Non-myeloablative Allogeneic Transplantation for the Treatment of Multiple Myeloma

Study Overview
=================
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.

Official Title
-----------------
Non-myeloablative Allogeneic Transplantation for the Treatment of Multiple Myeloma

Conditions
-----------------
Blood Cancer, Multiple Myeloma

Intervention / Treatment
-----------------
* Procedure: Autologous hematopoietic cell transplant (Auto-HCT)
* Procedure: Allogeneic hematopoietic cell transplant (Allo-HCT)
* Drug: Cyclophosphamide
* Drug: Filgrastim
* Drug: Melphalan
* Radiation: Total body irradiation (TBI)
* Procedure: Cyclosporine (CSP)
* Drug: Mycophenolate Mofetil (MMF)


Participation Criteria
=================
Eligibility 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 EXCLUSION CRITERIA Serious medical or psychological illness Pregnant or lactating Prior malignancies within the last 5 years, except for non-melanoma skin cancers

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Auto- then Allo-HCT<br>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. | Procedure: Autologous hematopoietic cell transplant (Auto-HCT)<br>* The target cell dose is 2.6 x 10e6 CD34+ cells/kg<br>Procedure: Allogeneic hematopoietic cell transplant (Allo-HCT)<br>* The target cell dose is 5 x 10e6 CD34 cells/kg<br>Drug: Cyclophosphamide<br>* Cyclophosphamide administered intravenously (IV) at 4 mg /m² mobilize peripheral blood progenitor cells (PBPC) for autologous re-infusion<br>* Other names: Neosar;Drug: Filgrastim<br>* 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)<br>* Other names: Granulocyte-colony stimulating factor (G-CSF);Drug: Melphalan<br>* Melphalan 200 mg/m2 (high-dose) intravenously as conditioning for Auto-HCT<br>* Other names: Melphalan HCl;Radiation: Total body irradiation (TBI)<br>* 200 centigray (cGy) total body irradiation delivered on Day 0<br>Procedure: Cyclosporine (CSP)<br>* Cyclosporine administered twice-daily by mouth at a dose of 6.25 mg/kg from Day -3 through Day 56<br>* Other names: Cyclosporine A;Drug: Mycophenolate Mofetil (MMF)<br>* Mycophenolate mofetil will begin at 15 mg/kg twice-daily by mouth from Day 0 to Day 27<br>* Other names: CellCept;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 3 years | 
| 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. | 3 years | 
| Acute Graft-vs-Host-Disease (aGvHD) | Development of acute graft-vs-host-disease (aGvHD) within 6 months, for participants receiving Allo-HCT. | 6 months | 
| 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). | 3 years |