Denosumab Compared to Zoledronic Acid in the Treatment of Bone Disease in Patients With Multiple Myeloma
Condition: Cancer; Hematologic Malignancies; Multiple Myeloma; Oncology; Bone Metastases; Multiple Myeloma Bone Lesions
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasm Metastasis; Neoplasms; Hematologic Neoplasms; Bone Diseases
Intervention: Denosumab; Zoledronic acid; Placebo to Denosumab; Placebo to zoledronic acid; Denosumab (for the open-label treatment phase)
Intervention description: Administered by subcutaneous injection once every 4 weeks.; Administered by intravenous infusion over 15 minutes once every 4 weeks; Administered by subcutaneous injection once every 4 weeks.; Administered by intravenous infusion over 15 minutes once every 4 weeks; Administered by subcutaneous injection once every 4 weeks.
Intervention MeSH terms: Zoledronic Acid; Denosumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 1718.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: zoledronic acid; hematologic malignancies; SRE; skeletal-related event; blood cancer; lytic bone lesions; bone metastases; myeloma; fractures; spinal cord compression; radiation to bone; surgery to bone; bisphosphonates; Neoplasms, Plasma Cell; Paraproteinemias; Neoplasms; Neoplasm Metastasis; Bone Neoplasms; Bone Marrow Diseases; Blood Protein Disorders; Hematologic Diseases; multiple myeloma; denosumab; Neoplastic Processes; Bone Diseases; Diphosphonates; Bone Density Conservation Agents

Summary:

      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