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

Alternate Title

Combination Chemotherapy 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 to 65	Other	CKTO-2001-02 HOVON-50MM, EU-20133, HOVON-CKVO-2001-02, NCT00028886

Objectives

1. Compare the efficacy of doxorubicin, dexamethasone, and high-dose melphalan with versus without thalidomide, in terms of event-free survival, of patients with multiple myeloma.
2. Determine the response rate, complete response rate, overall survival, and progression-free survival of patients treated with these regimens.
3. Determine the safety and toxicity of thalidomide in combination with intensive chemotherapy in these patients.
4. Assess the value of prognostic factors at diagnosis in individual patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically confirmed multiple myeloma
  • Stage II or III



• No systemic amyloid light-chain amyloidosis

Prior/Concurrent Therapy:

Biologic therapy:

• Patients 18 to 55 years of age must not have been allocated before study randomization to allogeneic stem cell transplantation with an HLA-identical sibling donor

Chemotherapy:

• No more than 2 prior courses of melphalan and prednisone therapy for local myeloma progression
• No other prior chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• Prior local radiotherapy for local myeloma progression allowed
• No other prior radiotherapy

Surgery:

• Not specified

Patient Characteristics:

Age:

• 18 to 65

Performance status:

• WHO 0-3

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• No significant hepatic dysfunction*
• Bilirubin less than 1.75 mg/dL*
• AST/ALT less than 2.5 times normal*

 [Note: *Unless related to myeloma]

Renal:

• Not specified

Cardiovascular:

• No severe cardiac dysfunction
• No New York Heart Association class II, III, or IV heart disease

Other:

• HIV negative
• No active uncontrolled infection
• No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix
• No known intolerance to thalidomide
• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 450 patients (225 per treatment arm) will be accrued for this study within 4 years.

Outcomes

Event-free survival

Partial response and complete response
Overall survival
Progression-free survival
Toxicity

Outline

This is a randomized, multicenter study. Patients are stratified according to participating center and treatment policy (1 course vs 2 courses of high-dose melphalan). Patients are randomized to 1 of 2 treatment arms.

Arm I:

• Patients receive induction chemotherapy (AD) comprising doxorubicin IV on days 1-4 and oral dexamethasone on days 1-4, 9-12, and 17-20. Patients receive oral thalidomide daily beginning on day 1 and continuing until 2 weeks before start of stem cell mobilization. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.



• Patients receive stem cell mobilization with chemotherapy comprising cyclophosphamide IV on day 1 and doxorubicin IV and oral dexamethasone on days 1-4 (CAD). Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 5 and continuing until last apheresis.



• Beginning 8-10 weeks after stem cell collection, patients receive low-dose oral thalidomide daily and high-dose melphalan IV on days -3 and -2 as intensification. Patients undergo stem cell infusion on day 0. Patients may receive a second course of high-dose melphalan 2-3 months after the first course, in which case, stem cell infusion follows the second course of melphalan.



• Patients receive maintenance therapy with oral thalidomide daily until disease progression or after 3 months if no response.



• Beginning 2 months after the last course, patients with an HLA-identical sibling donor undergo nonmyeloablative stem cell transplantation after radiotherapy.

Arm II:

• Patients receive induction chemotherapy (VAD) comprising vincristine IV and doxorubicin IV on days 1-4 and dexamethasone on days 1-4, 9-12, and 17-20. Treatment repeats every 28 days for 3 courses in the absence of disease progression or unacceptable toxicity.



• Patients receive stem cell mobilization with CAD chemotherapy as in arm I. G-CSF is given as in arm I.



• Patients receive high-dose melphalan and undergo stem cell infusion as in arm I.



• Patients receive maintenance therapy with interferon alfa SC 3 times weekly until progression or after 3 months if no partial response.



• Beginning 2 months after the last course, patients with an HLA-identical sibling donor undergo nonmyeloablative stem cell transplantation after radiotherapy.

All patients are followed every 6 months for 3 years and then annually thereafter.

Lokhorst HM, Schmidt-Wolf I, Sonneveld P, et al.: Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica 93 (1): 124-7, 2008.[PUBMED Abstract]

Lokhorst H, van der Holt B, Zweegman S, et al.: Final analysis of HOVON-50 randomized phase III study on the effect of thalidomide combined with adriamycine,dexamethasone (AD) and high dose melphalan (HDM) in patients with multiple myeloma (MM). [Abstract] Blood 112 (11): A-157, 2008.

Johnson DC, Corthals S, Ramos C, et al.: Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping. Blood 112 (13): 4924-34, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Commissie Voor Klinisch Toegepast Onderzoek

H. Lokhorst, MD, PhD, Protocol chair		Ph: 31-30-250-7230 Email: h.lokhorst@azu.nl

Registry Information
Official Title		A Randomized Phase III Study On The Effect Of Thalidomide Combined With Adriamycin, Dexamethasone (AD) And High Dose Melphalan In Patients With Multiple Myeloma
Trial Start Date		2001-03-01
Registered in ClinicalTrials.gov		NCT00028886
Date Submitted to PDQ		2001-10-30
Information Last Verified		2009-01-06