Clinical trial NCT00432458: Zoledronate With or Without Thalidomide in Treating Patients With Early Stage Multiple Myeloma
Official title: A Phase III Randomized Trial of Thalidomide Plus Zoledronic Acid Versus Zoledronic Acid Alone in Patients With Early Stage Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma and Plasma Cell Neoplasm
Keywords: stage I multiple myeloma
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-02-07
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Zoledronate may prevent bone loss and stop the growth of cancer cells in bone. Thalidomide may stop the growth of cancer cells by blocking blood flow to the cancer. It is not yet know whether giving zoledronate together with thalidomide is more effective than zoledronate alone in treating multiple myeloma.

PURPOSE: This randomized phase III trial is studying zoledronate and thalidomide see how well they work compared with zoledronate alone in treating patients with early stage multiple myeloma.

Detailed description: OBJECTIVES:

Primary

* Compare time to progression in patients with early stage multiple myeloma treated with zoledronate with or without thalidomide.

Secondary

* Compare the response rate, 1-year progression-free survival rate, duration of response, and time to next therapy in patients treated with these regimens.
* Assess differences in toxicity of these regimens in these patients.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to the presence of lytic lesions on metastatic bone survey (yes vs no), beta-2 microglobulin level (high vs normal), and bone marrow labeling index (high \[\> 1.0%\] vs low \[≤ 1.0%\]). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral thalidomide on days 1-28. Treatment with thalidomide repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive zoledronate IV over 15 minutes on day 1. Treatment with zoledronate repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 84 days for 1 year and once a year thereafter in the absence of disease progression or unacceptable toxicity.

Blood samples are collected for research studies at baseline and after courses 3, 6, 9, and 12. Bone marrow aspirates are performed at baseline and after courses 6 and 12. Samples are evaluated for bone marrow angiogenesis; vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1), and VEGFR-2 expression; bone marrow angiogenesis-VEGF relationship; bone marrow angiogenesis/apoptosis rate relationship; bone marrow angiogenesis/plasma cell (PC) proliferation rate relationship; VEGF expression/apoptosis rate relationship; and VEGFR expression/PC proliferation rate relationship.

After completion of study treatment, patients are followed every 6 months for up to 5 years.

PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of multiple myeloma (MM)

  * Previously untreated asymptomatic disease
  * No requirement for immediate chemotherapy for active MM, such as hypercalcemia from myeloma or painful bone lesions
* No solitary plasmacytoma
* Measurable or evaluable disease as defined by one of the following:

  * Serum monoclonal protein ≥ 1.0 g by protein electrophoresis
  * More than 200 mg of monoclonal protein in the urine by 24-hour electrophoresis
  * Measurable soft tissue plasmacytoma by physical exam with ruler or by MRI or positron emission tomography/CT scan

    * If the only measurable lesion is the plasmacytoma, it must be ≥ 1.5 cm in 1 dimension
* Must have ≥ 10% plasma cells as measured on the bone marrow aspirate, bone marrow biopsy, or labeling index
* No amyloidosis

PATIENT CHARACTERISTICS:

* Performance status 0-2
* Absolute neutrophil count ≥ 1,500/mm³
* Platelet count ≥ 100,000/mm³
* Hemoglobin ≥ 8.0 g/dL
* Creatinine ≤ 2.0 mg/dL (elevation above normal range should not be felt to be related to myeloma)
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and for 4 weeks after completion of study treatment
* No uncontrolled infection
* No other active malignancy
* No New York Heart Association class III or IV heart disease
* No pre-existing neuropathy ≥ grade 2
* No concurrent major dental work

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Prior corticosteroids (for nonmalignant disorders) allowed
* Prior therapy with experimental agents not shown to have significant activity in MM, such as clarithromycin, dehydroepiandrosterone, and anakinra allowed
* No prior thalidomide or corticosteroids for MM
* No more than 3 doses of IV zoledronate or pamidronate within the past 12 months
* At least 3 months since prior radiotherapy, including radiotherapy for solitary plasmacytoma
* No concurrent oral bisphosphonate therapy for osteoporosis

Primary outcomes:
measure: Time to Disease Progression (TTP)
timeFrame: randomization to progression (up to 5 years)
Secondary outcomes:
measure: 12-month Progression-free Survival (PFS)
timeFrame: 12 months
measure: Number of Participants With a Confirmed Response (Complete Response [CR], Very Good Partial Response [VGPR] or Partial Response [PR]) on Two Consecutive Evaluations at Least 2 Weeks Apart in the First 12 Months of Treatment
timeFrame: 12 months
measure: Duration of Response (Complete Response, Partial Response, and Very Good Partial Response)
timeFrame: time from start of response to progression (up to 5 years)
measure: Time to Subsequent Treatment
timeFrame: time from end of treatment to subsequent treatment (up to 5 years)
measure: Time to Treatment Failure
timeFrame: time from randomization to treatment failure (up to 5 years)
measure: Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events
timeFrame: During treatment (up to 5 years)
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Mayo Clinic
name: Thomas E. Witzig, MD
role: STUDY_CHAIR
affiliation: Mayo Clinic
name: Craig Reeder, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Vivek Roy, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. doi: 10.1038/leu.2012.236. Epub 2012 Aug 20.