eligibility criteria. Patients who have achieved at least a partial remission to initial
        (primary) conventional chemotherapy will be encouraged to proceed to autologous
        transplantation, but will also be eligible for this protocol.

        Patients 18-75 years of age. The upper age limit was chosen as it is felt that the
        toxicities would exceed potential benefit in this older population.

        Karnofsky performance status greater than or equal to 80%.

        Life expectancy greater than 6 months.

        Left ventricular ejection fraction has to be greater than 50% by either multi-gated
        acquisition scan (MUGA) or 2-D echo.

        Carbon monoxide diffusing capacity (DLCO) greater than 50% of the expected value when
        corrected for hemoglobin (Hb)(96).

        Creatinine less than or equal to 1.5 mg/dl and a creatinine clearance greater than or equal
        to 50 ml/min.

        Direct bilirubin less than or equal to 2.0 mg/dl serum glutamic oxaloacetic transaminase
        (SGOT) less than 4x top normal.

        M-protein: the concentration in the harvested plasma must be greater than 70% of the total
        Ig of the corresponding isotype.

        Patients must be human immunodeficiency virus (HIV)-negative. There is the theoretical
        possibility that the degree of immune suppression associated with the treatment may result
        in progression of HIV infection. Patients may be Hepatitis B core antigen positive, but
        surface antigen negative and without evidence of active infection. Patients must be
        Hepatitis C negative.

        Not pregnant or lactating. Patients of childbearing potential must use an effective method
        of contraception. The effects of the chemotherapy, the subsequent transplant and the
        medications used after the transplant are highly likely to be harmful to a fetus. The
        effects upon breast milk are also unknown and may potentially be harmful to the infant.

        Consenting first degree relative matched at 6/6 or 5/6 HLA antigens, this may include a
        mismatch at the D locus.

        Ability to give informed consent.

        INCLUSION CRITERIA: Donor:

        Age 18-75 years. As the potential cerebrovascular and cardiac complications may potentially
        increase with age, age 75 has been chosen arbitrarily as the upper age limit. However, if
        it is determined after initial accrual of patients in this upper age range that this
        procedure is relatively safe, the age range may be extended.

        No physical contraindications to stem cell donation (i.e. severe atherosclerosis,
        auto-immune disease, cerebrovascular accident, active malignancy (97). Patients with severe
        atherosclerosis by history will receive a cardiology consult and be judged eligible on a
        case by case basis.

        Donors must be HIV-negative, hepatitis B surface antigen (HBsAg-), and Hepatitis C antibody
        negative. This is to prevent the possible transmission of these infections to the
        recipient.

        Not pregnant or lactating. Donors of childbearing potential must use an effective method of
        contraception. The effects of cytokine administration on a fetus are unknown and may be
        potentially harmful. The effects upon breast milk are also unknown and may potentially be
        harmful to the infant.

        Normal cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) numbers as
        defined by Clinical Center standards.

        Ability to give informed consent.