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

Conditions

Multiple Myeloma

Keywords

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

Brief summary

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

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.

Related papers

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Interventions

DRUGBortezomib

1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles

DRUGZoledronic Acid

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

DRUGDexamethasone

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

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
Bone Mineral Density (BMD)	day 84	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)

Secondary

Measure	Time frame	Description
Bone Mineral Density (BMD)	day 168	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)
Bone Remodelling	day 84	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 \[osteocalcin (OC)\].
Bone Pain	On the day 84	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.
Skeletal Survey for New Osteolytic Lesions/Fractures	day 168	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)
New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery)	day 168	New Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) following 8 cycles (day 168) of therapy

Countries

Greece

Participant flow

Participants by arm

Arm	Count
Bortezomib/Dexamethasone/Zoledronic Acid 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 Bortezomib: 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles Zoledronic Acid: 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 Dexamethasone: 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	17
Total	17

Arm

Count

Bortezomib/Dexamethasone/Zoledronic Acid

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 Bortezomib: 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles Zoledronic Acid: 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 Dexamethasone: 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

17

Total

17

Baseline characteristics

Characteristic	Bortezomib/Dexamethasone/Zoledronic Acid
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	12 Participants
Age, Categorical Between 18 and 65 years	5 Participants
BMD Femoral neck (FN)	-2.83 T-score
BMD Lumbar spine (L1-L4)	-0.29 T-score
Bone pain	5 units on a scale
Bone remodelling CTX	0.6 ng/ml
Bone remodelling OC	5.1 ng/ml
Bone remodelling	15.8 U/L
Region of Enrollment Greece	17 participants
Sex: Female, Male Female	10 Participants
Sex: Female, Male Male	7 Participants
Skeletal survey for osteolytic lesions/fractures	17 participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	0 / 17
serious Total, serious adverse events	7 / 17

Outcome results

Primary

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)

Time frame: day 84