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