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

NCT00002548 | Completed Phase 3 DMC

• 5 other identifiers: SWOG-9321CLB-9312E-S9321INT-0141U10CA032102
• Study Type: interventional
• Target: 899
• Locations: 1 country
• Sites: 34

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.

Conditions

Multiple Myeloma

Keywords

stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma

Outcome Measures

Primary Outcomes (1)

• survival

  3 years from randomization

Study Arms (4)

HDCTX and PBSC

ACTIVE COMPARATOR

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; Drug: melphalan; Drug: prednisone; Drug: vincristine sulfate; Procedure: peripheral blood stem cell transplantation

HDCTX with PBSC and Autologous BMT

EXPERIMENTAL

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; Drug: cyclophosphamide; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: melphalan; Drug: prednisone; Procedure: allogeneic bone marrow transplantation; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy

HDCTX with PBSC and interferon

EXPERIMENTAL

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; Drug: doxorubicin hydrochloride; Drug: melphalan; Drug: prednisone; Drug: vincristine sulfate; Procedure: peripheral blood stem cell transplantation

HDCTX with PBSC and transplant plus IFN

EXPERIMENTAL

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; Drug: carmustine; Drug: cyclophosphamide; Drug: dexamethasone; Drug: doxorubicin hydrochloride; Drug: melphalan; Drug: prednisone; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy

Interventions

recombinant interferon alfa BIOLOGICAL

3 million units/m2 SQ Monday-Wednesday -Friday (3 times a week)

Also known as: IFN, alpha interferon

HDCTX with PBSC and interferon; HDCTX with PBSC and transplant plus IFN

carmustine DRUG

20 mg/m2 I.V. day 1 q 35 days

Also known as: BCNU

HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and transplant plus IFN

cyclophosphamide DRUG

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)

Also known as: cytoxan

HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and transplant plus IFN

dexamethasone DRUG

40 mg/day PO or IVPB days 1-4, 9-12, 17-20 q 5 weeks

Also known as: steroid, decadron

HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and transplant plus IFN

doxorubicin hydrochloride DRUG

10 mg/m2/day continuous 1 - 4 q 5 weeks

Also known as: Adriamycin

HDCTX and PBSC; HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and interferon; HDCTX with PBSC and transplant plus IFN

melphalan DRUG

140 mg/m2 is given IV within 30 minutes of constitution on Day -5

HDCTX and PBSC; HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and interferon; HDCTX with PBSC and transplant plus IFN

prednisone DRUG

40 mg/m2 PO days 1-7 q 35 days

HDCTX and PBSC; HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and interferon; HDCTX with PBSC and transplant plus IFN

vincristine sulfate DRUG

0.5 mg/day continuous 1 - 4 q 5 weeks

HDCTX and PBSC; HDCTX with PBSC and interferon

allogeneic bone marrow transplantation PROCEDURE

day 0

HDCTX with PBSC and Autologous BMT

autologous bone marrow transplantation PROCEDURE

day 0

HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and transplant plus IFN

peripheral blood stem cell transplantation PROCEDURE

day 0

HDCTX and PBSC; HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and interferon; HDCTX with PBSC and transplant plus IFN

radiation therapy RADIATION

administered in fractionated doses of 150 cGy, 6 - 10 hours apart bid, on Days -4, -3, -2, and -1 (Total 1,200 cGy)

HDCTX with PBSC and Autologous BMT; HDCTX with PBSC and transplant plus IFN

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• SWOG Cancer Research Network: lead
• National Cancer Institute (NCI): collaborator
• Cancer and Leukemia Group B: collaborator
• Eastern Cooperative Oncology Group: collaborator

Study Sites (34)

CCOP - Scottsdale Oncology Program

Scottsdale, Arizona, 85259-5404, United States

Location

CCOP - Colorado Cancer Research Program, Inc.

Denver, Colorado, 80209-5031, United States

Location

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612-9497, United States

Location

Robert H. Lurie Comprehensive Cancer Center, Northwestern University

Chicago, Illinois, 60611-3013, United States

Location

Veterans Affairs Medical Center - Lakeside Chicago

Chicago, Illinois, 60611, United States

Location

CCOP - Evanston

Evanston, Illinois, 60201, United States

Location

CCOP - Illinois Oncology Research Association

Peoria, Illinois, 61602, United States

Location

CCOP - Carle Cancer Center

Urbana, Illinois, 61801, United States

Location

Indiana University Cancer Center

Indianapolis, Indiana, 46202-5289, United States

Location

Veterans Affairs Medical Center - Indianapolis (Roudebush)

Indianapolis, Indiana, 46202, United States

Location

CCOP - Iowa Oncology Research Association

Des Moines, Iowa, 50309-1016, United States

Location

CCOP - Ochsner

New Orleans, Louisiana, 70121, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231-2410, United States

Location

New England Medical Center Hospital

Boston, Massachusetts, 02111, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

CCOP - Ann Arbor Regional

Ann Arbor, Michigan, 48106, United States

Location

CCOP - Kalamazoo

Kalamazoo, Michigan, 49007-3731, United States

Location

CCOP - Duluth

Duluth, Minnesota, 55805, United States

Location

University of Minnesota Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

CCOP - Metro-Minnesota

Saint Louis Park, Minnesota, 55416, United States

Location

Veterans Affairs Medical Center - New York

New York, New York, 10010, United States

Location

NYU School of Medicine's Kaplan Comprehensive Cancer Center

New York, New York, 10016, United States

Location

University of Rochester Cancer Center

Rochester, New York, 14642, United States

Location

Albert Einstein Comprehensive Cancer Center

The Bronx, New York, 10461, United States

Location

Ireland Cancer Center

Cleveland, Ohio, 44106-5065, United States

Location

CCOP - Toledo Community Hospital Oncology Program

Toledo, Ohio, 43623-3456, United States

Location

CCOP - Geisinger Clinic and Medical Center

Danville, Pennsylvania, 17822-2001, United States

Location

Hahnemann University Hospital

Philadelphia, Pennsylvania, 19102-1192, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 15213-3489, United States

Location

CCOP - Marshfield Medical Research and Education Foundation

Marshfield, Wisconsin, 54449, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Veterans Affairs Medical Center - Milwaukee (Zablocki)

Milwaukee, Wisconsin, 53295, United States

Location

Related Publications (14)

• van Ness BG, Ramos C, Kumar V, et al.: Analytical approaches for the BOAC SNP panel association with progression free survival in myeloma. [Abstract] Blood 112 (11): A-2715, 2008.

  BACKGROUND

• Crowley JJ, McCoy J, LeBlanc M, et al.: Extreme regression: a statistical technique for finding good or poor prognostic groups, illustrated using myeloma patient data from Intergroup trial S9321. [Abstract] Blood 104 (11): A-5202, 2004.

  BACKGROUND

• Greipp PR, Kumar S, Blood EA, et al.: A simple classification to identify poor-risk untreated myeloma. [Abstract] Blood 100 (11 Pt 1): A-2351, 598a, 2002.

  BACKGROUND

• Tian E, Bumm K, Xiao Y, et al.: A protocol for triple color interphase FISH on archived bone marrow biopsies from myeloma prepared with precipitating fixatives. [Abstract] Blood 96 (11 pt 1): A-665, 155a, 2000.

  BACKGROUND

• Rajkumar V, Leong T, Fonseca R, et al.: Bone marrow angiogenesis has prognostic value in multiple myeloma: an Eastern Cooperative Oncology Group study. [Abstract] Proceedings of the American Society of Clinical Oncology 18: A68, 19a, 1999.

  BACKGROUND

• Rimsza LM, Campbell K, Dalton WS, Salmon S, Willcox G, Grogan TM. The major vault protein (MVP), a new multidrug resistance associated protein, is frequently expressed in multiple myeloma. Leuk Lymphoma. 1999 Jul;34(3-4):315-24. doi: 10.3109/10428199909050956.

  PMID: 10439368 BACKGROUND

• Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. doi: 10.1200/JCO.2005.04.5807. Epub 2006 Jan 23.

  PMID: 16432076 RESULT

• Van Ness BG, Crowley JC, Ramos C, et al.: SNP genotypes show association with common toxicities during both VAD induction and high dose melphalan with autologous transplant support in intergroup trial S9321 for myeloma: from the Bank on a Cure. [Abstract] Blood 106 (11): A-3488, 2005.

  RESULT

• Crowley J, Fonseca R, Greipp P, et al.: Comparable survival in newly diagnosed multiple myeloma (MM) after VAD induction with high dose therapy using melphalan 140mg/m2 + TBI 12 Gy (MEL+TBI) versus standard therapy with VBMCP and no benefit from interferon (IFN) maintenance: final clinical results of intergroup trial S9321 in the context of IFM 90 and MRC VII trials. [Abstract] Blood 104 (11): A-539, 2004.

  RESULT

• Santana-Davila R, Crowley J, Durie B, et al.: Genetic polymorphisms associated with clinical outcome in the intergroup trial S9321, comparing high dose therapy with standard dose therapy for myelomaon, on behalf of ECOG, SWOG, CALGB, and the Bank on a Cure. [Abstract] Blood 104 (11): A-1495, 2004.

  RESULT

• Lee CK, McCoy J, Anderson KC, et al.: Long-term follow-up of previously untreated symptomatic myeloma patients treated with myeloablative therapy and sibling-matched allogeneic transplantation of the SWOG study 9321. [Abstract] Blood 100 (11 pt 1): A-1644, 2002.

  RESULT

• Greipp PR, Jacobson JL, Crowley JJ, et al.: BETA 2 microglobulin (beta 2M) and plasma cell labeling index (PCLI) constitute a strong prognostic index in the SWOG intergroup transplant trial S9321: observations on gender and age. [Abstract] Blood 96 (11 pt 1): A-653, 152a, 2000.

  RESULT

• Desika R, Salmon S, Anderson K, et al.: Planned melphalan-total body irradiation (MEL-TBI) - based allogeneic transplantation for multiple myeloma (MM) up to age 55: an intergroup experience (CALGB, ECOG and SWOG) under the auspices of the Southwest Oncology Group (SWOG 9321). [Abstract] Blood 94 (10 Pt 1): A-1546, 346a, 1999.

  RESULT

• Usmani SZ, Heuck C, Mitchell A, Szymonifka J, Nair B, Hoering A, Alsayed Y, Waheed S, Haider S, Restrepo A, Van Rhee F, Crowley J, Barlogie B. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica. 2012 Nov;97(11):1761-7. doi: 10.3324/haematol.2012.065698. Epub 2012 Jun 11.

  PMID: 22689675 DERIVED

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Interferon-alpha; Carmustine; Cyclophosphamide; Dexamethasone; Steroids; Calcium Dobesilate; Doxorubicin; Melphalan; Prednisone; Vincristine; Peripheral Blood Stem Cell Transplantation; Radiotherapy

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Aminoglycosides; Glycosides; Carbohydrates; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Pregnadienediols; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative

Study Officials

• Bart Barlogie, MD

  University of Arkansas

  STUDY CHAIR

• Kenneth C. Anderson, MD

  Dana-Farber Cancer Institute

  STUDY CHAIR

• Robert A. Kyle, MD

  Mayo Clinic

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 1999
• First Posted: August 11, 2003
• Study Start: January 1, 1994
• Primary Completion: October 1, 2003
• Study Completion: November 1, 2006
• Last Updated: March 6, 2015

Record last verified: 2015-03

Locations

US (34)