SWOG-9321 Melphalan, TBI, and Transplant vs Combo Chemo in Untreated Myeloma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage cancer cells. Combining chemotherapy and radiation therapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy and radiation therapy and kill more cancer cells. It is not yet known which treatment regimen is more effective for multiple myeloma. PURPOSE: Randomized phase III trial to compare the effectiveness of melphalan, total-body irradiation, and peripheral stem cell transplantation with that of combination chemotherapy in treating patients who have previously untreated multiple myeloma.

Detailed Description
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OBJECTIVES: Compare tumor cytoreduction achieved with VBMCP (vincristine/carmustine/melphalan/cyclophosphamide/prednisone) vs myeloablative melphalan (L-PAM) and total-body irradiation (TBI) with peripheral blood stem cell (PBSC) rescue in symptomatic myeloma patients with stable or responding disease after induction therapy with VAD (vincristine/doxorubicin/dexamethasone) followed by high dose cyclophosphamide plus filgrastim (G-CSF). Compare the efficacy of interferon alfa vs no maintenance therapy in those patients achieving at least 75% cytoreduction to either VBMCP or myeloablative therapy with PBSC rescue. Assess allogeneic bone marrow transplantation following the same myeloablative regimen of L-PAM/TBI in patients up to age 55 with an HLA-compatible, MLC-nonreactive donor. (As of 8/1/97, permanent partial closure) Determine whether myeloablative therapy with PBSC rescue can extend the duration of survival by 33% compared to results from standard dose VBMCP. Evaluate the toxic effects and possible long term side effects, including development of myelodysplastic disease and/or acute myeloblastic leukemia, associated with these treatments. OUTLINE: This is a randomized study. Patients are registered at 5 different points, with stratification occurring at some of these registrations. Registration I: Induction I Registration II: Induction II. Patients are stratified according to stage of disease (I/II vs IIIA vs IIIB), beta-2 microglobulin at diagnosis (less than 6 micrograms/mL vs at least 6 micrograms/mL), and response to Induction I (75-100% regression vs 50-74% regression vs less than 50% regression vs not applicable). Registration III: Patients are randomized to allogeneic bone marrow transplant (BMT) (this arm closed as of 8/1/97) or autologous BMT. Patients are stratified according to treatment received (high dose cyclophosphamide (CTX) and peripheral blood stem cells (PBSC) prior to autologous BMT vs prior to chemotherapy) and beta-2 microglobulin at this registration (less than 2 micrograms/mL vs no greater than 3 micrograms/mL vs unknown). Registration IV: Patients are randomized to maintenance therapy or no further therapy. Those patients who are randomized to maintenance therapy are stratified according to treatment (autologous BMT vs chemotherapy vs chemotherapy followed by autologous BMT) and response to treatment (75-99% regression vs complete response). Registration V: Patients receive autologous BMT as in registration III. Patients are stratified according to prior best response (50% or better vs less than 50% vs not applicable), duration of chemotherapy (at least 6 months vs less than 6 months), and progression after therapy (chemotherapy vs interferon alfa vs observation). Induction I: Patients receive vincristine IV and doxorubicin IV by continuous infusion on days 1-4 and dexamethasone IV or orally on days 1-4, 9-12, and 17-20. Treatment repeats every 5 weeks for up to 4 courses. Patients with progressive disease after 2 courses proceed to PBSC stimulation/harvest. Allogeneic BMT arm is permanently closed as of 8/1/97. Autologous BMT: Therapy begins 4-8 weeks following high dose cyclophosphamide. Patients receive melphalan IV over 1 hour on day -5 and total body irradiation twice a day on days -4 to -1. PBSC are reinfused on day 0. G-CSF SQ is administered beginning on day 1 until blood counts recover. Chemotherapy: Patients receive vincristine IV, carmustine IV, and cyclophosphamide IV on day 1, oral melphalan on days 1-4, and oral prednisone on days 1-7. Treatment repeats every 5 weeks for at least 12 months. Patients who have at least a 75% response to autologous BMT or chemotherapy are randomized to maintenance vs no further therapy. Patients who progress on chemotherapy proceed to autologous BMT (registration V). Maintenance therapy: Therapy begins between 5 and 12 weeks after PBSC rescue. Patients receive interferon alfa SQ three times a week. Treatment continues for 4 years in the absence of disease progression or unacceptable toxicity. Patients who progress on chemotherapy undergo an autologous BMT within 8 weeks after the last course of chemotherapy. Patients who are randomized to receive no further therapy are observed for 1 year. PROJECTED ACCRUAL: A total of 500 patients will be randomized over about 4 years to autologous transplantation vs chemotherapy as follows: about 250 patients/year will be accrued for induction of whom 200 will achieve at least stable disease, 125 will be randomized, and 15 will have a suitable donor for allogeneic transplant (as of 8/1/97, allogeneic arm of study is closed). Approximately 300 patients are expected to be randomized to maintenance vs no further therapy.

Official Title
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Standard Dose Versus Myeloablative Therapy for Previously Untreated Symptomatic Multiple Myeloma, A Phase III Intergroup Study

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: recombinant interferon alfa
* Drug: carmustine
* Drug: cyclophosphamide
* Drug: dexamethasone
* Drug: doxorubicin hydrochloride
* Drug: melphalan
* Drug: prednisone
* Drug: vincristine sulfate
* Procedure: allogeneic bone marrow transplantation
* Procedure: autologous bone marrow transplantation
* Procedure: peripheral blood stem cell transplantation
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Newly diagnosed, active multiple myeloma of any stage requiring treatment Smoldering myeloma (Durie-Salmon stage I) must have a 25% or greater increase in M component levels and/or Bence-Jones protein excretion or development of symptoms Quantifiable M component of IgG, IgA, IgD, IgE, and/or urinary kappa or lambda light chain (Bence-Jones protein) excretion required Plasmacytosis of at least 30% allowed for non-secretory disease or secretory disease without quantifiable protein IgM peaks excluded Evaluation of siblings as potential allogeneic bone marrow transplant donors required for patients 55 years of age and younger (As of 8/1/97, permanently closed) HLA followed by DR and MLC testing required Renal failure, even on dialysis, eligible provided: Cause is attributed to myeloma (Bence-Jones protein or hypercalcemia) Duration does not exceed 2 months If medically appropriate, the following conditions should be treated prior to registration: Pathologic fractures Pneumonia at diagnosis Hyperviscosity with shortness of breath PATIENT CHARACTERISTICS: Age: 70 and under Performance status: SWOG 0-2 (SWOG 3 or 4 based solely on bone pain allowed) Hematopoietic: Not specified Hepatic: Not specified Renal: See Disease Characteristics Cardiovascular: Normal ejection fraction by ECHO or MUGA No myocardial infarction within 6 months No unstable angina No difficult to control congestive heart failure No uncontrolled hypertension No difficult to control arrhythmias No history of chronic cerebral vascular accident Pulmonary: No history of chronic obstructive or restrictive pulmonary disease Pulmonary function studies and DLCO at least 50% of predicted except for demonstrated myeloma involvement on bronchoscopy and/or open lung biopsy Other: No uncontrolled diabetes No significant comorbid medical condition No uncontrolled, life-threatening infection No prior malignancy within 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix No prior malignancy treated with cytotoxic drugs used on this protocol Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior chemotherapy Endocrine therapy: Not specified Radiotherapy: No prior radiotherapy except local radiotherapy provided the following cumulative dose limits for prior dose plus potential TBI dose on protocol are not exceeded: Less than 5,000 cGy to bone Less than 4,000 cGy to mediastinum, heart, small bowel, brain, and spinal cord Less than 2,000 cGy to the liver Less than 1,500 cGy to the kidney and lungs Surgery: Not specified

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: HDCTX and PBSC<br>High dose chemotherapy with peripheral blood stem cells High dose chemotherapy with peripheral blood stem cells IND (q 5 weeks): vincristine 0.5 mg/d cont IV D1-4; adriamycin 10mg/m2/d cont IV D1-4; dex 40 mg/d PO or IVPB D1-4, 9-12, 17-20 2nd Reg: cyclophosphamide 1.5g/m2 IV over 1 hr every 3 hrs x 3 (4.5g/m2 total); MESNA 4.5 g/m2 24 hr IV start with cyclo; GCSF 0.25 mg/m2/d SQ; PBSC collection Chemo: vincristine 1.2 mg/m2 IV D1, BCNU 20 mg/m2 IV D1, melphalan 8 mg/m2 PO D1-4, cyclophosphamide 400 mg/m2 IV D1, prednisone 40 mg/m2 PO D1-7 | Drug: doxorubicin hydrochloride<br>* 10 mg/m2/day continuous 1 - 4 q 5 weeks<br>* Other names: Adriamycin;Drug: melphalan<br>* 140 mg/m2 is given IV within 30 minutes of constitution on Day -5<br>Drug: prednisone<br>* 40 mg/m2 PO days 1-7 q 35 days<br>Drug: vincristine sulfate<br>* 0.5 mg/day continuous 1 - 4 q 5 weeks<br>Procedure: peripheral blood stem cell transplantation<br>* day 0<br>|
| Experimental: HDCTX with PBSC and Autologous BMT<br>High dose chemotherapy with peripheral blood stem cells and autologous bone marrow transplant High dose chemotherapy with peripheral blood stem cells and autologous bone marrow transplant High dose chemotherapy with peripheral blood stem cells IND (q 5 weeks): vincristine 0.5 mg/d cont IV D1-4; adriamycin 10mg/m2/d cont IV D1-4; dex 40 mg/d PO or IVPB D1-4, 9-12, 17-20 2nd Reg: cyclophosphamide 1.5g/m2 IV over 1 hr every 3 hrs x 3 (4.5g/m2 total); MESNA 4.5 g/m2 24 hr IV start with cyclo; GCSF 0.25 mg/m2/d SQ; PBSC collection Auto Trans: Mel 140mg/m2 IV D-5; TBI 150cGy D-4, -3, -2, -1; infusion D0 | Drug: carmustine<br>* 20 mg/m2 I.V. day 1 q 35 days<br>* Other names: BCNU;Drug: cyclophosphamide<br>* 1.5 g/m2 in 100 ml of D5W, IV intravenously over 1 hour every 3 hour x 3 (total dose 4.5 g/m2)<br>* Other names: cytoxan;Drug: dexamethasone<br>* 40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks<br>* Other names: steroid, decadron;Drug: doxorubicin hydrochloride<br>* 10 mg/m2/day continuous 1 - 4 q 5 weeks<br>* Other names: Adriamycin;Drug: melphalan<br>* 140 mg/m2 is given IV within 30 minutes of constitution on Day -5<br>Drug: prednisone<br>* 40 mg/m2 PO days 1-7 q 35 days<br>Procedure: allogeneic bone marrow transplantation<br>* day 0<br>Procedure: autologous bone marrow transplantation<br>* day 0<br>Procedure: peripheral blood stem cell transplantation<br>* day 0<br>Radiation: radiation therapy<br>* administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)<br>|
| Experimental: HDCTX with PBSC and interferon<br>High dose chemotherapy with peripheral blood stem cells and interferon Experimental: HDCTX with PBSC and interferon High dose chemotherapy with peripheral blood stem cells and interferon High dose chemotherapy with peripheral blood stem cells IND (q 5 weeks): vincristine 0.5 mg/d cont IV D1-4; adriamycin 10mg/m2/d cont IV D1-4; dex 40 mg/d PO or IVPB D1-4, 9-12, 17-20 2nd Reg: cyclophosphamide 1.5g/m2 IV over 1 hr every 3 hrs x 3 (4.5g/m2 total); MESNA 4.5 g/m2 24 hr IV start with cyclo; GCSF 0.25 mg/m2/d SQ; PBSC collection Chemo: vincristine 1.2 mg/m2 IV D1, BCNU 20 mg/m2 IV D1, melphalan 8 mg/m2 PO D1-4, cyclophosphamide 400 mg/m2 IV D1, prednisone 40 mg/m2 PO D1-7 IFN: IFN 3 million units/m2 MWF SQ | Biological: recombinant interferon alfa<br>* 3 million units/m2 SQ Monday-Wednesday -Friday (3 times a week)<br>* Other names: IFN, alpha interferon;Drug: doxorubicin hydrochloride<br>* 10 mg/m2/day continuous 1 - 4 q 5 weeks<br>* Other names: Adriamycin;Drug: melphalan<br>* 140 mg/m2 is given IV within 30 minutes of constitution on Day -5<br>Drug: prednisone<br>* 40 mg/m2 PO days 1-7 q 35 days<br>Drug: vincristine sulfate<br>* 0.5 mg/day continuous 1 - 4 q 5 weeks<br>Procedure: peripheral blood stem cell transplantation<br>* day 0<br>|
| Experimental: HDCTX with PBSC and transplant plus IFN<br>High dose chemotherapy with peripheral blood stem cells and autologous bone marrow transplant plus alpha interferon Experimental: HDCTX with PBSC and transplant plus IFN High dose chemotherapy with peripheral blood stem cells and autologous bone marrow transplant plus alpha interferon High dose chemotherapy with peripheral blood stem cells IND (q 5 weeks): vincristine 0.5 mg/d cont IV D1-4; adriamycin 10mg/m2/d cont IV D1-4; dex 40 mg/d PO or IVPB D1-4, 9-12, 17-20 2nd Reg: cyclophosphamide 1.5g/m2 IV over 1 hr every 3 hrs x 3 (4.5g/m2 total); MESNA 4.5 g/m2 24 hr IV start with cyclo; GCSF 0.25 mg/m2/d SQ; PBSC collection Trans: Mel 140mg/m2 IV D-5; TBI 150cGy D-4, -3, -2, -1; infusion D0 IFN: 3 million units/m2 MWF SQ | Biological: recombinant interferon alfa<br>* 3 million units/m2 SQ Monday-Wednesday -Friday (3 times a week)<br>* Other names: IFN, alpha interferon;Drug: carmustine<br>* 20 mg/m2 I.V. day 1 q 35 days<br>* Other names: BCNU;Drug: cyclophosphamide<br>* 1.5 g/m2 in 100 ml of D5W, IV intravenously over 1 hour every 3 hour x 3 (total dose 4.5 g/m2)<br>* Other names: cytoxan;Drug: dexamethasone<br>* 40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks<br>* Other names: steroid, decadron;Drug: doxorubicin hydrochloride<br>* 10 mg/m2/day continuous 1 - 4 q 5 weeks<br>* Other names: Adriamycin;Drug: melphalan<br>* 140 mg/m2 is given IV within 30 minutes of constitution on Day -5<br>Drug: prednisone<br>* 40 mg/m2 PO days 1-7 q 35 days<br>Procedure: autologous bone marrow transplantation<br>* day 0<br>Procedure: peripheral blood stem cell transplantation<br>* day 0<br>Radiation: radiation therapy<br>* administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival |  | 3 years from randomization | 

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