Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Lenalidomide and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	ECOG-E4A03 E4A03, NCT00098475

Special Category: CTSU trial

Objectives

Primary

1. Compare the response rate in patients with newly diagnosed multiple myeloma treated with lenalidomide and standard-dose vs low-dose dexamethasone.
2. Compare the toxicity of these regimens in these patients.

Secondary

1. Determine the response rate in patients who do not achieve an objective response at any point during the first 4 courses of lenalidomide and dexamethasone and are subsequently treated with salvage therapy comprising thalidomide and dexamethasone.
2. Determine the efficacy of aspirin (325 mg/day) versus warfarin (dose adjusted to maintain a target INR of 2-3) in preventing deep vain thrombosis in patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Diagnosis of multiple myeloma within the past 90 days, confirmed by the following criteria:
  • Bone marrow plasmacytosis with ≥ 10% plasma cells or sheets of plasma cells OR biopsy-proven plasmacytoma within the past 4 weeks
  • Measurable monoclonal protein ≥ 1.0 g/dL by serum protein electrophoresis OR monoclonal light chain ≥ 200 mg by 24-hour urine protein electrophoresis within the past 4 weeks



• Symptomatic disease



• Prior plasmacytoma treated with curative-intent radiotherapy allowed provided disease progressed to active multiple myeloma



• No smoldering myeloma



• No monoclonal gammopathy of undetermined significance

Prior/Concurrent Therapy:

Biologic therapy

• No concurrent sargramostim (GM-CSF)

Chemotherapy

• Not specified

Endocrine therapy

• No prior glucocorticosteroid therapy for multiple myeloma
• The following treatments for non-malignant disorders are allowed:
  • Prior systemic glucocorticosteroids
  • Prior or concurrent topical or localized glucocorticosteroids
  • Concurrent systemic glucocorticosteroids at a dose of ≤ 10 mg of prednisone per day (or equivalent)

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior palliative and/or localized radiotherapy

Surgery

• Not specified

Other

• No prior systemic therapy for multiple myeloma except bisphosphonates

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin > 7 g/dL
• Platelet count > 75,000/mm³
• Absolute neutrophil count > 1,000/mm³

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• ALT and AST ≤ 2.5 times upper limit of normal (ULN)

Renal

• Creatinine < 2.5 mg/dL

Cardiovascular

• No uncontrolled hypertension
• No uncontrolled cardiac arrhythmia
• No symptomatic congestive heart failure
• No unstable angina
• No prior or concurrent deep vein thrombosis

Pulmonary

• No prior or concurrent pulmonary embolism

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double-method contraception (1 highly effective and one additional method) for 4 weeks prior, during, and for 4 weeks after completion of study treatment
• No other active malignancy
  • Prior malignancy with a low expectation of recurrence within the next 6 months allowed
• No prior Stevens Johnson syndrome
• No active uncontrolled seizure disorder
  • No seizures within the past 6 months
• No active uncontrolled infection
• No uncontrolled psychiatric illness or social situation that would preclude study compliance
• No peripheral neuropathy ≥ grade 2 due to other medical conditions
• No other uncontrolled illness
• Patients must be willing and able to take antithrombosis prophylaxis
• Patients must

Expected Enrollment

A total of 412 patients (206 per treatment arm) will be accrued for this study within 24 months.

Outcomes

Comparison of treatment regimens

Toxicity
Response rate

Outline

This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral lenalidomide once daily on days 1-21, oral acetylsalicyclic acid (or other deep vein thrombosis prophylaxis at the discretion of the principal investigator) once daily on days 1-28, and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20.



• Arm II: Patients receive oral lenalidomide and acetylsalicyclic acid as in arm I and low-dose oral dexamethasone once daily on days 1, 8, 15, and 22.

In both arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. Patients not responding at any point during the first 4 courses of lenalidomide and dexamethasone are assigned to 1 of 2 salvage therapy arms. Patients who progress during treatment on arms I or II have the option to register on salvage therapy arms III or IV respectively.

• Arm III (patients with no response after treatment on arm I): Patients receive oral thalidomide once daily on days 1-28 and standard-dose oral dexamethasone once daily on days 1-4, 9-12, and 17-20.



• Arm IV (patients with no response after treatment on arm II): Patients receive oral thalidomide as in arm III and low-dose oral dexamethasone once daily on days 1, 8, 15, and 22.

In both salvage therapy arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression. After completion of 4 courses of therapy, patients may undergo stem cell harvest (using growth factors only) for cryopreservation.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 2 years.

Jacobus S, Kumar S, Callander NS, et al.: Effect of venous thrombotic events on overall survival in multiple myeloma: analysis of thrombotic events occurring in E4A03: A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma, a trial coordinated by the Eastern Cooperative Oncology Group (ECOG). [Abstract] Blood 112 (11): A-1740, 2008.

Rajkumar SV, Jacobus S, Callander N, et al.: A randomized phase III trial of lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. [Abstract] Blood 108 (11): A-799, 2006.

Ballester O: The emperor's new clothes or the current practice of clinical trials for multiple myeloma in the USA. Cancer Invest 26 (5): 445-7, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

S. Rajkumar, MD, Protocol chair		Ph: 507-284-2511 Email: rajks@mayo.edu
Rafael Fonseca, MD, Protocol co-chair		Ph: 480-301-6118 Email: fonseca.rafael@mayo.edu

Registry Information
Official Title		A Randomized Phase III Study of CC-5013 plus Dexamethasone versus CC-5013 plus Low Dose Dexamethasone in Multiple Myeloma With Thalidomide plus Dexamethasone Salvage Therapy for Non-Responders
Trial Start Date		2004-10-26
Registered in ClinicalTrials.gov		NCT00098475
Date Submitted to PDQ		2004-10-26
Information Last Verified		2007-04-12
NCI Grant/Contract Number		CA21115