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

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.


Eligibility Criteria:
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