Clinical trialPhase 3Multiple myeloma

Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study

The Lancet Oncology · 20181718 patients (859 in each group)

Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, et al. The Lancet Oncology. 2018. 19:370-381

Study type: Clinical trial
Phase: Phase 3
Design: International, double-blind, double-dummy, randomised, active-controlled (non-inferiority) trial at 259 centres in 29 countries
Sample size: 1718 patients (859 in each group)
Source: The Lancet Oncology · 2018
Trial registration: NCT01345019

In plain words

Multiple myeloma can weaken the bones and cause fractures or pressure on the spinal cord. In this large study, two bone-protecting drugs were compared: denosumab (an injection under the skin) and zoledronic acid (an injection into a vein). Denosumab was no worse than zoledronic acid at preventing bone complications. Kidney problems were reported less often with denosumab, and low blood calcium more often.

Key results

HR 0.98 (95% CI 0.85–1.14)

Time to first skeletal-related event (denosumab vs zoledronic acid)

Non-inferiority met; P for non-inferiority = 0.010

85 patients (10%) vs 146 patients (17%)

Renal toxicity

Denosumab vs zoledronic acid

144 patients (17%) vs 106 patients (12%)

Hypocalcaemia

Denosumab vs zoledronic acid

35 patients (4%) vs 24 patients (3%)

Osteonecrosis of the jaw

P=0.147; not significant

Drugs in this study:Denosumab (Xgeva)

Dose and schedule cards

Zoledronic acid

All patients with newly diagnosed myeloma requiring treatment, with or without bone lesions (IMWG preferred agent)Cycle length: Every 3–4 weeksOn the page “Multiple myeloma” · Dosing of bone-protecting drugs

All patients with newly diagnosed myeloma requiring treatment, with or without bone lesions (IMWG preferred agent)

Drug	Dose	Route	Schedule
Zoledronic acid	4 mg (CrCl above 60); 50–60: 3.5 mg; 40–49: 3.3 mg; 30–39: 3 mg	IV (over at least 15 minutes)	Every 3–4 weeks

Cycle length: Every 3–4 weeks
Duration: Per IMWG guideline

Dose and renal adjustment from the FDA label: measure creatinine before each dose and stop treatment if renal function worsens; not recommended in severe renal impairment; calcium supplement 500 mg and a multivitamin containing 400 IU of vitamin D daily. Place in therapy from the IMWG guideline. Dental examination before starting, and avoidance of invasive dental procedures during treatment (risk of osteonecrosis of the jaw); in the head-to-head trial, osteonecrosis of the jaw occurred in 4% with denosumab and 3% with zoledronic acid.

On the page “Multiple myeloma” · Dosing of bone-protecting drugs

Denosumab

Myeloma with bone disease; a suitable option, especially in renal impairmentCycle length: Every 4 weeksOn the page “Multiple myeloma” · Dosing of bone-protecting drugs

Myeloma with bone disease; a suitable option, especially in renal impairment

Drug	Dose	Route	Schedule
Denosumab	120 mg	SC	Every 4 weeks

Cycle length: Every 4 weeks
Duration: Per IMWG guideline

Dose from the FDA label; calcium and vitamin D to prevent or treat hypocalcaemia. In the head-to-head trial (denosumab 120 mg SC vs zoledronic acid 4 mg IV every 4 weeks), denosumab was non-inferior, with less renal toxicity (10% vs 17%) but more hypocalcaemia. Place in therapy from the IMWG guideline.

On the page “Multiple myeloma” · Dosing of bone-protecting drugs

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Denosumab

Denosumab 120 mg subcutaneously plus IV placebo, every 4 weeks. Investigator's choice of first-line antimyeloma therapy was also given.

2Zoledronic acid

Zoledronic acid 4 mg IV plus subcutaneous placebo, every 4 weeks. Investigator's choice of first-line antimyeloma therapy was also given.

Source of the regimen details: Abstract of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 years or older with newly diagnosed symptomatic multiple myeloma and at least one documented lytic bone lesion. Randomisation was stratified by intent to undergo autologous transplantation, type of antimyeloma therapy, ISS stage, previous skeletal-related events and geographical region.

Endpoints

Primary endpoint: non-inferiority of denosumab to zoledronic acid for time to first skeletal-related event in the full analysis set (all randomised patients). Safety endpoints were analysed in the safety analysis set (all randomised patients who received at least one dose of active study drug).

Safety and side effects

1702 patients received at least one dose of study drug (850 denosumab and 852 zoledronic acid). Most common grade 3 or worse adverse events (denosumab versus zoledronic acid): neutropenia (126 patients [15%] versus 125 [15%]), thrombocytopenia (120 [14%] versus 103 [12%]), anaemia (100 [12%] versus 85 [10%]), febrile neutropenia (96 [11%] versus 87 [10%]) and pneumonia (65 [8%] versus 70 [8%]). The most common serious adverse event in both groups was pneumonia (71 [8%] versus 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest considered treatment-related.

Clinical significance and place in guidelines

Based on the results of this study, denosumab could be an additional option in the standard of care for patients with multiple myeloma and bone disease. Its exact status in clinical guidelines and drug approvals should be checked separately.

Limitations

The abstract does not mention limitations of the study. The study was funded by the manufacturer of denosumab (Amgen). More details in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.