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Active Immunization of Sibling Stem Cell Transplant Donors Against Purified Myeloma Protein of the Stem Cell Recipient With Multiple Myeloma in the Setting of Non-Myeloablative, HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation


Phase 2
18 Years
75 Years
Open (Enrolling)
Both
Multiple Myeloma

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Trial Information

Active Immunization of Sibling Stem Cell Transplant Donors Against Purified Myeloma Protein of the Stem Cell Recipient With Multiple Myeloma in the Setting of Non-Myeloablative, HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation


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.

Inclusion 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Immune Response

Outcome Description:

Immune cell depletion is defined as immunosuppression of participants T cells prior to transplant measured by cluster of differentiation 4 (CD4) counts (i.e. cells) > 50 cells per ul.Immune T-cell depletion helps to reduce the ability to reject allogeneic cells in participants and is required for engraftment. Engraftment is the body's ability to accept donor cells.

Outcome Time Frame:

105 days

Safety Issue:

No

Principal Investigator

Claude Sportes, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

000201

NCT ID:

NCT00006184

Start Date:

August 2000

Completion Date:

July 2013

Related Keywords:

  • Multiple Myeloma
  • Immunoablative
  • Mobilization
  • Apheresis
  • Multiple Myeloma
  • IgG Multiple Myeloma
  • IgA Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892