Blood Cancer, Multiple Myeloma
Conditions
Brief summary
Mixed chimerism transplantation is an approach to allogeneic transplants that attempts to decrease regimen-related toxicity by using non-myeloablative preparatory regimens; establish mixed chimerism using low dose total body irradiation along with immunosuppression using cyclosporine and mycophenolate mofetil; suppress graft-vs-host and host-vs-graft reactions to allow a mixed chimeric state to be established, encourage tolerance and prevent graft-vs-host disease (GvHD) during the mixed chimerism period and use donor lymphocyte infusions to convert the patient to a full chimera while developing a graft-vs-tumor effect.
Detailed description
Participants are mobilized with cyclophosphamide 4 g/m2 and filgrastim 10 µg/kg/day for peripheral blood progenitor cell (PBPC) collection by apheresis. Transplant conditioning is high-dose melphalan 200 mg/m2, followed by PBPC infusion as melphalan rescue \[ie, autologous hematopoietic cells transplant (auto-HCT)\]. Post-infusion support includes filgrastim 5 µg/kg/day, starting 6 days following melphalan. Participants with stable or responsive disease at 4 weeks eligible to continue on to the planned allogenic HCT (allo-HCT). For allo-HCT, a sibling donor that is fully matched for human leukocyte antigen (HLA-matched) is identified. Participants receive a single dose of total body irradiation (TBI) 200 centigray (cGy) as well as immunosuppression with cyclosporine (CSP) 6.25 mg/kg and mycophenolate mofetil (MMF) 15 mg/kg. The HLA-matched donor begins filgrastim injections 16 µg/kg/day on day -4 continuing to Day 0, with apheresis collections on Day -1 and Day 0, to a target of \> 5 x 10e6 CD34 cells/kg. Allo-HCT is infused to participant on Day 0, with premedication hydrocortisone 100 mg IV and diphenhydramine 50 mg IV. CSP will be tapered beginning Day 56 with a goal of discontinuing CSP on Day 180, adjusted as needed.
Interventions
PROCEDUREAutologous hematopoietic cell transplant (Auto-HCT)
The target cell dose is 2.6 x 10e6 CD34+ cells/kg
PROCEDUREAllogeneic hematopoietic cell transplant (Allo-HCT)
The target cell dose is 5 x 10e6 CD34 cells/kg
DRUGCyclophosphamide
Cyclophosphamide administered intravenously (IV) at 4 mg /m² mobilize peripheral blood progenitor cells (PBPC) for autologous re-infusion
DRUGFilgrastim
* Filgrastim 10 µg/kg/day to mobilize peripheral blood progenitor cells (PBPC) for autologous re-infusion (Auto-HCT) * Filgrastim 5 µg/kg/day starting 6 days after melphalan (Day 4 after Auto-HCT) * Filgrastim 16 µg/kg/day to mobilize donor peripheral blood progenitor cells (PBPC) for allogeneic transplant (Allo-HCT)
DRUGMelphalan
Melphalan 200 mg/m2 (high-dose) intravenously as conditioning for Auto-HCT
RADIATIONTotal body irradiation (TBI)
200 centigray (cGy) total body irradiation delivered on Day 0
PROCEDURECyclosporine (CSP)
Cyclosporine administered twice-daily by mouth at a dose of 6.25 mg/kg from Day -3 through Day 56
DRUGMycophenolate Mofetil (MMF)
Mycophenolate mofetil will begin at 15 mg/kg twice-daily by mouth from Day 0 to Day 27
Sponsors
Wen-Kai Weng
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
PATIENT INCLUSION CRITERIA * Multiple myeloma, early Stage II-III or relapsed / progression after initial treatment of Stage I disease * Patient has HLA-identical sibling donor * Age ≤ 70 years * No prior therapy which would preclude the use of low-dose total body irradiation * Pathology review and diagnosis confirmation by Stanford University Medical Center * Karnofsky performance status (KPS) \> 70% * DLCO ≥ 60% predicted * ALT and AST \< 2 x upper limit of normal (ULN) * Total bilirubin \< 2 mg/dL * Serum creatinine \< 2.0, or 24-hour creatinine clearance ≥ 60 mL/min * HIV-negative * Signed informed consent document PATIENT
Exclusion criteria
* Smoldering multiple myeloma; monoclonal gammopathy of unknown significance; or primary amyloidosis * Severe psychological or medical illness * Prior allogeneic hematopoietic cell transplantation * Pregnant or lactating ALLOGENEIC DONOR INCLUSION CRITERIA * Age ≥ 17 * HIV-seronegative * Signed informed consent document ALLOGENEIC DONOR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | 3 years | Event-free survival (EFS) as determined for all participants who received the initial Auto-HCT treatment. Event was defined as any of the following within 3 years of the participant's last infusion of Auto-HCT or Allo-HCT: relapse; death; or last follow-up if there is no data to document the participant remained alive at 3 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Rate | 3 years | Relapse rate as determined for all participants who received the initial Auto-HCT treatment. Relapse was protocol-specified as progressive disease, indicated by an increase as compared to pre-Auto-HCT baseline, of serum or urine monoclonal protein \>25%; bone marrow plasmacytosis \>25%; or bone lesions on skeletal survey (any increase). |
| Overall Survival (OS) | 3 years | Overall Survival (OS) as determined for all participants who received the initial Auto-HCT treatment, as assessed from the date of the last transplant. |
| Acute Graft-vs-Host-Disease (aGvHD) | 6 months | Development of acute graft-vs-host-disease (aGvHD) within 6 months, for participants receiving Allo-HCT. |
| Chronic Graft-vs-Host-Disease (cGvHD) | 3 years | Development of chronic graft versus host disease (cGvHD) within 3 years, for participants receiving Allo-HCT. Reported as Extensive cGvHD; cGvHD, Not Extensive; or No cGvHD, as determined by investigator judgement (no protocol-specified criteria). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Auto- Then Allo-HCT Auto-HCT mobilization is cyclophosphamide 4 g/m2 + filgrastim 10 µg/kg/day for peripheral blood progenitor cell (PBPC) collection by apheresis. Transplant conditioning is high-dose melphalan 200 mg/m2, followed by PBPC infusion as melphalan rescue \[ie, autologous hematopoietic cells transplant (Auto-HCT)\]. Post-infusion support is filgrastim 5 µg/kg/day, starting 6 days after melphalan. Stable/responsive disease at 4 weeks continues to allogenic HCT (Allo-HCT) from sibling donor fully-matched for human leukocyte antigen (HLA). Allo-HCT conditioning is total body irradiation (TBI) 200 centigray (cGy) + cyclosporine (CSP) 6.25 mg/kg + mycophenolate mofetil (MMF) 15 mg/kg. Donor mobilization is filgrastim 16 µg/kg/day on day -4 to Day 0; apheresis collections on Day -1 & Day 0, to a target of \> 5 x 10e6 CD34 cells/kg. Allo-HCT is infused to participant on Day 0, with premedication hydrocortisone 100 mg IV & diphenhydramine 50 mg IV. CSP tapering on Day 56 to Day 180, adjusted as needed. | 63 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Inter-treatment Period | Lack of allogenic donor | 1 |
| Inter-treatment Period | Physician Decision | 1 |
| Inter-treatment Period | Relapse | 2 |
Baseline characteristics
| Characteristic | Auto- Then Allo-HCT |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 60 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 21 / 63 |
| other Total, other adverse events | 63 / 63 |
| serious Total, serious adverse events | 63 / 63 |
Outcome results
Primary
Event-free Survival (EFS)
Event-free survival (EFS) as determined for all participants who received the initial Auto-HCT treatment. Event was defined as any of the following within 3 years of the participant's last infusion of Auto-HCT or Allo-HCT: relapse; death; or last follow-up if there is no data to document the participant remained alive at 3 years.
Time frame: 3 years
Population: The outcome data are reported as the number of participants who do not experience an EFS event within 3 years from the date of the last transplant, for the Auto-HCT only population, the Auto-HCT then Allo-HCT population, and the overall study population (ie, Auto-HCT only plus +Auto-HCT then Allo-HCT).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auto- Then Allo-HCT | Event-free Survival (EFS) | Auto-HCT only | 0 Participants |
| Auto- Then Allo-HCT | Event-free Survival (EFS) | Auto-HCT then Allo-HCT | 24 Participants |
| Auto- Then Allo-HCT | Event-free Survival (EFS) | All Participants | 24 Participants |
Secondary
Acute Graft-vs-Host-Disease (aGvHD)
Development of acute graft-vs-host-disease (aGvHD) within 6 months, for participants receiving Allo-HCT.
Time frame: 6 months
Population: Graft versus host disease (aGvHD) only occurs in participants receiving Allo-HCT, as determined by investigator judgement (no protocol-specified criteria).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Auto- Then Allo-HCT | Acute Graft-vs-Host-Disease (aGvHD) | 7 Participants |
Secondary
Chronic Graft-vs-Host-Disease (cGvHD)
Development of chronic graft versus host disease (cGvHD) within 3 years, for participants receiving Allo-HCT. Reported as Extensive cGvHD; cGvHD, Not Extensive; or No cGvHD, as determined by investigator judgement (no protocol-specified criteria).
Time frame: 3 years
Population: Graft versus host disease (aGvHD) only occurs in participants receiving Allo-HCT.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Auto- Then Allo-HCT | Chronic Graft-vs-Host-Disease (cGvHD) | Extensive cGvHD | 30 Participants |
| Auto- Then Allo-HCT | Chronic Graft-vs-Host-Disease (cGvHD) | cGvHD, not Extensive | 8 Participants |
| Auto- Then Allo-HCT | Chronic Graft-vs-Host-Disease (cGvHD) | No cGvHD | 21 Participants |
Secondary
Overall Survival (OS)
Overall Survival (OS) as determined for all participants who received the initial Auto-HCT treatment, as assessed from the date of the last transplant.
Time frame: 3 years
Population: The outcome data are reported as the number of participants who could be documented as remaining alive through 3 years from the date of the last transplant, for the Auto-HCT only population, the Auto-HCT then Allo-HCT population, and the overall study population (ie, Auto-HCT only plus +Auto-HCT then Allo-HCT).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Auto- Then Allo-HCT | Overall Survival (OS) | Auto-HCT only | 1 participants |
| Auto- Then Allo-HCT | Overall Survival (OS) | Auto-HCT then Allo-HCT | 41 participants |
| Auto- Then Allo-HCT | Overall Survival (OS) | All Participants | 42 participants |
Secondary
Relapse Rate
Relapse rate as determined for all participants who received the initial Auto-HCT treatment. Relapse was protocol-specified as progressive disease, indicated by an increase as compared to pre-Auto-HCT baseline, of serum or urine monoclonal protein \>25%; bone marrow plasmacytosis \>25%; or bone lesions on skeletal survey (any increase).
Time frame: 3 years
Population: The outcome data are reported as the number of participants who relapse per criteria within 3 years.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Auto- Then Allo-HCT | Relapse Rate | Auto-HCT only | 2 participants |
| Auto- Then Allo-HCT | Relapse Rate | Auto-HCT then Allo-HCT | 29 participants |
| Auto- Then Allo-HCT | Relapse Rate | All Participants | 31 participants |