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

Inclusion Criteria:

• Documented evidence of multiple myeloma (per local assessment; see section 7.2):
• 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; see section 7.2): 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