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


Phase 3
18 Years
70 Years
Not Enrolling
Both
Multiple Myeloma

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Trial Information

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


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.

Inclusion 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

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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

survival

Outcome Time Frame:

3 years from randomization

Safety Issue:

No

Principal Investigator

Bart Barlogie, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of Arkansas

Authority:

United States: Federal Government

Study ID:

CDR0000063310

NCT ID:

NCT00002548

Start Date:

January 1994

Completion Date:

November 2006

Related Keywords:

  • Multiple Myeloma
  • stage I multiple myeloma
  • stage II multiple myeloma
  • stage III multiple myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell

Name

Location

Albert Einstein Comprehensive Cancer CenterBronx, New York  10461
Mayo Clinic Cancer CenterRochester, Minnesota  55905
H. Lee Moffitt Cancer Center and Research InstituteTampa, Florida  33612
Indiana University Cancer CenterIndianapolis, Indiana  46202-5265
CCOP - Ann Arbor RegionalAnn Arbor, Michigan  48106
University of Minnesota Cancer CenterMinneapolis, Minnesota  55455
University of Rochester Cancer CenterRochester, New York  14642
Ireland Cancer CenterCleveland, Ohio  44106-5065
Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111
Robert H. Lurie Comprehensive Cancer Center, Northwestern UniversityChicago, Illinois  60611
CCOP - Colorado Cancer Research Program, Inc.Denver, Colorado  80209-5031
CCOP - Illinois Oncology Research AssociationPeoria, Illinois  61602
CCOP - Carle Cancer CenterUrbana, Illinois  61801
Veterans Affairs Medical Center - Indianapolis (Roudebush)Indianapolis, Indiana  46202
CCOP - Iowa Oncology Research AssociationDes Moines, Iowa  50309-1016
Beth Israel Deaconess Medical CenterBoston, Massachusetts  02215
New England Medical Center HospitalBoston, Massachusetts  02111
CCOP - KalamazooKalamazoo, Michigan  49007-3731
CCOP - Metro-MinnesotaSaint Louis Park, Minnesota  55416
Hahnemann University HospitalPhiladelphia, Pennsylvania  19102-1192
University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15213
CCOP - DuluthDuluth, Minnesota  55805
CCOP - Scottsdale Oncology ProgramScottsdale, Arizona  85259-5404
CCOP - OchsnerNew Orleans, Louisiana  70121
CCOP - Toledo Community Hospital Oncology ProgramToledo, Ohio  43623-3456
NYU School of Medicine's Kaplan Comprehensive Cancer CenterNew York, New York  10016
Medical College of WisconsinMilwaukee, Wisconsin  53226
Veterans Affairs Medical Center - Milwaukee (Zablocki)Milwaukee, Wisconsin  53295
CCOP - EvanstonEvanston, Illinois  60201
CCOP - Geisinger Clinic and Medical CenterDanville, Pennsylvania  17822-2001
Veterans Affairs Medical Center - Lakeside ChicagoChicago, Illinois  60611
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Veterans Affairs Medical Center - New YorkNew York, New York  10010
CCOP - Marshfield Medical Research and Education FoundationMarshfield, Wisconsin  54449