Melphalan and Stem Cell Transplant Before Total-Body Irradiation and Donor Stem Cell Transplant in Treating Patients With Stage I-III Multiple Myeloma

Study Overview
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Brief Summary
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In this study donor bone marrow transplantation is divided into a two step process to try to significantly reduce the side effects of the procedure yet still provide patients with multiple myeloma the benefits of this procedure

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate engraftment of human leukocyte antigen (HLA) identical peripheral blood stem cell (PBSC) allografts given after conditioning with total-body irradiation (TBI) (200 cGy) and post-grafting immunosuppression with cyclosporine (CSP)/mycophenolate mofetil (MMF) in myeloma patients initially cytoreduced with high-dose melphalan. II. To evaluate non-relapse mortality at day 100 post allografting. III. To evaluate the efficacy of this allografting strategy in terms of long-term progression free survival (PFS). OUTLINE: CONDITIONING REGIMEN: Patients receive high-dose melphalan intravenously (IV) over 15-20 minutes on day -2. TRANSPLANTATION: Patients undergo autologous bone marrow or PBSC transplantation (PBSCT) on day 0. NON-MYELOABLATIVE CONDITIONING REGIMEN: Beginning 40-120 days after autologous transplant, patients undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV twice daily (BID) on days -1 and 0 and orally (PO) BID on days 1-80 with taper based on evaluation of disease response and graft-versus-host disease (GVHD). Patients also receive mycophenolate mofetil PO BID on days 0-27. POST-TRANSPLANTATION DONOR LYMPHOCYTE INFUSION (DLI): Beginning 4 weeks after immunosuppression, patients achieving persistent or progressive disease may undergo DLI over 30 minutes every 4 weeks for up to 3 treatments. After completion of study treatment, patients are followed up for 3 years.

Official Title
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Allogeneic Stem Cell Transplantation For Multiple Myeloma: A Two Step Approach To Reduce Toxicity Involving High Dose Melphalan and Autologous Stem Cell Transplant Followed By PBSC Allografting After Low Dose TBI

Conditions
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Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

Intervention / Treatment
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* Drug: melphalan
* Procedure: autologous hematopoietic stem cell transplantation
* Procedure: autologous bone marrow transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: total-body irradiation
* Procedure: peripheral blood stem cell transplantation
* Drug: cyclosporine
* Drug: mycophenolate mofetil
* Biological: therapeutic allogeneic lymphocytes


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet Salmon and Durie criteria for initial diagnosis of multiple myeloma; transplant will be offered to patients with stage II or III multiple myeloma (MM) at diagnosis or have received chemotherapy and/or radiation therapy for progressive MM after initial diagnosis of stage I disease The patient must have the capacity to give informed consent Have received at least 4 cycles of conventional dose chemotherapy for MM DONOR: HLA genotypically identical sibling DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis for both peripheral blood stem cell (PBSC) allograft and subsequent DLI DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) DONOR: Age < 75, older donors may be considered after consultation by Psychological Consultation Center (PCC) Exclusion Criteria: Karnofsky score less than 60, unless due solely to myeloma Left ventricular ejection fraction less than 40% Bilirubin greater than 2 X the upper limit of normal Serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2 X the upper limit of normal Diffusion lung capacity of carbon monoxide (DLCO) < 50% (corrected) or receiving continuous supplemental oxygen Patients with poorly controlled hypertension Pregnancy Seropositive for the human immunodeficiency virus Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Creatinine clearance < 40 cc/min at the time of initial autografting evaluation Prior autograft (can be treated on alternative protocol) DONOR: Identical twin DONOR: Age less than 12 years DONOR: Pregnancy DONOR: Infection with human immunodeficiency virus (HIV) DONOR: Inability to achieve adequate venous access DONOR: Known allergy to G-CSF DONOR: Current serious systemic illness DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) criteria for stem cell donation as described in the standard practice guidelines of the institution

Ages Eligible for Study
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Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (Melphalan and PBSCT before TBI and Donor PBSCT)<br>CONDITIONING REGIMEN: Patients receive high-dose melphalan IV over 15-20 minutes on day -2. TRANSPLANTATION: Patients undergo autologous bone marrow or PBSCT on day 0. NON-MYELOABLATIVE CONDITIONING REGIMEN: Beginning 40-120 days after autologous transplant, patients undergo TBI on day 0. TRANSPLANTATION: Patients undergo donor PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine IV BID on days -1 and 0 and PO BID on days 1-80 with taper based on evaluation of disease response and GVHD. Patients also receive mycophenolate mofetil PO BID on days 0-27. POST TRANSPLANT DLI: Beginning 4 weeks after immunosuppression, patients achieving persistent or progressive disease may undergo DLI over 30 minutes every 4 weeks for up to 3 treatments. | Drug: melphalan<br>* Given IV<br>* Other names: L-Sarcolysin;Procedure: autologous hematopoietic stem cell transplantation<br>* Undergo autologous bone marrow or PBSCT<br>Procedure: autologous bone marrow transplantation<br>* Undergo autologous bone marrow or PBSCT<br>* Other names: transplantation, autologous bone marrow;Procedure: peripheral blood stem cell transplantation<br>* Undergo autologous bone marrow or PBSCT<br>* Other names: transplantation, peripheral blood stem cell;Radiation: total-body irradiation<br>* Undergo TBI<br>* Other names: TBI;Procedure: peripheral blood stem cell transplantation<br>* Undergo donor PBSCT<br>* Other names: transplantation, peripheral blood stem cell;Drug: cyclosporine<br>* Given IV and PO<br>* Other names: Sandimmune;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: MMF;Biological: therapeutic allogeneic lymphocytes<br>* Undergo DLI<br>* Other names: ALLOLYMPH;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS | The current study will be regarded as potentially efficacious if the observed 3-year PFS rate among all patients treated exceeds 30%. The Kaplan-Meier (KM) estimate of PFS will be used. | From the date of transplant until the time of progression, relapse, death, or the date the patient was last known to be in remission, up to 3 years | 
| Decrease in the short-term transplant-related mortality |  | Day 100 after allograft | 
| Establish stable allogeneic engraftment (mixed or full donor chimerism) |  | At day 56 after allografting | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Estimated by the method of Kaplan and Meier. Confidence intervals will be estimated. | Up to 3 years | 
| Relapse rate | Summarized using cumulative incidence estimates. Confidence intervals will be estimated. | Up to 3 years | 
| Response rate | Confidence intervals will be estimated. | Up to 3 years | 
| Ability to convert mixed to full donor chimerism with DLI | Confidence intervals will be estimated. | Up to 3 years |