Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of 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.

Conditions

• Multiple Myeloma

Interventions

DRUG

Myeloma Immunoglobulin Idiotype Vaccine

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)

DRUG

Bortezomib

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)

DRUG

Cyclophosphamide

Induction chemotherapy: 600 mg/m\^2 day 4 Transplant: 1200 mg/m\^2 intravenous x 4 days (days -6, -5, -4, -3)

DRUG

Cyclosporine

Transplant: 2 mg/kg intravenous every 12 hours continuous intravenous or by mouth (PO) until day + 180

DRUG

Doxorubicin hydrochloride

Induction chemotherapy: 10 mg/m\^2 day continuous intravenous (CIV) days 1-3

DRUG

Etoposide

Induction chemotherapy: 50 mg/m\^2 day continuous intravenous days 1-3

DRUG

Fludarabine phosphate

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 )

DRUG

Prednisone

60 mg/m\^2 day 1-4

DRUG

Vincristine Sulfate

Induction chemotherapy: 0.5 mg/m\^2 day continuous intravenous days 1-3

DRUG

Methotrexate

Transplant: 5 mg/m\^2 intravenous on days +1, +3, +6, +11

BIOLOGICAL

GMCSF (granulocyte macrophage colony stimulating factor)

250 mcg/m\^2 subcutaneously every day, days 1-4

BIOLOGICAL

GCSF (granulocyte colony stimulating factor)

10 mcg/kg per day subcutaneously daily from day 5 until absolute neutrophil count (ANC) \> 1000/ul x 2 days

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Claude Sportes, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

75 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2001-02-08

Primary Completion

2008-01-12

Completion

2008-01-12

FDA Drug

Yes

Countries

• United States

Study Locations