Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Patients With Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine if denosumab is non-inferior to zoledronic acid in the treatment of bone disease from multiple myeloma.

Official Title
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A Randomized, Double-Blind, Multicenter Study of Denosumab Compared With Zoledronic Acid in the Treatment of Bone Disease in Subjects With Newly Diagnosed Multiple Myeloma

Conditions
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Cancer, Hematologic Malignancies, Multiple Myeloma, Oncology, Bone Metastases, Multiple Myeloma Bone Lesions

Intervention / Treatment
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* Drug: Denosumab
* Drug: Zoledronic acid
* Drug: Placebo to Denosumab
* Drug: Placebo to zoledronic acid
* Drug: Denosumab (for the open-label treatment phase)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented evidence of multiple myeloma (per local assessment): Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma, and Monoclonal protein present in the serum and/or urine Radiographic (X-ray, or computer tomography [CT]) evidence of at least 1 lytic bone lesion (or at least 1 focal lesion per magnetic resonance imaging [MRI]) Plan to receive or is receiving primary frontline anti-myeloma therapies Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Age ≥ 18 years Adequate organ function, as defined by the following criteria (per central or local laboratory values): Serum aspartate aminotransferase (AST) ≤ 2.0 x upper limit of normal (ULN) Serum alanine aminotransferase ≤ (ALT) 2.0 x ULN Serum total bilirubin ≤ 2.0 x ULN Creatinine clearance ≥ 30 mL/min Serum calcium or albumin-adjusted serum calcium 2.0 mmol/L (8.0 mg/dL) and 2.9 mmol/L (11.5 mg/dL) Written informed consent before any study-specific procedure is performed Exclusion Criteria: Nonsecretory multiple myeloma based upon standard M-component criteria (ie, measurable serum/urine M-component) unless the baseline serum free light chain level is elevated POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) Plasma cell leukemia More than 30 days of previous treatment (before screening) with anti-myeloma therapy (does not include radiotherapy or a single short course of steroid [ie, less than or equal to the equivalent of dexamethasone 60 mg/day for 4 days]). Planned radiation therapy or surgery to the bone (does not include procedures performed before randomization) Prior administration of denosumab Use of oral bisphosphonates with a cumulative exposure of more than 1 year More than 1 previous dose of IV bisphosphonate administration Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw Active dental or jaw condition which requires oral surgery, including tooth extraction Non-healed dental/oral surgery, including tooth extraction Planned invasive dental procedures Evidence of any of the following conditions per subject self-report or medical chart review: Any prior invasive malignancy within 5 years before randomization Any non-invasive malignancy not treated with curative intent or with knownactive disease within 5 years before randomization Major surgery or significant traumatic injury occurring within 4 weeks before randomization Active infection with Hepatitis B virus or Hepatitis C virus Known infection with human immunodeficiency virus (HIV) Active infection requiring IV anti-infective therapy Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after end of treatment Female subject of child bearing potential is not willing to use highly effective contraception during treatment and for 5 months after the end of treatment (see section 6.3) Known sensitivity to any of the products to be administered during the study (eg, mammalian derived products, calcium or vitamin D) Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication) Subject will not be available for follow-up assessment Any major medical or psychiatric disorder that in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Zoledronic acid<br>Zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaniously (SC) once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) | Drug: Zoledronic acid<br>* Administered by intravenous infusion over 15 minutes once every 4 weeks<br>* Other names: Zometa®;Drug: Placebo to Denosumab<br>* Administered by subcutaneous injection once every 4 weeks.<br>Drug: Denosumab (for the open-label treatment phase)<br>* Administered by subcutaneous injection once every 4 weeks.<br>* Other names: AMG 162;|
| Experimental: Denosumab<br>Denosumab 120 mg subcutaniously (SC) plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years) | Drug: Denosumab<br>* Administered by subcutaneous injection once every 4 weeks.<br>* Other names: AMG 162;Drug: Placebo to zoledronic acid<br>* Administered by intravenous infusion over 15 minutes once every 4 weeks<br>Drug: Denosumab (for the open-label treatment phase)<br>* Administered by subcutaneous injection once every 4 weeks.<br>* Other names: AMG 162;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First On-study Skeletal Related Event | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 
| Percentage of Participants With an On-study Skeletal Related Event | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 
| Kaplan-Meier Estimate of Percentage of Participants With an On-study Skeletal Related Event | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. The Kaplan-Meier estimate at weeks 25, 49 and 109 is reported. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to First On-study Skeletal Related Event - Superiority Analysis | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. If there was no known event, and the participant was monitored for any one of the four SRE components, time to first on-study SRE was censored at the end of the treatment phase date or the primary analysis data cut-off date, whichever came first. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 
| Time to First and Subsequent On-Study Skeletal Related Event - Number of Events Per Patient | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The average number of events per patient is reported. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 
| Time to First and Subsequent On-Study Skeletal Related Event - Number of Events | A skeletal-related event (SRE) is defined as one of the following: pathologic fracture (vertebral or non-vertebral), radiation therapy to bone (including the use of radioisotopes), surgery to bone, or spinal cord compression. Time to first on-study SRE is defined as the time interval (in days) from the randomization date to the date of first occurrence of on-study SRE. Time to a subsequent SRE is defined, similarly to the time to first on-study SRE, as the time interval from the randomization date to the date of a subsequent occurrence of on-study SRE, which had to be at least 21 days after the previous SRE. A multiple event analysis was used, which accounts for both the absolute number of SREs and for the time between two consecutive events, and therefore, provides a more sensitive assessment of the risk of experiencing an SRE. The total number of events is reported. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 
| Overall Survival | Overall survival was defined as the time interval (in days) from the randomization date to the date of death. If a participant was still alive at the primary analysis data cut-off date or was lost to follow-up by the primary analysis data cut-off date, survival time was censored at their last contact date or the primary analysis data cut-off date, whichever was first. | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 
| Percentage of Participants Who Died |  | From randomization until the primary analysis data cut-off date of 19 July 2016 (per protocol); median time on study was 17.6 and 17.3 months in each treatment group respectively. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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zoledronic acid, hematologic malignancies, SRE, skeletal-related event, blood cancer, lytic bone lesions, bone metastases, myeloma, fractures, spinal cord compression, radiation to bone, surgery to bone, bisphosphonates, Neoplasms, Plasma Cell, Paraproteinemias, Neoplasms, Neoplasm Metastasis, Bone Neoplasms, Bone Marrow Diseases, Blood Protein Disorders, Hematologic Diseases, multiple myeloma, denosumab, Neoplastic Processes, Bone Diseases, Diphosphonates, Bone Density Conservation Agents