Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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 allo-engraftment. 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-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 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.

      Consenting first degree relative matched at 6/6 or 5/6 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.
    

Intervention name(s): 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 type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Biological; Biological
Intervention description(s): 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
Other intervention name(s): Velcade; PS341; Cytoxan; CTX; Sandimmune; Cyclosporin A; Vepesid; Fludara; Deltasone; MTX; Methotrexate sodium; Filgrastim; Neupogen
Intervention MeSH terms: Cyclosporine; Prednisone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Fludarabine; Fludarabine phosphate; Etoposide; Vincristine; Bortezomib; Molgramostim; Cyclosporins; Immunoglobulins; Lenograstim; Sargramostim; Immunoglobulin Idiotypes
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Immunoablative; Mobilization; Apheresis; Multiple Myeloma; IgG Multiple Myeloma; IgA Multiple Myeloma