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

Sponsor

Southwest Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00002548

Collaborator

National Cancer Institute (NCI) (NIH), Cancer and Leukemia Group B (Other), Eastern Cooperative Oncology Group (Other)

899

Enrollment

Locations

Arms

154

Duration (Months)

26.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	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	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

899 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jan 1, 1994

Actual Primary Completion Date :

Oct 1, 2003

Actual Study Completion Date :

Nov 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: HDCTX and PBSC 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 10 mg/m2/day continuous 1 - 4 q 5 weeks Other Names: Adriamycin Drug: melphalan 140 mg/m2 is given IV within 30 minutes of constitution on Day -5 Drug: prednisone 40 mg/m2 PO days 1-7 q 35 days Drug: vincristine sulfate 0.5 mg/day continuous 1 - 4 q 5 weeks Procedure: peripheral blood stem cell transplantation day 0
Experimental: HDCTX with PBSC and Autologous BMT 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 20 mg/m2 I.V. day 1 q 35 days Other Names: BCNU Drug: cyclophosphamide 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) Other Names: cytoxan Drug: dexamethasone 40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks Other Names: steroid, decadron Drug: doxorubicin hydrochloride 10 mg/m2/day continuous 1 - 4 q 5 weeks Other Names: Adriamycin Drug: melphalan 140 mg/m2 is given IV within 30 minutes of constitution on Day -5 Drug: prednisone 40 mg/m2 PO days 1-7 q 35 days Procedure: allogeneic bone marrow transplantation day 0 Procedure: autologous bone marrow transplantation day 0 Procedure: peripheral blood stem cell transplantation day 0 Radiation: radiation therapy administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)
Experimental: HDCTX with PBSC and interferon 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 3 million units/m2 SQ Monday-Wednesday -Friday (3 times a week) Other Names: IFN, alpha interferon Drug: doxorubicin hydrochloride 10 mg/m2/day continuous 1 - 4 q 5 weeks Other Names: Adriamycin Drug: melphalan 140 mg/m2 is given IV within 30 minutes of constitution on Day -5 Drug: prednisone 40 mg/m2 PO days 1-7 q 35 days Drug: vincristine sulfate 0.5 mg/day continuous 1 - 4 q 5 weeks Procedure: peripheral blood stem cell transplantation day 0
Experimental: HDCTX with PBSC and transplant plus IFN 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 3 million units/m2 SQ Monday-Wednesday -Friday (3 times a week) Other Names: IFN, alpha interferon Drug: carmustine 20 mg/m2 I.V. day 1 q 35 days Other Names: BCNU Drug: cyclophosphamide 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) Other Names: cytoxan Drug: dexamethasone 40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks Other Names: steroid, decadron Drug: doxorubicin hydrochloride 10 mg/m2/day continuous 1 - 4 q 5 weeks Other Names: Adriamycin Drug: melphalan 140 mg/m2 is given IV within 30 minutes of constitution on Day -5 Drug: prednisone 40 mg/m2 PO days 1-7 q 35 days Procedure: autologous bone marrow transplantation day 0 Procedure: peripheral blood stem cell transplantation day 0 Radiation: radiation therapy administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)

Outcome Measures

Primary Outcome Measures

survival [3 years from randomization]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CCOP - Scottsdale Oncology Program	Scottsdale	Arizona	United States	85259-5404
2	CCOP - Colorado Cancer Research Program, Inc.	Denver	Colorado	United States	80209-5031
3	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612-9497
4	Robert H. Lurie Comprehensive Cancer Center, Northwestern University	Chicago	Illinois	United States	60611-3013
5	Veterans Affairs Medical Center - Lakeside Chicago	Chicago	Illinois	United States	60611
6	CCOP - Evanston	Evanston	Illinois	United States	60201
7	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61602
8	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
9	Indiana University Cancer Center	Indianapolis	Indiana	United States	46202-5289
10	Veterans Affairs Medical Center - Indianapolis (Roudebush)	Indianapolis	Indiana	United States	46202
11	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309-1016
12	CCOP - Ochsner	New Orleans	Louisiana	United States	70121
13	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
14	New England Medical Center Hospital	Boston	Massachusetts	United States	02111
15	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
16	CCOP - Ann Arbor Regional	Ann Arbor	Michigan	United States	48106
17	CCOP - Kalamazoo	Kalamazoo	Michigan	United States	49007-3731
18	CCOP - Duluth	Duluth	Minnesota	United States	55805
19	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
20	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
21	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
22	Albert Einstein Comprehensive Cancer Center	Bronx	New York	United States	10461
23	Veterans Affairs Medical Center - New York	New York	New York	United States	10010
24	NYU School of Medicine's Kaplan Comprehensive Cancer Center	New York	New York	United States	10016
25	University of Rochester Cancer Center	Rochester	New York	United States	14642
26	Ireland Cancer Center	Cleveland	Ohio	United States	44106-5065
27	CCOP - Toledo Community Hospital Oncology Program	Toledo	Ohio	United States	43623-3456
28	CCOP - Geisinger Clinic and Medical Center	Danville	Pennsylvania	United States	17822-2001
29	Hahnemann University Hospital	Philadelphia	Pennsylvania	United States	19102-1192
30	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
31	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15213-3489
32	CCOP - Marshfield Medical Research and Education Foundation	Marshfield	Wisconsin	United States	54449
33	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
34	Veterans Affairs Medical Center - Milwaukee (Zablocki)	Milwaukee	Wisconsin	United States	53295