Combination Chemotherapy With or Without Thalidomide in Treating Patients With Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Thalidomide may stop the growth of cancer cells by stopping blood flow to the cancer. 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 cancer cells. The donated stem cells may also help destroy any remaining cancer cells (graft-versus-tumor effect). It is not yet known whether chemotherapy followed by peripheral blood stem cell transplant is more effective with or without thalidomide in treating multiple myeloma. PURPOSE: This randomized phase III trial is studying giving combination chemotherapy with thalidomide to see how well it works compared with giving combination chemotherapy without thalidomide in treating patients with multiple myeloma.

Detailed Description
-----------------
OBJECTIVES: Compare the efficacy of doxorubicin, dexamethasone, and high-dose melphalan with versus without thalidomide, in terms of event-free survival, of patients with multiple myeloma. Determine the response rate, complete response rate, overall survival, and progression-free survival of patients treated with these regimens. Determine the safety and toxicity of thalidomide in combination with intensive chemotherapy in these patients. Assess the value of prognostic factors at diagnosis in individual patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center and treatment policy (1 course vs 2 courses of high-dose melphalan). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive induction chemotherapy (AD) comprising doxorubicin IV on days 1-4 and oral dexamethasone on days 1-4, 9-12, and 17-20. Patients receive oral thalidomide daily beginning on day 1 and continuing until 2 weeks before start of stem cell mobilization. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive stem cell mobilization with chemotherapy comprising cyclophosphamide IV on day 1 and doxorubicin IV and oral dexamethasone on days 1-4 (CAD). Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until last apheresis. Beginning 8-10 weeks after stem cell collection, patients receive low-dose oral thalidomide daily and high-dose melphalan IV on days -3 and -2 as intensification. Patients undergo stem cell infusion on day 0. Patients may receive a second course of high-dose melphalan 2-3 months after the first course, in which case, stem cell infusion follows the second course of melphalan. Patients receive maintenance therapy with oral thalidomide daily until disease progression or after 3 months if no response. Beginning 2 months after the last course, patients with an HLA-identical sibling donor undergo nonmyeloablative stem cell transplantation after radiotherapy. Arm II: Patients receive induction chemotherapy (VAD) comprising vincristine IV and doxorubicin IV on days 1-4 and dexamethasone on days 1-4, 9-12, and 17-20. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients receive stem cell mobilization with CAD chemotherapy as in arm I. G-CSF is given as in arm I. Patients receive high-dose melphalan and undergo stem cell infusion as in arm I. Patients receive maintenance therapy with interferon alfa SC 3 times weekly until progression or after 3 months if no partial response. Beginning 2 months after the last course, patients with an HLA-identical sibling donor undergo nonmyeloablative stem cell transplantation after radiotherapy. All patients are followed every 6 months for 3 years and then annually thereafter. PROJECTED ACCRUAL: A total of 450 patients (225 per treatment arm) will be accrued for this study within 4 years.

Official Title
-----------------
A Randomized Phase III Study On The Effect Of Thalidomide Combined With Adriamycin, Dexamethasone (AD) And High Dose Melphalan In Patients With Multiple Myeloma

Conditions
-----------------
Multiple Myeloma and Plasma Cell Neoplasm

Intervention / Treatment
-----------------
* Biological: filgrastim
* Biological: recombinant interferon alfa
* Drug: cyclophosphamide
* Drug: dexamethasone
* Drug: doxorubicin hydrochloride
* Drug: melphalan
* Drug: thalidomide
* Drug: vincristine sulfate
* Procedure: bone marrow ablation with stem cell support
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed multiple myeloma Stage II or III No systemic amyloid light-chain amyloidosis PATIENT CHARACTERISTICS: Age: 18 to 65 Performance status: WHO 0-3 Life expectancy: Not specified Hematopoietic: Not specified Hepatic: No significant hepatic dysfunction* Bilirubin less than 1.75 mg/dL* AST/ALT less than 2.5 times normal* NOTE: *Unless related to myeloma Renal: Not specified Cardiovascular: No severe cardiac dysfunction No New York Heart Association class II, III, or IV heart disease Other: HIV negative No active uncontrolled infection No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix No known intolerance to thalidomide Not pregnant Negative pregnancy test Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Patients 18 to 55 years of age must not have been allocated before study randomization to allogeneic stem cell transplantation with an HLA-identical sibling donor Chemotherapy: No more than 2 prior courses of melphalan and prednisone therapy for local myeloma progression No other prior chemotherapy Endocrine therapy: Not specified Radiotherapy: Prior local radiotherapy for local myeloma progression allowed No other prior radiotherapy Surgery: Not specified

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: filgrastim|nan|
|Biological: recombinant interferon alfa|nan|
|Drug: cyclophosphamide|nan|
|Drug: dexamethasone|nan|
|Drug: doxorubicin hydrochloride|nan|
|Drug: melphalan|nan|
|Drug: thalidomide|nan|
|Drug: vincristine sulfate|nan|
|Procedure: bone marrow ablation with stem cell support|nan|
|Procedure: peripheral blood stem cell transplantation|nan|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Partial response and complete response |  |  | 
| Overall survival |  |  | 
| Progression-free survival |  |  | 
| Toxicity |  |  | 

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