Chemotherapy, Stem Cell Transplantation and Donor and Patient Vaccination for Treatment of Multiple Myeloma
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
2 other identifiers
interventional
20
1 country
1
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_2 multiple-myeloma
Started Feb 2001
Longer than P75 for phase_2 multiple-myeloma
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 23, 2000
CompletedFirst Posted
Study publicly available on registry
August 24, 2000
CompletedStudy Start
First participant enrolled
February 8, 2001
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 12, 2008
CompletedStudy Completion
Last participant's last visit for all outcomes
January 12, 2008
CompletedResults Posted
Study results publicly available
January 24, 2013
CompletedOctober 20, 2017
September 1, 2017
6.9 years
August 23, 2000
December 13, 2012
September 19, 2017
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
Immune Response
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.
105 days
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For a detailed list of adverse events see the adverse event module.
9 years
Study Arms (2)
Recipient - Chemotherapy Group
EXPERIMENTALInduction 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.
Donor - Vaccine Generation Group
OTHER3 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
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 )
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
Eligibility Criteria
You may qualify if:
- 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.
- 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.
- +9 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892, United States
Related Publications (5)
Stevenson GT, Stevenson FK. Antibody to a molecularly-defined antigen confined to a tumour cell surface. Nature. 1975 Apr 24;254(5502):714-6. doi: 10.1038/254714a0. No abstract available.
PMID: 47617BACKGROUNDStevenson GT, Elliott EV, Stevenson FK. Idiotypic determinants on the surface immunoglobulin of neoplastic lymphocytes: a therapeutic target. Fed Proc. 1977 Aug;36(9):2268-71. No abstract available.
PMID: 69552BACKGROUNDMiller RA, Maloney DG, Warnke R, Levy R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody. N Engl J Med. 1982 Mar 4;306(9):517-22. doi: 10.1056/NEJM198203043060906. No abstract available.
PMID: 6173751BACKGROUNDFoglietta M, Neelapu SS, Kwak LW, Jiang Y, Nattamai D, Lee ST, Fowler DH, Sportes C, Gress RE, Steinberg SM, Vence LM, Radvanyi L, Dwyer KC, Qazilbash MH, Bryant RN, Bishop MR. Neoantigen and tumor antigen-specific immunity transferred from immunized donors is detectable early after allogeneic transplantation in myeloma patients. Bone Marrow Transplant. 2013 Feb;48(2):269-77. doi: 10.1038/bmt.2012.132. Epub 2012 Jul 9.
PMID: 22773122RESULTJamshed S, Fowler DH, Neelapu SS, Dean RM, Steinberg SM, Odom J, Bryant K, Hakim F, Bishop MR. EPOCH-F: a novel salvage regimen for multiple myeloma before reduced-intensity allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011 May;46(5):676-81. doi: 10.1038/bmt.2010.173. Epub 2010 Jul 26.
PMID: 20661232DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Dr, Claude Sportes, M.D.
- Organization
- National Cancer Institute, National Institutes of Health
Study Officials
- PRINCIPAL INVESTIGATOR
Claude Sportes, M.D.
National Cancer Institute (NCI)
Publication Agreements
- PI is Sponsor Employee
- No
- Restrictive Agreement
- No
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
August 23, 2000
First Posted
August 24, 2000
Study Start
February 8, 2001
Primary Completion
January 12, 2008
Study Completion
January 12, 2008
Last Updated
October 20, 2017
Results First Posted
January 24, 2013
Record last verified: 2017-09
Data Sharing
- IPD Sharing
- Will not share