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.

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

De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.

Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.