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

- 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

- 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