Zoledronate With or Without Thalidomide in Treating Patients With Early Stage Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT00432458
• Recruitment Status: Completed
• First Posted: February 7, 2007
• Results First Posted: July 4, 2012
• Last Update Posted: July 4, 2012
• Sponsor: Mayo Clinic
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Mayo Clinic

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: Thalidomide; Drug: zoledronic acid	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Trial of Thalidomide Plus Zoledronic Acid Versus Zoledronic Acid Alone in Patients With Early Stage Multiple Myeloma
• Study Start Date: July 2003
• Actual Primary Completion Date: June 2011
• Actual Study Completion Date: April 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I: Thal/ZLD; Thalidomide (Thal) + Zolendronic acid (ZLD)	Drug: Thalidomide; 200 mg orally on days 1-28 of 28 day cycle; Drug: zoledronic acid; 4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter
Experimental: Arm II: ZLD; Zoledronic acid (ZLD)	Drug: zoledronic acid; 4 mg^2 by IV on day 1 every 84 days for 1 year and once per year thereafter

Outcome Measures

Primary Outcome Measures :

1. Time to Disease Progression (TTP) [ Time Frame: randomization to progression (up to 5 years) ]
   Time to disease progression (TTP) was defined as the time from randomization to the earliest documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method, a two-sided (stratified) log-rank test was calculated.

Secondary Outcome Measures :

1. 12-month Progression-free Survival (PFS) [ Time Frame: 12 months ]
   PFS at 12 months is a dichotomized outcome indicating whether or not a participant was progression free (and alive) at 12 months from the date of randomization.
2. 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 [ Time Frame: 12 months ]

   Response is defined as follows:

   • CR: Complete disappearance of M-protein from serum & urine on immunofixation, <5% plasma cells in bone marrow (BM)
   • VGPR: >=90% reduction in serum M-component; Urine M-Component <100 mg per 24 hours; <=5% plasma cells in BM
   • PR: >= 50% reduction in serum M-Component and/or Urine M-Component >= 90% reduction or <200 mg per 24 hours; or >= 50% decrease in difference between involved and uninvolved FLC levels
3. Duration of Response (Complete Response, Partial Response, and Very Good Partial Response) [ Time Frame: time from start of response to progression (up to 5 years) ]
   Duration of response (DOR) is defined as the time from first documentation of response (CR, VGPR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method
4. Time to Subsequent Treatment [ Time Frame: time from end of treatment to subsequent treatment (up to 5 years) ]
   Time to subsequent treatment (TTS) was defined as time from end of active (protocol) treatment to the start of subsequent treatment for participants with progressive disease. The median TTS with 95% CI was estimated using the Kaplan Meier method
5. Time to Treatment Failure [ Time Frame: time from randomization to treatment failure (up to 5 years) ]
   Time to treatment failure (TTF) was defined as the time from randomization to the date at which the patient was removed from (protocol) treatment due to disease progression, unacceptable toxicity, participant refusal or death. The median TTF with 95% CI was estimated using the Kaplan Meier method
6. Number of Participants With Severe (Grade 3, 4 or 5) Adverse Events [ Time Frame: During treatment (up to 5 years) ]

   Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 2.

   Description of Grades:

   Grade 1: Mild Grade 2: Moderate Grade 3: Severe Grade 4: Life-threatening Grade 5: Death

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Scottsdale

Scottsdale, Arizona, United States, 85259-5499

United States, Florida

Mayo Clinic - Jacksonville

Jacksonville, Florida, United States, 32224

United States, Minnesota

Mayo Clinic Cancer Center

Rochester, Minnesota, United States, 55905

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

Sponsors and Collaborators

Mayo Clinic

National Cancer Institute (NCI)

Investigators

• Study Chair: Thomas E. Witzig, MD; Mayo Clinic
• Principal Investigator: Craig Reeder, M.D.; Mayo Clinic
• Principal Investigator: Vivek Roy, M.D.; Mayo Clinic

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00432458
• Other Study ID Numbers: CDR0000530050; P30CA015083 ( U.S. NIH Grant/Contract ); MC0289 ( Other Identifier: Mayo Clinic Cancer Center ); 421-03 ( Other Identifier: Mayo Clinic IRB )
• First Posted: February 7, 2007
• Results First Posted: July 4, 2012
• Last Update Posted: July 4, 2012
• Last Verified: June 2012

Keywords provided by Mayo Clinic:

stage I multiple myeloma

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Zoledronic Acid; Thalidomide; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Leprostatic Agents; Anti-Bacterial Agents; Anti-Infective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antineoplastic Agents; Bone Density Conservation Agents