Phase III Randomized Study of Bortezomib Versus High-Dose Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

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Alternate Title

Bortezomib Compared With Dexamethasone in Treating Patients With Relapsed or Refractory Multiple Myeloma

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosed18 and overNCI, Pharmaceutical / IndustryMILLENNIUM-M34101-039
FHCRC-1746.00, NCI-G02-2130, NCT00048230


  1. Compare time to progression in patients with relapsed or refractory multiple myeloma when treated with bortezomib vs high-dose dexamethasone.
  2. Compare improvement in selected measures of clinical benefit in patients treated with these drugs.
  3. Compare overall survival in patients treated with these drugs.
  4. Compare response rate (complete and partial) in patients treated with these drugs.
  5. Compare quality of life of patients treated with these drugs.
  6. Compare safety and tolerability of these drugs in these patients.

Entry Criteria

Disease Characteristics:

  • Diagnosis of multiple myeloma, based on standard criteria
  • Currently requires second-, third-, or fourth-line therapy because of progressive disease or relapse from a complete response
    • Progressive disease defined as a 25% increase in M-protein, development of new or worsening of existing lytic bone lesions or soft tissue plasmacytomas, or hypercalcemia (calcium greater than 11.5 mg/dL)
  • Measurable disease
    • For secretory multiple myeloma: Any quantifiable serum monoclonal protein value and, where applicable, urine light chain excretion at least 200 mg/24 hours
    • For oligo- or non-secretory multiple myeloma: At least the presence of soft tissue (not bone) plasmacytomas as determined by clinical examination or MRI
  • No disease refractory to prior high-dose dexamethasone (more than 500 mg over 10 weeks, either alone or as part of the vincristine, doxorubicin, and dexamethasone regimen), defined as experiencing progressive disease within 6 months or less than a partial response or discontinued because of unacceptable dexamethasone-related toxicity

Prior/Concurrent Therapy:

    Biologic therapy

  • More than 3 weeks since prior thalidomide
  • More than 4 weeks since prior plasmapheresis
  • More than 8 weeks since prior immunotherapy or antibody therapy
  • No concurrent thalidomide


  • See Disease Characterisitics
  • More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas)

    Endocrine therapy

  • See Disease Characteristics
  • More than 3 weeks since prior corticosteroids (i.e., more than 10 mg/day of prednisone)
  • No concurrent corticosteroids


  • More than 3 weeks since prior radiotherapy
  • No concurrent radiotherapy


  • More than 4 weeks since prior major surgery
    • Kyphoplasty is not considered major surgery


  • More than 3 weeks since prior clarithromycin
  • No prior bortezomib
  • No concurrent enrollment in another clinical trial
  • No other concurrent investigational agents
  • No other concurrent antineoplastic treatment for this disease
  • No concurrent clarithromycin

Patient Characteristics:


  • 18 and over

    Performance status

  • Karnofsky 60-100%

    Life expectancy

  • More than 3 months


  • Platelet count at least 50,000/mm3 (without transfusion support)
  • Hemoglobin at least 7.5 g/dL (without transfusion support)
  • Absolute neutrophil count at least 750/mm3 (without use of colony-stimulating factors)


  • Bilirubin no greater than 1.5 times upper limit of normal (ULN)
  • AST and ALT no greater than 2.5 times ULN
  • Hepatitis B surface antigen negative
  • No known active hepatitis C infection


  • Creatinine clearance at least 20 mL/min
  • Calcium less than 14 mg/dL


  • No prior myocardial infarction within the past 6 months
  • No New York Heart Association class III or IV heart failure
  • No uncontrolled angina
  • No severe uncontrolled ventricular arrhythmias
  • No EKG evidence of acute ischemia or active conduction abnormalities
  • No cardiac amyloidosis
  • No poorly controlled hypertension


  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective barrier contraception
  • No diabetes mellitus
  • HIV negative
  • No prior allergic reaction attributable to compounds containing boron or mannitol
  • No active systemic infection requiring treatment
  • No other cancer within the past 5 years except basal cell carcinoma or carcinoma in situ of the cervix
  • No peripheral neuropathy grade 2 or greater
  • No other serious medical or psychiatric condition that would preclude study participation

Expected Enrollment

A total of 612 patients (306 per treatment arm) will be accrued for this study within 9 months.


This is a randomized, open-label, multicenter study. Patients are stratified according to number of prior treatment regimens (1 vs more than 1), disease progression (during or within 6 months of treatment vs more than 6 months after receiving treatment), and baseline ß2-microglobulin level (greater than 2.5 mg/L vs no greater than 2.5 mg/L). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive bortezomib IV on days 1, 4, 8, and 11 every 21 days for 8 courses and then again on days 1, 8, 15, and 22 every 35 days for 3 courses.
  • Arm II: Patients receive high-dose oral dexamethasone on days 1-4, 9-12, and 17-20 every 35 days for 4 courses and then again on days 1-4 every 28 days for 3 courses.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 6 weeks during treatment, at the end of treatment, and then every 6 weeks until disease progression.

Patients are followed every 6 weeks until disease progression and then every 3 months thereafter.

Published Results

Vogl DT, Stadtmauer EA, Richardson PG, et al.: Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma. Br J Haematol 147 (4): 531-4, 2009.[PUBMED Abstract]

Richardson PG, Sonneveld P, Schuster MW, et al.: Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma. Br J Haematol 137 (5): 429-35, 2007.[PUBMED Abstract]

Richardson PG, Sonneveld P, Schuster MW, et al.: Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352 (24): 2487-98, 2005.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Millennium Pharmaceuticals, Incorporated

Lynne Nibert, Protocol chair
Ph: 617-551-4934

Registry Information

Official TitleAn International, Multi-Center, Randomized, Open-Label Study of PS-341 Versus High-Dose Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma
Registered in ClinicalTrials.govNCT00048230
Date Submitted to PDQ2002-09-19
Information Last Verified2003-12-05
NCI Grant/Contract NumberCA15704

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.