Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Melphalan, Total-Body Irradiation, and Peripheral Stem Cell Transplantation Compared With Combination Chemotherapy in Treating Patients With Previously Untreated Multiple Myeloma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	70 and under	NCI	SWOG-9321 CLB-9312, E-S9321, INT-0141, NCT00002548

Objectives

1. 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).
2. 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.
3. 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)
4. Determine whether myeloablative therapy with PBSC rescue can extend the duration of survival by 33% compared to results from standard dose VBMCP.
5. Evaluate the toxic effects and possible long term side effects, including development of myelodysplastic disease and/or acute myeloblastic leukemia, associated with these treatments.

Entry Criteria

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

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

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

Expected Enrollment

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.

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.

Barlogie B, Kyle RA, Anderson KC, et al.: Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 24 (6): 929-36, 2006.[PUBMED Abstract]

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Rimsza LM, Campbell K, Dalton WS, et al.: The major vault protein (MVP), a new multidrug resistance associated protein, is frequently expressed in multiple myeloma. Leuk Lymphoma 34 (3-4): 315-24, 1999.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Southwest Oncology Group

Bart Barlogie, MD, Protocol chair		Ph: 501-526-2873

Cancer and Leukemia Group B

Kenneth Anderson, MD, Protocol chair		Ph: 617-632-2144; 866-790-4500 Email: kenneth_anderson@dfci.harvard.edu

Eastern Cooperative Oncology Group

Robert Kyle, MD, Protocol chair		Ph: 507-266-3039 Email: kyle.robert@mayo.edu

Registry Information
Official Title		STANDARD DOSE VERSUS MYELOABLATIVE THERAPY FOR PREVIOUSLY UNTREATED SYMPTOMATIC MULTIPLE MYELOMA, A PHASE III INTERGROUP STUDY
Trial Start Date		1994-01-15
Registered in ClinicalTrials.gov		NCT00002548
Date Submitted to PDQ		1994-01-15
Information Last Verified		2008-12-29
NCI Grant/Contract Number		U10-CA32102