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

Amgen

Status and phase: Completed; Phase 3

Conditions: Multiple Myeloma Bone Lesions; Oncology; Multiple Myeloma; Cancer; Bone Metastases; Hematologic Malignancies

Treatments: Drug: Denosumab (for the open-label treatment phase); Drug: Zoledronic acid; Drug: Denosumab; Drug: Placebo to zoledronic acid; Drug: Placebo to Denosumab

Study type: Interventional

Funder types: Industry

Identifiers

NCT01345019

20090482

2010-020454-34 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 1,718 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Supportive Care

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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1,718 participants in 2 patient groups

Zoledronic acid

Active Comparator group

Description:

Zoledronic acid 4 mg intravenously plus placebo to denosumab subcutaniously (SC) once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years)

Treatment:

Drug: Zoledronic acid

Drug: Denosumab (for the open-label treatment phase)

Drug: Placebo to Denosumab

Denosumab

Experimental group

Description:

Denosumab 120 mg subcutaniously (SC) plus placebo to zoledronic acid intravenously once every 4 weeks (Q4W) in the double-blind treatment period (Since denosumab was determined to have a positive benefit:risk profile in the primary analysis of the study, per protocol, participants who were still undergoing Q4W scheduled assessments were offered open-label denosumab 120 mg SC Q4W for up to 2 years)

Treatment:

Drug: Denosumab

Drug: Denosumab (for the open-label treatment phase)

Drug: Placebo to zoledronic acid