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NCI HIGH PRIORITY CLINICAL TRIAL --- Phase III Randomized Study of Melphalan/Total Body Irradiation with Peripheral Blood Stem Cell Rescue vs VBMCP (Vincristine/Carmustine/Melphalan/Cyclophosphamide/Prednisone) Following Standard Induction for Previously Untreated Symptomatic Multiple Myeloma, with Further Randomization for Major Responders to Interferon alfa vs Observation
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 | Protocol IDs |
---|
Phase III | Treatment | Closed | 70 and under | SWOG-9321 CLB-9312, E-S9321, INT-0141, NCT00002548 |
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.
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: Chemotherapy: Endocrine therapy: 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: Patient Characteristics:
Age: Performance status: - SWOG 0-2 (SWOG 3 or 4 based solely on bone pain
allowed)
Hematopoietic: Hepatic: 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 500A 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. Published ResultsBarlogie 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. Related Publicationsvan 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 | | | |
Cancer and Leukemia Group B | | | Kenneth Anderson, MD, Protocol chair | | | |
Eastern Cooperative Oncology Group | | | Robert Kyle, MD, Protocol chair | | | |
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 |
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol. Back to Top |
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