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Combination Chemotherapy With or Without PSC 833 in Treating Patients With Relapsed or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT00002878
Recruitment Status : Completed
First Posted : July 9, 2003
Last Update Posted : August 29, 2013
National Cancer Institute (NCI)
Southwest Oncology Group
Cancer and Leukemia Group B
NCIC Clinical Trials Group
European Organisation for Research and Treatment of Cancer - EORTC
Information provided by:
Eastern Cooperative Oncology Group

Brief Summary:

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Some tumors become resistant to chemotherapy drugs. Combining PSC 833 with chemotherapy may reduce resistance to the drug, and allow more tumor cells to be killed. It is not yet known whether combination chemotherapy plus PSC 833 is more effective than combination chemotherapy alone in treating patients with relapsed or refractory multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without PSC 833 in treating patients with relapsed or refractory multiple myeloma.

Condition or disease Intervention/treatment Phase
Multiple Myeloma and Plasma Cell Neoplasm Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: valspodar Drug: vincristine sulfate Phase 3

Detailed Description:


  • Compare the overall survival and objective response rate of patients with relapsed or refractory multiple myeloma treated with vincristine, doxorubicin, and dexamethasone (VAD) with or without PSC 833.
  • Compare event free survival and subjective response in patients treated with these regimens.
  • Correlate treatment outcome with p-glycoprotein expression.
  • Determine whether prognostic factors previously determined to be useful in untreated patients (i.e., plasma cell labeling index and multidrug resistance determined from bone marrow aspirates, serum beta 2-microglobulin and interleukin-6 receptor levels) correlate with objective and subjective response and event-free and overall survival in patients treated with these regimens.
  • Compare the toxicity of VAD with or without PSC 833.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by response to prior treatment, prior doxorubicin and/or vincristine, prior autologous peripheral blood stem cell transplantation, and center.

Patients are randomized to 1 of 2 treatment arms:

  • Arm I: The first group receives vincristine, doxorubicin, and dexamethasone (VAD). Patients receive higher dose vincristine IV over 96 hours and higher dose doxorubicin IV over 96 hours on days 1-4 and oral dexamethasone daily on days 1-4 and 15-18.
  • Arm II: The second group receives VAD plus oral PSC 833. Patients receive oral PSC 833 every 6 hours beginning on day 1 and continuing for 20 doses. Patients receive lower dose vincristine IV over 96 hours and lower dose doxorubicin IV over 96 hours on days 2-5 and oral dexamethasone daily on days 2-5 and 16-19.

Treatment in both arms repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of 2 courses, patients are reevaluated, and those with stable or responding disease continue treatment for 2 courses beyond maximum response. Doxorubicin is discontinued in patients who receive a maximum lifetime dose but still have stable or responding disease.

Patients are followed every 2 months for survival.

PROJECTED ACCRUAL: A total of 360 patients will be accrued for this study over approximately 20 months.

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Study Type : Interventional  (Clinical Trial)
Allocation: Randomized
Primary Purpose: Treatment
Study Start Date : March 1997
Actual Primary Completion Date : April 2003

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Multiple myeloma of any stage confirmed by:

    • Bone marrow plasmacytosis with at least 10% plasma cells, sheets of plasma cells, or biopsy proven plasmacytosis
    • Myeloma (M) protein in serum and/or urine
  • Measurable disease by at least one of the following:

    • Serum M-component at least 1.0 g/dL by electrophoresis

      • Baseline measurement by nephelometry also, if used to follow response
    • Urine M-protein excretion greater than 200 mg/24 hours by electrophoresis
  • The following are not considered measurable but are followed for response:

    • Lytic bone lesions
    • Bone marrow plasmacytosis
    • Anemia
    • Serum beta 2-microglobulin
  • Objective evidence of progression by at least one of the following:

    • Increased serum M-protein (by electrophoresis unless M-spike less than 1.5 g/dL)

      • At least 50% above lowest remission level or by at least 2 g/dL
      • To more than 1.0 g/dL if sole protein indication of relapse
      • Nephelometry may be used instead of electrophoresis
    • Increased urine M-protein

      • To 50% above lowest level OR by 2 g/24 hours
      • To greater than 200 mg/24 hours
    • Definite new lytic bone lesions or at least a 50% increase in size of existing lesions (discussion with ECOG Study Chairman required if sole indication of progression)
    • Increase in serum or urine M-protein by 25% to under 50% (as above) plus one of the following:

      • Serum calcium greater than 12 mg/dL without other cause
      • Hemoglobin decreased by more than 2.0 g/dL not attributed to chemotherapy, interferon therapy, or a myelodysplastic syndrome

        • Less than 11 g/dL in men
        • Less than 10 g/dL in women
      • At least a 50% increase in bone marrow plasmacytosis
  • Failure of prior cytotoxic therapy defined by one of the following:

    • Never responded
    • Relapsed within 2 months of last treatment
    • Relapsed 2-12 months after last treatment following initial response
  • Adequate prior chemotherapy required, e.g.:

    • At least 2 courses of combination chemotherapy (e.g., VBMCP, VBAP, MP)

      • Prior vincristine, doxorubicin, and dexamethasone (VAD) allowed

        • No demonstrated resistance to VAD
        • At least 3 months since prior VAD
      • Cumulative doxorubicin dose no more than 250 mg/m2
      • Prior autologous peripheral blood stem cell transplant allowed if performed prior to development of drug resistance

        • No prior allogeneic transplant
  • No smoldering myeloma, localized plasmacytoma, or monoclonal gammopathy of undetermined significance (MGUS)



  • 18 and over

Performance status:

  • ECOG 0-3

Life expectancy:

  • At least 2 months


  • Absolute neutrophil count at least 1,000/mm^3
  • Platelet count at least 50,000/mm^3


  • Bilirubin less than 1.5 times upper limit of normal (ULN)
  • AST less than 1.5 times ULN
  • No chronic or active hepatitis or cirrhosis


  • Creatinine less than 3.0 mg/dL


  • Ejection fraction at least 50%
  • No history of congestive heart failure
  • No overt angina despite medication
  • No myocardial infarction within 2 months
  • No poorly controlled hypertension (i.e., pressure 200/110 or higher despite medication)
  • No arrhythmia requiring therapy (i.e., sustained atrial or ventricular arrhythmia or multifocal premature ventricular contraction)

    • Digoxin to control ventricular rate of atrial fibrillation that has been chronic for more than 1 month allowed


  • No peripheral neuropathy with weakness
  • No cerebellar disease with ataxia


  • Adequate gastrointestinal function to allow absorption of PSC 833
  • No active peptic ulcer


  • No hypersensitivity to PSC 833 or cyclosporine
  • No active infection
  • HIV negative
  • No uncontrolled diabetes mellitus
  • No second malignancy within the past 5 years except curatively treated nonmelanomatous skin cancer, carcinoma in situ of the cervix, or other localized cancer treated with surgery alone
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No other serious medical problem unless sufficiently stabilized


Biologic therapy:

  • Prior biologic therapy (e.g., interferon) allowed


  • See Disease Characteristics
  • At least 3 weeks since other prior chemotherapy (including plicamycin)

Endocrine therapy:

  • At least 2 weeks since high dose steroids (at least 100 mg/m2/day of prednisone or at least 40 mg/day of dexamethasone (including steroids for hypercalcemia)


  • At least 2 weeks since prior radiotherapy except limited radiotherapy to a single bone lesion


  • At least 4 weeks since prior major surgery


  • No concurrent anticoagulants
  • No concurrent drugs known to modulate cyclosporine blood concentrations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00002878

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Sponsors and Collaborators
Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Southwest Oncology Group
Cancer and Leukemia Group B
NCIC Clinical Trials Group
European Organisation for Research and Treatment of Cancer - EORTC
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Study Chair: William R. Friedenberg, MD Guthrie Cancer Center at Guthrie Clinic Sayre
Study Chair: Karl H. Hanson, MD Saint Luke's Cancer Institute at Saint Luke's Hospital
Study Chair: Richard A. Larson, MD University of Chicago
Study Chair: Chaim Shustik, MD Royal Victoria Hospital - Montreal
Study Chair: Pieter Sonneveld, MD, PhD University Medical Center Rotterdam at Erasmus Medical Center
Publications of Results:
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ClinicalTrials.gov Identifier: NCT00002878    
Other Study ID Numbers: CDR0000065178
First Posted: July 9, 2003    Key Record Dates
Last Update Posted: August 29, 2013
Last Verified: August 2013
Keywords provided by Eastern Cooperative Oncology Group:
refractory multiple myeloma
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Liposomal doxorubicin
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents