Combination Chemotherapy in Treating Patients With Multiple Myeloma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. It is not yet known which combination chemotherapy regimen is most effective in treating patients with multiple myeloma. PURPOSE: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens in treating patients with multiple myeloma.

Detailed Description
-----------------
OBJECTIVES: Compare the overall survival of patients with previously untreated stage I-III multiple myelome treated with melphalan combined with dexamethasone or prednisone as induction therapy. Compare the overall survival of patients with stable or responding disease after induction treated with dexamethasone vs observation alone as maintenance therapy. Compare the time to progression, response rate, and quality of life of patients treated with these regimens. Compare the toxic effects of these regimens in these patients. OUTLINE: This is a randomized, multicenter study. Patients are stratified by center, stage (I or II vs III), creatinine (less than 2.0 mg/dL vs 2.0 mg/dL or greater), and intention to use prophylactic bisphosphonate (yes vs no). Induction: Patients are randomized to 1 of 4 treatment arms. Arms I and II: Patients receive induction comprising oral prednisone followed by oral melphalan on days 1-4. Arms III and IV: Patients receive induction comprising oral melphalan and oral dexamethasone (DM) on days 1-4 of all courses and DM on days 15-18 of courses 1-3. Induction for arms I-IV continues every 4 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease after induction proceed to maintenance therapy. Maintenance: Arms I and III: Patients undergo observation. Arms II and IV: Patients receive oral DM on days 1-4. Maintenance therapy continues every 4 weeks for arms II and IV and every 3 months for arms I and III in the absence of disease progression or unacceptable toxicity. Patients on arms I-IV who develop disease progression proceed to reinduction. Reinduction: Patients restart induction on the arm to which they were originally randomized. Reinduction continues every 4 weeks in the absence of stable response lasting 16 weeks, disease progression, or unacceptable toxicity. Patients who achieve a stable response lasting 16 weeks restart maintenance therapy. Patients who experience further disease progression during reinduction are taken off study. Quality of life is assessed at baseline, on day 1 of courses 1-3 and then every 3 courses during induction, and then every 3 months during maintenance therapy. Patients are followed every 6 months. PROJECTED ACCRUAL: A maximum of 600 patients will be accrued for this study within 6 years.

Official Title
-----------------
Comparative Study of Dexamethasone vs Prednisone (Both in Combination With Melphalan) as Induction Therapy in Untreated Symptomatic Myeloma With an Additional Assessment of Dexamethasone vs no Additional Treatment as Maintenance Therapy in Non-Progressing Patients

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

Intervention / Treatment
-----------------
* Drug: dexamethasone
* Drug: melphalan
* Drug: prednisone


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically proven previously untreated stage I-III multiple myeloma Patients with stage I disease must be symptomatic Must meet at least 1 of the following conditions: Plasma cells in osteolytic lesion or soft tissue tumor biopsy At least 10% plasmacytosis in bone marrow aspirate and/or biopsy Less than 10% plasma cells in bone marrow but at least 1 bony lesion Detectable serum M-component of IgG, IgA, IgD, or IgE If only light chain disease (urine M-protein) present, urinary excretion of light chain (Bence Jones) protein must be at least 1.0 g/24 hours PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-4 Life expectancy: Not specified Hematopoietic: Not specified Hepatic: Not specified Renal: Not specified Other: No other concurrent serious illness Concurrent diabetes allowed, at the discretion of the treating physician, if changes in insulin requirements can be managed No other prior or concurrent malignancy except curatively treated nonmelanomatous skin cancer or carcinoma in situ of the cervix PRIOR CONCURRENT THERAPY: Biologic therapy: No concurrent immunizations No concurrent filgrastim (G-CSF) or other growth factors as prophylaxis Concurrent epoetin alfa for anemia allowed Chemotherapy: No prior chemotherapy Endocrine therapy: Prior dexamethasone or prednisone with radiotherapy for spinal cord compression allowed if cumulative dexamethasone dose no greater than 120 mg and cumulative prednisone dose no greater than 792 mg Prior or concurrent corticosteroids for hypercalcemia allowed Radiotherapy: See Endocrine therapy Prior focal radiotherapy allowed Concurrent focal radiotherapy during induction allowed Concurrent radiotherapy for palliation (e.g., painful osteolytic lesions or spinal cord compression) allowed Surgery: At least 2 years since prior surgery for radiologic or endoscopic diagnosis of gastric or duodenal ulcer Other: At least 2 years since prior medication for radiologic or endoscopic diagnosis of gastric or duodenal ulcer Prior or concurrent bisphosphonates for hypercalcemia allowed

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

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

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

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Melphan plus prednisone<br>melphalan plus prednisone qd x 4 28 day cycles x 12 cycles; No treatment after stable response. | Drug: melphalan<br>* 9 mg/m2 daily for 4 days given orally on an empty stomach every 4 weeks<br>Drug: prednisone<br>* 100 mg daily for 4 days given orally on a full stomach with each cycle of melphalan<br>|
| Active Comparator: Melphan, prednisone pluse dexamethasone<br>melphalan plus prednisone qd x 4 28 day cycles x 12 cycles; dexamethasone qd x 4 q 28 days after non-progression | Drug: dexamethasone<br>* 40 mg daily for four days given orally and repeated every 28 days should commence on day 29 of the twelfth cycle of induction therapy.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | To compare overall survival between: i) patients receiving melphalan-prednisone and those receiving melphalan-dexamethasone as induction therapy ii) patients maintained by dexamethasone and those on no additional treatment in the subgroup whose disease has not progressed at the time of the 12th induction cycle | 9 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression |  | 9 years | 
| Response rates |  | 9 years | 
| Toxicity |  | 9 years | 
| Quality of Life |  | 9 years | 

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