Effect of Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Disease in Patients With Multiple Myeloma Relapsed After 1-3 Prior Lines of Therapy

Study Overview
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Brief Summary
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The aim of this study is to evaluate the effect of bortezomib in combination with dexamethasone and zoledronic acid on bone mineral density (BMD) and skeletal related events (SREs) in Patients with Multiple Myeloma who Have Relapsed after 1-3 Prior Lines of Therapy

Detailed Description
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Multiple Myeloma represents a malignant proliferation of plasma cells derived from a single clone. The most common symptom in myeloma, affecting more than 70% of patients at diagnosis, is bone pain. The pain usually involves the back and ribs, and is precipitated by movement. Bone fractures are commonly seen in myeloma patients and may present with persistent localized pain. VELCADE (bortezomib) is a proteasome inhibitor used for the treatment of multiple myeloma. VELCADE seems to be the first agent to combine significant anti-myeloma activity and beneficial effects on bone remodeling. Thus, it appears to be a very promising tool for the treatment of myeloma patients. In this study, a regimen consisting of bortezomib/dexamethasone/zoledronic acid will be used. The rationale for using this regimen is that: VELCADE (bortezomib) is indicated for the treatment of relapsed myeloma patients participating in the study and it has also a beneficial effect on biochemical markers of bone formation. In phase II studies, the addition of dexamethasone in patients with a suboptimal response to bortezomib alone improved efficacy in relapsed or refractory multiple myeloma patients, without increasing adverse events. Therefore, in this study, the addition of dexamethasone aims at providing the optimal therapy for participating myeloma patients. Zoledronic acid, the most potent i.v. bisphosphonate, is used because of its established effect on reducing skeletal related events in patients with multiple myeloma due to its inhibitory effect on osteoclastic bone resorption. Dosages and timing of dosages are based on current recommendations and guidelines for the treatment of myeloma patients who Have Relapsed after 1-3 Prior Lines of Therapy.

Official Title
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A Prospective, Multicenter, Non-comparative, Open-label, Phase II Study to Evaluate the Effects of the Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Mineral Density, Bone Metabolism, Radiographically-detected Osteolytic Bone Lesions, Skeletal-related Events and Bone Pain in Patients With Multiple Myeloma Who Have Relapsed After 1-3 Prior Lines of Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Zoledronic Acid
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with Multiple Myeloma who Have Relapsed after 1-3 Prior Lines of Therapy Women > 50 years old Κarnofsky performance status ≥ 60 (patients with lower performance status due to myeloma bone disease can also be included) Measurable disease Platelet count >50x10(9)/L Neutrophil count >0.75x10(9)/L Hemoglobin ≥7.0 g/dL (the use of recombinant human erythropoietin or red blood Hell transfusions to maintain hemoglobin levels above 7.0 g/dL is not an exclusion criterion) Serum ALT and AST ≤ 3-fold of upper normal limit Serum bilirubin ≤ 2-fold of upper normal limit Serum Calcium ≤ 10.5 mg/dL Expected survival ≥ 2 months Signed informed consent Exclusion Criteria: Presence of another cancer Serious medical or psychiatric illness likely to interfere with participation in this clinical study Grade 2-4 peripheral neuropathy or neuropathic pain Grade 2 or higher as defined by NCI CTCAE version 3 Pregnant women > 50 years old or breast-feeding Woman > 50 years old capable of becoming pregnant [anyone who has not undergone a hysterectomy, has not had both ovaries removed or has not been post-menopausal for more than 24 months in a row not using adequate contraception Known or suspected hypersensitivity or intolerance to bortezomib, boron, mannitol, zoledronic acid, dexamethasone, or heparin (if an indwelling catheter is used) Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months prior to first dose of study drug) Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrolment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 4, NYHA Classification of Cardiac Disease), uncontrolled angina, pericardial disease, or cardiac amyloidosis Acute diffuse infiltrative pulmonary disease History of hypotension or patient has decreased blood pressure (sitting systolic blood pressure [SBP] 100 mmHg and/or sitting diastolic blood pressure [DBP] 60 mmHg) Patient has received extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 4 weeks prior to enrolment Patient has received any drugs or agents that inhibit (e.g., cimetidine, erythromycin, fluoxetine, ketoconazole, paroxetine) or induce (e.g., carbamazepine, glucocorticoids, phenobarbital, rifampin) CYP2C19 or CYP3A4 within 14 days before the first dose of VELCADE (proton pump inhibitors are allowed) Need for therapy with concomitant CYP 3A4 inhibitors (e.g., itraconazole, fluconazole, clarithromycin, erythromycin, norfloxacin, fluvoxamine, cimetidine, indinavir, ritonavir) or inducers (e.g., efavirenz, barbiturates, phenytoin, rifampin, glitazones). Proton pump inhibitors are allowed. Patient has received an experimental drug or has used an experimental medical device within 4 weeks prior to the planned start of treatment. Concurrent participation in non-treatment studies is allowed, provided it will not interfere with participation in this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bortezomib/Dexamethasone/Zoledronic Acid<br>For this study, Velcade will be administered at the standard dose of 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle. Dexamethasone will be administered at a dose of 12 mg/m2 p.o., on days 1-2, 4-5, 8-9 and 11-12 of the same cycle. Zoledronic acid will be administered at a dose of 4 mg, iv (15-minute infusion), every 28 days for up to 8 cycles, and then every 28 days for the next 18 months | Drug: Bortezomib<br>* 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles<br>* Other names: Velcade;Drug: Zoledronic Acid<br>* 4 mg, iv, at a 15 min infusion, Day 1 of every cycle for up to 8 cycles, and then every 28 days for the next 18 months<br>* Other names: Zometa;Drug: Dexamethasone<br>* 12 mg/m2 p.o. on days 1-2, 4-5, 8-9 and 11-12 of a 21-day cycle for up to 8 chemotherapy cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Mineral Density (BMD) | BMD of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) using a Hologic QDR-1000 scanner on day 21 of cycle 4 (day 84) | day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bone Mineral Density (BMD) | BMD of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by Dual Energy X-Absorptiometry scan (DEXA-scan) using a Hologic QDR-1000 scanner on day 21 of cycle 8 (day 168) | day 168 | 
| Bone Remodelling | Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation markers [osteocalcin (OC)]. | day 84 | 
| Bone Remodelling | Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 8 (day 168) using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation marker [osteocalcin (OC)]. | day 168 | 
| Bone Pain | Bone pain was measured with the use of the Visual Analogue Scale on day 21 of cycle 4 (day 84). Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. The VAS for Bone Pain was constructed as follows: None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome. | On the day 84 | 
| Bone Pain | Bone pain was measured with the use of the Visual Analogue Scale on day 21 of cycle 8 (day 168). Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured. The VAS for Bone Pain was constructed as follows: None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome. | On the day 168 | 
| Skeletal Survey for New Osteolytic Lesions/Fractures | Skeletal survey was measured using conventional radiography [imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)] on day 21 of cycle 8 (day 168) | day 168 | 
| Skeletal Survey for New Osteolytic Lesions/Fractures | Skeletal survey was measured using conventional radiography [imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)] every 6 months for up to 18 months | 18 months | 
| New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) | New Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) following 8 cycles (day 168) of therapy | day 168 | 
| New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) | New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) after 18 months post VD | 18 months | 
| Bone Remodelling | Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA) bone formation marker [bone-specific alkaline phosphatase (bALP)]. | day 84 | 
| Bone Remodelling | Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA): bone formation marker [bone-specific alkaline phosphatase (bALP) ]. | day 168 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, 1-3 Prior Lines of Therapy, bortezomib (Velcade), zoledronic acid (Zometa), Dexamethasone, bone mineral density, bone pain, bone metabolism, osteolytic lesions, DEXA-scans, X-ray radiography