Clinical trial NCT00006184
Conditions: Multiple Myeloma
Keywords: Immunoablative Mobilization Apheresis Multiple Myeloma IgG Multiple Myeloma IgA Multiple Myeloma
Sponsor: National Cancer Institute (NCI)
Start date: 2001-02-08; Completion date: 2008-01-12
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Induction chemotherapy with fludarabine, etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and granulocyte colony stimulating factor (GCSF) followed by transplant preparative regimen chemotherapy with fludarabine, cyclophosphamide, mesna, cyclosporine, and methotrexate, followed by stem cell infusion and immunization. arm 2: 3 subcutaneous 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 (Anti-idiotype-keyhole limpet hemocyanin) (0.5 mg subcutaneous day 1) and Granulocyte macrophage-colony stimulating factor (GM-CSF) (250 mcg/m\^2 subcutaneous on days 1-4). Stem cell collection is 4 weeks after the third vaccination.
Interventions: intervention 1: Myeloma Immunoglobulin Idiotype Vaccine intervention 2: Bortezomib intervention 3: Cyclophosphamide intervention 4: Cyclosporine intervention 5: Doxorubicin hydrochloride intervention 6: Etoposide intervention 7: Fludarabine phosphate intervention 8: Prednisone intervention 9: Vincristine Sulfate intervention 10: Methotrexate intervention 11: GMCSF (granulocyte macrophage colony stimulating factor) intervention 12: GCSF (granulocyte colony stimulating factor)
Intervention descriptions: intervention 1: 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) intervention 2: 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) intervention 3: Induction chemotherapy: 600 mg/m\^2 day 4 Transplant: 1200 mg/m\^2 intravenous x 4 days (days -6, -5, -4, -3) intervention 4: Transplant: 2 mg/kg intravenous every 12 hours continuous intravenous or by mouth (PO) until day + 180 intervention 5: Induction chemotherapy: 10 mg/m\^2 day continuous intravenous (CIV) days 1-3 intervention 6: Induction chemotherapy: 50 mg/m\^2 day continuous intravenous days 1-3 intervention 7: 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 ) intervention 8: 60 mg/m\^2 day 1-4 intervention 9: Induction chemotherapy: 0.5 mg/m\^2 day continuous intravenous days 1-3 intervention 10: Transplant: 5 mg/m\^2 intravenous on days +1, +3, +6, +11 intervention 11: 250 mcg/m\^2 subcutaneously every day, days 1-4 intervention 12: 10 mcg/kg per day subcutaneously daily from day 5 until absolute neutrophil count (ANC) \> 1000/ul x 2 days

Protocol documents: