Tandem Melphalan and Autolog. SCT in MM Patients 60 to 70 Years of Age With and Without Induction Chemotherapy

Study Overview
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Brief Summary
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Patients 60 to 70 years of age with newly diagnosed multiple myeloma were prospectively randomized between 4 cycles of anthracycline/dexamethasone-based induction chemotherapy (A1) or only 2 x 4 days of dexamethasone (A2). A reference arm included patients who could not be randomized (B). Tandem melphalan 140 mg/m² (MEL140) with autologous transplantation was scheduled for all patients.

Detailed Description
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In arm A1, patients received 4 cycles of conventional induction therapy with anthracycline/dexamethasone-based regimens. Specified in the protocol were vincristine/doxorubicin/dexamethasone (VAD), idarubicin/dexamethasone (ID) and cyclophosphamide/doxorubicin/dexamethasone (CAD). In arm A2, patients were planned to receive only dexamethasone 40 mg orally on days 1-4 and 8-11 for symptom control before stem cell mobilization. For the patients in arm B, a maximum of 6 cycles of induction chemotherapy was allowed. Following this, the treatment was identical for all patients. For stem cell mobilization, an age-adjusted IEV-regimen with granulocyte-colony stimulating factor (G-CSF) was recommended. The target dose for stem cell collection was 6 x 10E+6 CD34 (cluster of differentiation 34)-positive cells/kg (2 transplants and one back-up). The standard dose for each transplantation was 2 x 10E+6 CD34-positive cells/kg. High-dose melphalan at a total dose of 140 mg/m² (MEL140) was given in two doses of 70 mg/m² on days -3 and -2. Stem cell transplantation (SCT) was performed on day 0. A second MEL140 course was planned two months after the first. Regular bisphosphonate treatment was recommended.

Official Title
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Phase III-study for Evaluation of Induction Therapy Before Stem Cell Mobilization and Tandem High-dose Melphalan in Multiple Myeloma Patients 60 to 70 Years of Age

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Anthracycline/dexamethasone-based induction chemotherapy
* Drug: Dexamethasone for control of symptoms
* Drug: Tumor-reduction chemotherapy and stem cell mobilization
* Procedure: Stem cell apheresis
* Drug: Tandem high-dose chemotherapy (melphalan)
* Procedure: Autologous peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmed multiple myeloma stage II or III according to the classification of Salmon and Durie Aged between 60 and 70 years Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Signed and dated written informed consent No previous chemotherapy or not more than one cycle in total or previous chemotherapy of more than one cycle if paused for at least 6 months and not more than six cycles in total (arm A1 and A2 only) Ongoing primary chemotherapy of two to maximum six cycles (arm B only) Exclusion Criteria: Multiple myeloma stage I according to the classification of Salmon and Durie without need of any therapy Aged under 60 or over 70 years ECOG performance status >2 Previous chemotherapy of more than six cycles Informed consent missing Myocardial infarction within the last six months Cardiac dysrhythmia stage IV b according to the classification of Lown Heart failure >NYHA II according to the classification of the New York Heart Association (NYHA), left ventricular ejection fraction <50% in ECG Severe restrictive or obstructive pulmonary disease (diffusing capacity <60% under normal) Renal insufficiency including a serum creatinine level >2mg/dl if not caused by multiple myeloma and reversible Liver diseases combined with an elevation of transaminases and of bilirubin of three times above normal Severe infections (HIV, hepatitis B/C, syphilis etc. ) Severe psychiatric disease Other not curative treated malignant tumor within the last five years Concurrent participation in other clinical studies Other not curative treated malignant tumor within the last five years

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 70 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A1: Induction chemotherapy<br>Anthracycline/dexamethasone-based induction chemotherapy Tumor-reduction chemotherapy and stem cell mobilization Stem cell apheresis Tandem high-dose chemotherapy Autologous peripheral blood stem cell transplantation | Drug: Anthracycline/dexamethasone-based induction chemotherapy<br>* 4 cycles of anthracycline/dexamethasone-based chemotherapy<br>* Other names: ID, VAD, CAD;Drug: Tumor-reduction chemotherapy and stem cell mobilization<br>* Ifosfamide (day 1-3: 1.900mg/m² iv), epirubicin (day 1: 75 mg/m² iv), etoposide (day 1-3: 120 mg/m² iv) and G-CSF (day 5 until end of apheresis: 5µg/kg sc)<br>* Other names: IEV + G-CSF;Procedure: Stem cell apheresis<br>* stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg<br>* Other names: SC-apheresis;Drug: Tandem high-dose chemotherapy (melphalan)<br>* Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²)<br>* Other names: Tandem melphalan;Procedure: Autologous peripheral blood stem cell transplantation<br>* Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation)<br>* Other names: PBSCT;|
| Active Comparator: A2: No induction chemotherapy<br>Dexamethasone for control of symptoms Tumor-reduction chemotherapy and stem cell mobilization Stem cell apheresis Tandem high-dose chemotherapy Autologous peripheral blood stem cell transplantation | Drug: Dexamethasone for control of symptoms<br>* 2 x 4 days of dexamethasone (day 1-4 and day 8-11: 40mg)<br>* Other names: dexamethasone;Drug: Tumor-reduction chemotherapy and stem cell mobilization<br>* Ifosfamide (day 1-3: 1.900mg/m² iv), epirubicin (day 1: 75 mg/m² iv), etoposide (day 1-3: 120 mg/m² iv) and G-CSF (day 5 until end of apheresis: 5µg/kg sc)<br>* Other names: IEV + G-CSF;Procedure: Stem cell apheresis<br>* stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg<br>* Other names: SC-apheresis;Drug: Tandem high-dose chemotherapy (melphalan)<br>* Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²)<br>* Other names: Tandem melphalan;Procedure: Autologous peripheral blood stem cell transplantation<br>* Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation)<br>* Other names: PBSCT;|
| Other: B: Observation<br>Tumor-reduction chemotherapy and stem cell mobilization Stem cell apheresis Tandem high-dose chemotherapy Autologous peripheral blood stem cell transplantation | Drug: Anthracycline/dexamethasone-based induction chemotherapy<br>* 4 cycles of anthracycline/dexamethasone-based chemotherapy<br>* Other names: ID, VAD, CAD;Drug: Tumor-reduction chemotherapy and stem cell mobilization<br>* Ifosfamide (day 1-3: 1.900mg/m² iv), epirubicin (day 1: 75 mg/m² iv), etoposide (day 1-3: 120 mg/m² iv) and G-CSF (day 5 until end of apheresis: 5µg/kg sc)<br>* Other names: IEV + G-CSF;Procedure: Stem cell apheresis<br>* stem cell apheresis in peripheral blood, sought amount of CD34-cells: 6 * 10E6/kg<br>* Other names: SC-apheresis;Drug: Tandem high-dose chemotherapy (melphalan)<br>* Two cycles of high-dose melphalan (day -3 and day -2: 70mg/m²)<br>* Other names: Tandem melphalan;Procedure: Autologous peripheral blood stem cell transplantation<br>* Two infusions of collected stem cells (day 0: 2*10E6 CD34-cell/kg per transplantation)<br>* Other names: PBSCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival | Calculated according to the method of Kaplan and Meier | From randomization to 10 years follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Calculated according to the method of Kaplan and Meier | From randomization to 10 years follow up | 
| Rate of remission (Evaluation of the overall response rate) | Evaluation of the overall response rate. Overall repose is defined as complete response + partial response. The definition of remission followed the criteria of Bladé. | After last therapy to at least 6 weeks thereafter | 
| Quality of remission (Evaluation of the best response) | Evaluation of the best response. Response is evaluated after induction therapy, tumor-reduction chemotherapy and stem cell mobilization and each high-dose chemotherapy. The definition of remission followed the criteria of Bladé. | After last therapy to at least 6 weeks thereafter | 
| Short and long time toxicity according to NCI Common Terminology Criteria for Adverse Events (CTCAE) | Examination of the maximum grade of toxicity according to NCI Common Terminology Criteria for Adverse Events (CTCAE) | From randomization until 2 years after last therapy | 
| Cytogenetic examination (Univariate analysis according to the method of Kaplan and Meier. Multivariate analysis according to the method of Cox´s proportional hazards regression analysis.) | Examination of cytogenetic abnormalities wich are of major importance to define longer or shorter survival. Univariate analysis according to the method of Kaplan and Meier. Multivariate analysis according to the method of Cox´s proportional hazards regression analysis. | From randomization to 10 years follow up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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high-dose chemotherapy, autologous blood stem-cell transplantation, induction chemotherapy, elderly patients