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

A PHASE III STUDY OF PSC-833 IN COMBINATION WITH VINCRISTINE, DOXORUBICIN AND DEXAMETHASONE (PSC-833/VAD) VERSUS VAD ALONE IN PATIENTS WITH RELAPSING OR REFRACTORY MULTIPLE MYELOMA

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma and Plasma Cell Neoplasm
• Intervention / Treatment: Drug: dexamethasone; Drug: vincristine sulfate; Drug: doxorubicin hydrochloride; Drug: valspodar

Detailed Description

OBJECTIVES:

• 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.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1C 6ZB
      • Moncton Hospital
  • Ontario
    • London, Ontario, Canada, N6A 4L6
      • Cancer Care Ontario-London Regional Cancer Centre
    • St. Catharines, Ontario, Canada, L2R 5K3
      • Hotel Dieu Health Sciences Hospital - Niagara
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
    • Windsor, Ontario, Canada, N8W 2X3
      • Cancer Care Ontario - Windsor Regional Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University
    • Montreal, Quebec, Canada, H2L-4M1
      • Centre Hospitalier de l'Universite de Montreal
• United States
  • California
    • La Jolla, California, United States, 92093-0658
      • University of California San Diego Cancer Center
    • San Francisco, California, United States, 94143-0128
      • UCSF Cancer Center and Cancer Research Institute
  • Delaware
    • Wilmington, Delaware, United States, 19899
      • CCOP - Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20307-5000
      • Walter Reed Army Medical Center
  • Florida
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
  • Iowa
    • Iowa City, Iowa, United States, 52242-1009
      • Holden Comprehensive Cancer Center at the University of Iowa
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Marlene & Stewart Greenebaum Cancer Center, University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber Cancer Institute
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center - Columbia
    • Saint Louis, Missouri, United States, 63110
      • Barnes-Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3330
      • University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Southern Nevada Cancer Research Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • Schneider Children's Hospital at North Shore
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital - Cornell Campus
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center, NY
    • Syracuse, New York, United States, 13210
      • State University of New York - Upstate Medical University
    • Syracuse, New York, United States, 13217
      • CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center, UNC
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Winston-Salem, North Carolina, United States, 27104-4241
      • CCOP - Southeast Cancer Control Consortium
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Comprehensive Cancer Center at Wake Forest University
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • University of Tennessee, Memphis Cancer Center
  • Vermont
    • Burlington, Vermont, United States, 05401-3498
      • Vermont Cancer Center
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • MBCCOP - Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• 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)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-3

Life expectancy:

• At least 2 months

Hematopoietic:

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

Hepatic:

• 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

Renal:

• Creatinine less than 3.0 mg/dL

Cardiovascular:

• 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

Neurologic:

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

Gastrointestinal:

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

Other:

• 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

PRIOR CONCURRENT THERAPY:

Biologic therapy:

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

Chemotherapy:

• 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)

Radiotherapy:

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

Surgery:

• At least 4 weeks since prior major surgery

Other:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI); European Organisation for Research and Treatment of Cancer - EORTC; NCIC Clinical Trials Group; Cancer and Leukemia Group B; SWOG Cancer Research Network
• Investigators: Study Chair: Richard A. Larson, MD, University of Chicago; 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: Chaim Shustik, MD, Royal Victoria Hospital - Montreal; Study Chair: Pieter Sonneveld, MD, PhD, University Medical Center Rotterdam at Erasmus Medical Center

Publications and helpful links

General Publications

• Friedenberg WR, Rue M, Blood EA, Dalton WS, Shustik C, Larson RA, Sonneveld P, Greipp PR. Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group. Cancer. 2006 Feb 15;106(4):830-8. doi: 10.1002/cncr.21666.

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 1997
• Primary Completion (Actual): April 1, 2003

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: July 8, 2003
• First Posted (Estimated): July 9, 2003

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 14, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: refractory multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Dexamethasone; Doxorubicin; Liposomal doxorubicin; Vincristine
• Other Study ID Numbers: CDR0000065178; E-1A95; CAN-NCIC-MY8; CLB-E1A95; EORTC-E1A95/06971; SWOG-E1A95; CAN-NCIC-J1A95; CLB-9596; SWOG-S1A95