Transplantation, Homologous, Transplantation, Autologous, Multiple Myeloma, Blood and Marrow Transplant (BMT)
Conditions
Brief summary
To evaluate the toxicity and tolerability of this tandem autologous/allogeneic transplant approach for patients with advanced stage multiple myeloma.
Detailed description
Development of cell-based immunotherapy from allogeneic hematopoietic cell transplantation (HCT) is dependent upon stable T-cell engraftment and the success of this therapeutic approach is likely to be greatest when directed against a minimal rather than gross tumor burden. To this end, tandem transplants with high dose therapy and autologous hematopoietic cell transplantation (AHCT) for tumor cytoreduction followed by non-myeloablative allotransplant have been conducted. In myeloma, this tandem approach results in greater efficacy compared to conventional AHCT.
Interventions
PROCEDUREAutologous peripheral blood stem cells (auto-PBSC) transplantation
Auto-PBSC ≥ 2 to 3 x 10e6 CD34+ cells/kg are intravenously (IV) infused as part of the combination stem cell therapy. and allogeneic stem cells are administered intravenous (IV) infusion to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective
PROCEDUREAllogeneic peripheral blood stem cells (allo-PBSC) transplantation
Allo-PBSC (target collection ≥ 5 x 10e6 CD34+ cells/kg) are intravenously (IV) infused as part of the combination stem cell therapy.
DRUGFilgrastim
Filgrastim is administered subcutaneously (SC) at 10 µg/kg/day for auto-PBSC mobilization starting day 2 of mobilization until the last day of apheresis. Filgrastim is administered SC at 5 µg/kg/day from Day 6 after auto-PBSC infusion to hematologic recovery. Filgrastim is administered SC at 16 µg/kg/day for donor allo-PBSC mobilization at from Day - 4 to Day 0, prior to allo-PBSC collection.
DRUGCyclophosphamide
Cyclophosphamide is administered intravenously (IV) at 4 g/m2 on Day 1 of the auto-PBSC mobilization regimen.
DRUGMelphalan
Melphalan is administered after CSP at 200 mg/m2 intravenously (IV) on Day -2 before auto-PBSC infusion.
DRUGCyclosporine
Cyclosporine is administered by mouth (PO) for allo-PBSC graft vs host disease (GvHD) prophylaxis at 5 mg/kg from Day -3 through Bay +56. Tacrolimus may substituted.
RADIATIONTotal lymphoid irradiation
Total lymphoid irradiation is administered at 80 centigrey (cGy) on Day -11 to -7; and Day -4 to -2 before alllo-PBSC infusion. TLI is also administered at 80 centigrey (cGy) x 2 on Day -1 before alllo-PBSC infusion.
BIOLOGICALRabbit anti-thymocyte globulin
ATG 1.5 mg/kg is administered intravenously (IV) on Day -11 to -7 before allo-PBSC infusion.
MMF is administered at 15 mg/kg 3x/day by mouth (PO) after allo-PBSC through Day 40, followed by 10% dose reduction weekly (dose taper) through day 96, and adjusted if there is evidence of MMF-related GI toxicity or excessive myelosuppression
DRUGSolumedrol
Solumedrol 1 mg/kg is administered intravenously (IV) on Day -11 to -7 as a premedication for ATG and allo-PBSC infusion
DRUGDiphenhydramine
Diphenhydramine 25 to 50 mg is administered as a premedication for the ATG; allo-PBSC; and DLI infusions.
DRUGAcetaminophen
Acetaminophen 650 mg is administered as a premedication for the ATG and allo-PBSC infusions.
DRUGHydrocortisone
Hydrocortisone 100 mg is administered intravenously (IV) is a premedication for the allo-PBSC and DLI infusions.
Sponsors
Stanford University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
PARTICIPANT INCLUSION CRITERIA * Stage II-III multiple myeloma or have progression after initial treatment of Stage I disease (Durie Salmon Staging). Patients with plasma cell leukemia are also included. * Multiple myeloma / plasma cell leukemia diagnosis confirmed by pathology reviewed at Stanford University Medical Center. * 18 to ≤ 75 years of age * Karnofsky Performance Status \> 70%. * Corrected Carbon monoxide diffusing capacity (Dlco) \> 60% * Left ventricle ejection fraction (LVEF) \> 50%. * Alanine aminotransferase (ALT) ≤ 2 x normal * Aspartate aminotransferase (AST) ≤ 2 x normal * Total bilirubin ≤ 2 mg/dL, unless hemolysis or Gilbert's disease. * Estimated creatinine clearance \> 50 mL/min. * Identified related or unrelated Human leukocyte antigen (HLA)-identical donor or donor with one antigen/allele mismatch in (HLA-A, B, C or DRB1). * Signed informed consent. DONOR INCLUSION CRITERIA * At least 17 years of age * HIV-seronegative * Must be capable of giving signed, informed consent * No contraindication to the administration of filgrastim * Willing to have a central venous catheter placed for apheresis if peripheral veins are inadequate PARTICIPANT
Exclusion criteria
* Prior allogeneic hematopoietic cell transplantation * Uncontrolled active infection * Uncontrolled congestive heart failure or angina * HIV-positive * Pregnant or nursing DONOR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Graft Versus Host Disease (GvHD) | 2 years after the last participant is enrolled. | To evaluate the incidence acute GvHD of this tandem autologous/allogeneic transplant setting |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to Engraftment After Auto-PBSC Transplant | 1 month | Engraftment is assessed as: * Neutrophil engraftment is \> 0.5 x 10⁹/L after cytopenia * Platelet engraftment is \> 20 x 10⁹/L after cytopenia |
| Overall Response Rate (ORR) | 1 year | Overall response rate (ORR) = Complete Response Rate (CRR) + Partial Response Rate (PRR) |
| Complete Response Rate (CRR) | 1 year | Complete response rate (CRR) was assessed as all of: * Negative immunoflixation on the serum and urine * Disappearance of any soft tissue plasmacytomas * \< 5% plasma cells in bone marrow |
| Median Time to Engraftment After Allo-PBSC Transplant | 1 month | Engraftment is assessed as: * Neutrophil engraftment is \> 0.5 x 10⁹/L after cytopenia * Platelet engraftment is \> 20 x 10⁹/L after cytopenia |
| Event-free Survival (EFS) | 2 years after the last participant is enrolled | To evaluate the graft versus myeloma effect by monitoring rate of event-free survival (EFS) |
| Overall Survival (OS) | 2 years after the last participant is enrolled | To evaluate the graft versus myeloma effect by monitoring rate of overall survival (OS) |
| Partial Response Rate (PRR) | 1 year | Partial response rate (PRR) was assessed as * \> 50% reduction in serum M-protein plus urine M-protein reduction by 90% or \< 200 mg/24 hr * If serum M-protein is not measurable, then \> 50% reduction in the involved serum free light chain * If involved serum free light chain is not measurable, then \> 50% reduction in the bone marrow plasma cell percentage + \> 50% reduction in the size of any soft tissue plasmacytoma. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant A high-dose sequential chemotherapy approach with cyclophosphamide and etoposide followed by granulocyte colony stimulating factor (G-CSF) for collection of peripheral blood progenitor cells as well as for cytoreduction. Total Lymphoid irradiation and anti-thymocyte globulin (TLI/ATG).The preparatory regimens use BCNU and melphalan. | 9 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of suitable allogeneic donor | 2 |
Baseline characteristics
| Characteristic | Autologous-Allogeneic Hematopoietic Stem Cell Transplant |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Age, Continuous | 54 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 9 |
| serious Total, serious adverse events | 2 / 9 |
Outcome results
Primary
Incidence of Graft Versus Host Disease (GvHD)
To evaluate the incidence acute GvHD of this tandem autologous/allogeneic transplant setting
Time frame: 2 years after the last participant is enrolled.
Population: Due to the significance of the allo-PBSC transplant as a component to the treatment plan, participants who did not receive allo-PBSC are not included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Incidence of Graft Versus Host Disease (GvHD) | 1 Participants |
Secondary
Complete Response Rate (CRR)
Complete response rate (CRR) was assessed as all of: * Negative immunoflixation on the serum and urine * Disappearance of any soft tissue plasmacytomas * \< 5% plasma cells in bone marrow
Time frame: 1 year
Population: Includes all study participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Complete Response Rate (CRR) | 3 Participants |
Secondary
Event-free Survival (EFS)
To evaluate the graft versus myeloma effect by monitoring rate of event-free survival (EFS)
Time frame: 2 years after the last participant is enrolled
Population: Includes all study participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Event-free Survival (EFS) | 44 percentage of participants |
Secondary
Median Time to Engraftment After Allo-PBSC Transplant
Engraftment is assessed as: * Neutrophil engraftment is \> 0.5 x 10⁹/L after cytopenia * Platelet engraftment is \> 20 x 10⁹/L after cytopenia
Time frame: 1 month
Population: Due to the less intensive conditioning before allo-PBSC, only 2 participants experienced cytopenia, and thus only 2 participants could be evaluated for engraftment after allo-PBSC.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Median Time to Engraftment After Allo-PBSC Transplant | Neutrophil Engraftment | 24 Days |
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Median Time to Engraftment After Allo-PBSC Transplant | Platelet Engraftment | 10 Days |
Secondary
Median Time to Engraftment After Auto-PBSC Transplant
Engraftment is assessed as: * Neutrophil engraftment is \> 0.5 x 10⁹/L after cytopenia * Platelet engraftment is \> 20 x 10⁹/L after cytopenia
Time frame: 1 month
Population: Includes all study participants
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Median Time to Engraftment After Auto-PBSC Transplant | Neutrophil Engraftment | 11 Days |
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Median Time to Engraftment After Auto-PBSC Transplant | Platelet Engraftment | 15 Days |
Secondary
Overall Response Rate (ORR)
Overall response rate (ORR) = Complete Response Rate (CRR) + Partial Response Rate (PRR)
Time frame: 1 year
Population: Includes all study participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Overall Response Rate (ORR) | 7 Participants |
Secondary
Overall Survival (OS)
To evaluate the graft versus myeloma effect by monitoring rate of overall survival (OS)
Time frame: 2 years after the last participant is enrolled
Population: Includes all study participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Overall Survival (OS) | 67 percentage of participants |
Secondary
Partial Response Rate (PRR)
Partial response rate (PRR) was assessed as * \> 50% reduction in serum M-protein plus urine M-protein reduction by 90% or \< 200 mg/24 hr * If serum M-protein is not measurable, then \> 50% reduction in the involved serum free light chain * If involved serum free light chain is not measurable, then \> 50% reduction in the bone marrow plasma cell percentage + \> 50% reduction in the size of any soft tissue plasmacytoma.
Time frame: 1 year
Population: Includes all study participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous-Allogeneic Hematopoietic Stem Cell Transplant | Partial Response Rate (PRR) | 4 Participants |