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