Peripheral Stem Cell Transplant in Treating Patients With Multiple Myeloma

Study Overview
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Brief Summary
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RATIONALE: Peripheral blood stem cell transplant using stem cells from the patient or a donor may be able to replace immune cells that were destroyed by chemotherapy used to kill tumor cells. The donated stem cells may also help destroy any remaining cancer cells (graft-versus-tumor effect). PURPOSE: This phase II trial is studying how well autologous peripheral stem cell transplant followed by donor peripheral stem cell transplant works in treating patients with multiple myeloma.

Detailed Description
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OBJECTIVES: Determine whether autologous peripheral blood stem cell transplantation (PBSCT) followed by non-myeloablative allogeneic PBSCT is associated with no more than 20% treatment-related mortality rates at 6 months in patients with multiple myeloma. Determine the response rate of patients treated with this regimen. Determine the percent donor chimerism in patients treated with this regimen. Determine the rate of graft-vs-host disease in patients treated with this regimen. Determine the toxic effects of this regimen in these patients. Determine the disease-free and overall survival of patients treated with this regimen. Determine whether abnormal cytogenetics at presentation correlate with poor response in patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive cyclophosphamide IV over 1-2 hours on day 1 and filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until peripheral blood stem cell (PBSC) collection is complete. Approximately 2-4 weeks after PBSC collection, patients receive melphalan IV over 15-30 minutes on day -2. Patients then undergo autologous PBSC transplantation (PBSCT) on day 0. Patients receive G-CSF SC beginning on day 5 and continuing until blood counts recover. Approximately 2-4 months after autologous PBSCT, patients receive fludarabine IV over 30 minutes on days -7 to -3 and cyclophosphamide IV over 1 hour on days -4 to -3. Patients undergo allogeneic PBSCT on day 0. Patients receive G-CSF SC beginning on day 7 and continuing until blood counts recover. Patients receive graft-vs-host disease (GVHD) prophylaxis comprising oral tacrolimus twice daily on days -1 to 90 followed by a taper on days 91-150 and methotrexate IV on days 1, 3, and 6. After day 120, patients with stable or progressive disease and no evidence of active GVHD may receive donor lymphocyte infusion (DLI) over 2 hours. Patients may receive up to 3 DLIs every 8 weeks. Patients are followed every 3 months for 3 years, every 6 months for 5 years, and then annually for 15 years. PROJECTED ACCRUAL: A maximum of 63 patients will be accrued for this study.

Official Title
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Autologous Followed By Non-Myeloablative Allogeneic Transplant For Multiple Myeloma

Conditions
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Multiple Myeloma, Plasma Cell Neoplasm

Intervention / Treatment
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* Biological: filgrastim
* Biological: CD34+ cells
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Drug: melphalan
* Drug: methotrexate
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of active multiple myeloma that requires treatment Durie-Salmon stage I, II, and III No more than 1 progression after initial therapy Must have HLA-identical sibling donor (6/6) by serologic typing (A, B, DR) No syngeneic donors Must also be enrolled on protocol CLB-8461 (Cytogenetic Studies in Acute Leukemia) PATIENT CHARACTERISTICS: Age: Under 65 Performance status: NCI CTC 0-1 Life expectancy: Not specified Hematopoietic: Absolute neutrophil count greater than 500/mm^3 Platelet count greater than 50,000/mm^3 Hepatic: Bilirubin less than 2 mg/dL AST less than 3 times upper limit of normal (ULN) Alkaline phosphatase less than 3 times ULN Renal: Creatinine less than 2 mg/dL Creatinine clearance greater than 40 mL/min Cardiovascular: LVEF at least 30% by MUGA scan Pulmonary: DLCO greater than 40% of predicted No symptomatic pulmonary disease Other: HIV negative No uncontrolled diabetes mellitus No active serious infection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: At least 4 weeks since prior chemotherapy Prior alkylating-agent therapy allowed if no more than 12 months duration Endocrine therapy: Not specified Radiotherapy: At least 4 weeks since prior radiotherapy Surgery: At least 4 weeks since prior surgery Other: All prior therapy no more than 18 months duration

Ages Eligible for Study
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Maximum Age: 64 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous + Allogeneic Transplant<br>autologous PB stem cell transplant followed by non-myeloablative allogeneic transplant fr multiple myeloma | Biological: filgrastim<br>* PBSC collection: 10 ug/kg/d subQ inj D 5 until completion of collection Auto transpl: 5 ug/kg/d subQ inj D 5 until ANC >= 1500/uL for 2d or 5000/uL for 1 d Allo transpl: 5ug/kg/d subQ inj D 7 until ANC > 1000/uL for 3 days Donor pheresis: 10ug/kg/d subQ inj d -5 thru -2<br>* Other names: G-CSF;Biological: CD34+ cells<br>* 2-8,000,000/kg IV infusion allogeneic transplant 2,000,000/kg IV infusion autologous transplant<br>Drug: cyclophosphamide<br>* 4g/sq m IV infusion over 1-2 hrs D 1 for auto, and 1g/sq m/d IV infusion over 1 hr on D -4 thru -3 for allo, transplant prep<br>Drug: fludarabine phosphate<br>* 30mg/sq m/d IVPB over 30 min d -7 thru -3 allo transpl<br>Drug: melphalan<br>* 200mg/sq m IV infusion over 15-30 min D 2 auto transpl<br>Drug: methotrexate<br>* 5mg/sq m/d IV infusion D 1,3,& 6: allo transpl<br>Drug: tacrolimus<br>* 0.03mg/kg PO bid starting dose, D -1 thru +90, then taper thru D +150<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-related mortality |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Completion Rate |  | post treatment | 
| Respone Rate |  | 2-4 wks prior, and 3,6 mon then q 3 mon for 3 yrs, post allo transpl, then q 6 mon for max 15 yrs from study entry | 
| Chimerism Rate |  | 1,2,3,4, & 6 mon post allo transpl, & 100 d post DLI | 
| GVHD Incidence |  | post allo transpl, & pre & post DLI | 
| Survival | Overall and disease free survival will be assessed | 2 years | 
| Correlation of cytogenetics and response |  | 6, 12 mon then q 1 yr for 3 yrs post allo transpl | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory multiple myeloma, stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma