High-Dose Sequential Therapy and Single Autologous Transplantation for Multiple Myeloma

Study Overview
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Brief Summary
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This study uses a sequence of high-dose chemotherapy drugs and a stem cell transplant to treat multiple myeloma. The study is being performed to evaluate the efficacy and side effects of treatment. Specifically, the study is designed to reduce the risk of interstitial pneumonitis.

Detailed Description
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Analysis of 196 previously treated patients demonstrated a median event-free survival (EFS) of 36 months with a median overall survival of more than 6 years. The main toxicity of this therapy is related to carmustine-induced pneumonitis or interstitial pneumonitis (IP). This complication is related to the dose of carmustine. Institutional experience in myeloma patients using this dose of carmustine indicates an incidence of IP of34%. There have been recent studies evaluating the role of tandem autologous transplants for patients with multiple myeloma. These trials were based upon the hypothesis that performing tandem high-dose therapy regimens would lead to increased tumor cell kill, decreased tumor burden and an improvement in overall survival. Our results with high-dose sequential therapy including the dose-intense carmustine/melphalan transplant demonstrates similar median EFS and overall survival (OS) when compared with the results of tandem transplant approaches.The proposed trial will continue to use a high-dose sequential transplant approach, however, we will use a reduced dose of carmustine which we expect to be associated with a lower incidence of IP.

Official Title
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High-Dose Sequential Therapy and Single Autologous Transplantation for Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Etoposide
* Drug: Melphalan
* Drug: Carmustine
* Drug: Filgrastim


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Stage II to III multiple myeloma, or progression after initial treatment of Stage I disease; early or relapsed Age 18 to 75 years. Pathology reviewed and the diagnosis confirmed at Stanford University Medical Center. Patients with amyloidosis may be eligible for this trial, with approval by the Principle Investigator. Patients must have a Karnofsky performance status > 70%. Aspartate aminotransferase (AST) must be < 2 x upper limit of normal (ULN) Alanine aminotransferase (ALT) must be < 2 x ULN Total bilirubin < 2 mg/dL. Serum creatinine < 2.0 or 24-hour creatinine clearance ≥ 60 mL/min. Patients must be HIV-negative. Patients must provide signed, informed consent. EXCLUSION CRITERIA Severe psychological or medical illness Prior autologous hematopoietic cell transplantation Pregnant Lactating women Smoldering multiple myeloma, Monoclonal gammopathy of unknown significance or primary amyloidosis will be excluded from this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: High-Dose Sequential Therapy<br>Cyclophosphamide + Etoposide + Melphalan + Carmustine with Filgrastim | Drug: Cyclophosphamide<br>* Cyclophosphamide as a white powder in 100 mg, 200 mg and 500 mg vials, to be dissolved in  250 mL of saline or D5W and infused IV over 2 hours<br>* Other names: Neosar;Drug: Etoposide<br>* 100 mg etoposide as 5 mL solution in clear ampules for injection.<br>* Other names: Etoposide phosphate;Drug: Melphalan<br>* Melphalan as single-use glass vials of freeze-dried melphalan hydrochloride (equivalent to 50 mg of melphalan), to be reconstituted in 0.9% sodium chloride solution to not greater than 0.45 mg/mL, and administered within 1 hour of constitution.<br>* Other names: Phenylalanine mustard;Drug: Carmustine<br>* Carmustine as a powder for reconstitution in 100 mg vials, to be reconstituted with 3 mL sterile dehydrated ethanol and D5W. Carmustine should be dissolved in 500 mL of 5% dextrose in water (D5W) and infused IV over 2 hours.<br>* Other names: BCNU;Drug: Filgrastim<br>* Filgrastim in vials of 300 µg or 480 µg at a concentration of 300 µg/mL, to be given as a daily subcutaneous injection.<br>* Other names: Granulocyte-colony stimulating factor (G-CSF);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Pulmonary Toxicity | Pulmonary toxicity was assessed as the incidence of interstitial pneumonitis. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Participant Survival (OS) | Survival status was assessed 5 years after transplant. | 5 years | 
| Number of Participants That Relapse After Autologous Transplantation | Relapse was measured as the number of patients who relapse after high-dose sequential therapy then autologous transplantation | 5 years |