COMPARISON OF DENOSUMAB (DMB) WITH ZOLEDRONIC ACID (ZA) FOR THE TREATMENT OF BONE DISEASE IN PATIENTS (PTS) WITH NEWLY DIAGNOSED MULTIPLE MYELOMA; AN INTERNATIONAL, RANDOMIZED, DOUBLE BLIND TRIAL
Author(s): ,
Evangelos Terpos
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens, School of Medicine,Athens,Greece
,
G. David Roodman
Affiliations:
Indiana University Simon Cancer Center,Indianapolis,United States
,
Wolfgang Willenbacher
Affiliations:
Medical University of Innsbruck,Innsbruck,Austria
,
Kazuyuki Shimizu
Affiliations:
National Hospital Organization Higashi Nagoya National Hospital,Nagoya,Japan
,
Ramón García-Sanz
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Spain
,
Brian Durie
Affiliations:
Cedars-Sinai Medical Center,Los Angeles,United States
,
Li Zhu
Affiliations:
Amgen Inc.,Thousand Oaks,United States
,
Sumita Bhatta
Affiliations:
Amgen Inc.,Thousand Oaks,United States
Noopur Raje
Affiliations:
Massachusetts General Hospital Cancer Center,Boston,United States
(Abstract release date: May 18, 2017) EHA Learning Center. Terpos E. Jun 25, 2017; 182069
Assoc. Prof. Evangelos Terpos
Assoc. Prof. Evangelos Terpos

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Abstract
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Abstract: S782

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 08:45 - 09:00

Location: Hall D

Background
Multiple myeloma is characterized by osteolytic bone disease, with up to 80% of pts presenting with detectable lesions. Myeloma bone disease is mediated by osteoclast activating factors such as RANKL, increasing the risk of skeletal-related events (SREs) and impacting morbidity and mortality. DMB, a human monoclonal antibody that targets and binds to RANKL, can be administered subcutaneously (SC) to pts regardless of renal function.

Aims
This study evaluates the efficacy and safety of DMB compared with ZA in newly diagnosed myeloma pts.

Methods
Adult pts were randomized 1:1 to DMB 120mg SC Q4W or ZA 4mg IV (adjusted) Q4W along with anti-myeloma therapy. Key stratification factors included type of first-line therapy (novel or non-novel) and previous SRE. Pts with renal insufficiency were excluded if baseline creatinine clearance (CrCl)<30mL/min. The primary endpoint was non-inferiority of DMB to ZA with respect to time to first on-study SRE. Secondary endpoints included superiority of DMB for time to first on-study SRE and first-and-subsequent on-study SRE, and overall survival (OS). Progression-free survival (PFS) was an exploratory endpoint. Safety was also assessed.

Results
A total of 1718 pts were randomized, 859 to each arm. Baseline demographics and disease characteristics were balanced, with 66.0% of DMB and 67.2% of ZA pts reporting prior SRE history; CrCl≤60mL/min was reported in 26.7% of pts. During the primary blinded treatment period (median follow-up 17.4 months [m]), 43.8% DMB pts and 44.6% ZA pts had a first on-study SRE. The median time to first on-study SRE was similar between DMB (22.83 m) and ZA (23.98 m) pts.

DMB was non-inferior to ZA (P=0.01) in delaying time to first on-study SRE (HR[95%CI]=0.98[0.85,1.14]). Superiority was not demonstrated for time to first on-study SRE (P=0.82) and time to first-and-subsequent on-study SRE (P=0.84). In this high-risk study population the effect of antiresorptive therapy may only be evident later in the treatment course. A post-hoc, landmark analysis at 15 m for time to first SRE demonstrated a HR(95%CI)=0.66(0.44,0.98),P=0.039 (Figure 1) between DMB and ZA. OS was similar between DMB and ZA (HR[95%CI]=0.90[0.70,1.16],P=0.41), with fewer deaths with DMB (121[14.1%]) than ZA (129[15.0%]). PFS yielded a HR(95%CI)=0.82(0.68,0.99), descriptive P=0.036, with median times of 46.09m (95%CI:34.3,NE) for DMB and 35.38m (95%CI:30.19,NE) for ZA. The most common TEAEs(>25%) for DMB and ZA were diarrhea and nausea. The rates of SAEs (DMB,ZA [%];46.0,47.3), hypocalcemia (16.9,12.4; serious:0.9,0.2), and positively adjudicated ONJ (4.1,2.8) were comparable to known safety profiles. Fewer DMB pts (%) compared with ZA pts had AEs potentially related to renal toxicity (10.0,17.1;P<0.001), most notably in pts with baseline CrCl≤60mL/min (12.9,26.4). TEAEs led to IP discontinuation in 12.2% of all pts (12.9,11.5).

Conclusion
DMB demonstrated non-inferiority to ZA in delaying time to first on-study SRE in myeloma pts, meeting the primary endpoint of the study. A landmark analysis at 15 m suggests a significant benefit for DMB with respect to time to first SRE. The rates of renal AEs were significantly lower in DMB pts while the overall rates of AEs, including hypocalcemia and ONJ, were consistent with the known DMB safety profile. The results of the landmark analysis and possible prolongation of PFS with DMB therapy is promising.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Multiple Myeloma, Bone disease

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