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 tumor. It is not yet known if combination chemotherapy is more effective with or without thalidomide in treating multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without thalidomide in treating patients who have multiple myeloma.

Condition	Treatment or Intervention	Phase
stage II multiple myeloma stage III multiple myeloma	Drug: cyclophosphamide  Drug: dexamethasone  Drug: doxorubicin  Drug: filgrastim  Drug: interferon alfa  Drug: melphalan  Drug: thalidomide  Drug: vincristine  Procedure: anti-cytokine therapy  Procedure: antiangiogenesis therapy  Procedure: biological response modifier therapy  Procedure: bone marrow ablation with stem cell support  Procedure: chemotherapy  Procedure: colony-stimulating factor therapy  Procedure: cytokine therapy  Procedure: growth factor antagonist therapy  Procedure: high-dose chemotherapy  Procedure: interferon therapy  Procedure: peripheral blood stem cell transplantation	Phase III

Further Study Details: 

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.

Ages Eligible for Study:  18 Years   -   65 Years,  Genders Eligible for Study:  Both

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

Belgium
      U.Z. Gasthuisberg, Leuven,  B-3000,  Belgium; Recruiting
Netherlands
      Academisch Medisch Centrum, Amsterdam,  1105 AZ,  Netherlands; Recruiting
      Academisch Ziekenhuis Maastricht, Maastricht,  6202 AZ,  Netherlands; Recruiting
      Daniel Den Hoed Cancer Center at Erasmus Medical Center, Rotterdam,  3008 AE,  Netherlands; Recruiting
      Isala Klinieken - locatie Sophia, Zwolle,  8000 GK,  Netherlands; Recruiting
      Jeroen Bosch Ziekenhuis, 's-Hertogenbosch,  5211 NL,  Netherlands; Recruiting
      Leiden University Medical Center, Leiden,  2300 CA,  Netherlands; Recruiting
      Leyenburg Ziekenhuis, S. Gravenhage,  2545 CH,  Netherlands; Recruiting
      Meander Medisch Centrum, Amersfoort,  3816 CP,  Netherlands; Recruiting
      Medisch Centrum Leeuwarden - Zuid, Leeuwarden,  8934 AD,  Netherlands; Recruiting
      Medisch Spectrum Twente, ENSCHEDE,  7500 KA,  Netherlands; Recruiting
      Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam,  1066 CX,  Netherlands; Recruiting
      Sint Antonius Ziekenhuis, Nieuwegein,  3435 CM,  Netherlands; Recruiting
      University Medical Center Groningen, Groningen,  9713 EZ,  Netherlands; Recruiting
      University Medical Center Nijmegen, Nijmegen,  NL-6500 HB,  Netherlands; Recruiting
      University Medical Center Utrecht, Utrecht,  3584 CX,  Netherlands; Recruiting
      Vrije Universiteit Medisch Centrum, Amsterdam,  1081HV,  Netherlands; Recruiting

Study chairs or principal investigators

H. Lokhorst, MD, PhD,  Study Chair,  University Medical Center Utrecht   

Study ID Numbers:  CDR0000069144; CKVO-2001-02; HOVON-50MM; EU-20133; HOVON-CKVO-2001-02; NCT00028886
Record last reviewed:  September 2003
Last Updated:  April 4, 2005
Record first received:  January 4, 2002
ClinicalTrials.gov Identifier:  NCT00028886
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08