CARFILZOMIB AND DEXAMETHASONE VS SUBCUTANEOUS BORTEZOMIB AND DEXAMETHASONE IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA: SECONDARY ANALYSIS FROM THE PHASE 3 STUDY ENDEAVOR (NCT01568866)
Author(s): ,
Hartmut Goldschmidt
Affiliations:
Universitatsklinikum Heidelberg,Heidelberg,Germany
,
Phillipe Moreau
Affiliations:
University of Nantes,Nantes,France
,
Antonio Palumbo
Affiliations:
University of Torino,Torino,Italy
,
Douglas Joshua
Affiliations:
Royal Prince Alfred Hospital,Camperdown, New South Wales,Australia
,
Ludek Pour
Affiliations:
University Hospital Brno,Brno,Czech Republic
,
Roman Hajek
Affiliations:
University Hospital Ostrava and Faculty of Medicine, University of Ostrava,Ostrava,Czech Republic
,
Thierry Facon
Affiliations:
CHRU Lille Hopital Claude Huriez,Lille,France
,
Heinz Ludwig
Affiliations:
Wilhelminen Cancer Research Institute,Vienna,Austria
,
Ruben Niesvizky
Affiliations:
Weill Cornell Medical College,New York,United States
,
Albert Oriol
Affiliations:
Institut Catala d'Oncologia,Barcelona,Spain;Hospital Germans Tria i Pujol,Barcelona,Spain
,
Laura Rosinol
Affiliations:
Hospital Clinic de Barcelona,Barcelona,Spain
,
Jan Straub
Affiliations:
General University Hospital,Prague,Czech Republic
,
Aleksandr Suvorov
Affiliations:
First Republican Clinical Hospital of Udmurtia,Izhevsk,Russian Federation
,
Carla Araujo
Affiliations:
Centre Hospitalier de la cote Basque,Bayonne,France
,
Elena Rimashevskaya
Affiliations:
Semashko Central Clinical Hospital,Moscow,Russian Federation
,
Tomas Pika
Affiliations:
University Hospital Olomouc,Olomouc,Czech Republic
,
Gianluca Gaidano
Affiliations:
Amedeo Avogadro University of Eastern Piedmont,Novara,Italy
,
Katja Weisel
Affiliations:
Universitatsklinikum Tubingen,Tubingen,Germany
,
Vesselina Goronova-Marinova
Affiliations:
Hematology Clinic University Multiprofile Hospital for Active Treatment,Plovdiv,Bulgaria
,
Anthony Schwarer
Affiliations:
Box Hill Hospital,Box Hill, Victoria,Australia
,
Leonard Minuk
Affiliations:
London Health Sciences Centre, Western University,Ontario,Canada
,
Tamas Masszi
Affiliations:
St Istvan and St Laszlo Hospital,Budapest,Hungary
,
Ievgenii Karamanesht
Affiliations:
Kyiv Center for Bone Marrow Transplantation,Kyiv,Ukraine
,
Massimo Offidani
Affiliations:
Clinica di Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti Umberto I-G.M. Lancisi-G. Salesi di Ancona,Ancona,Italy
,
Vania Hungria
Affiliations:
Irmandade de Santa Casa de Misericordia de Sao Paulo,Sao Paulo,Brazil
,
Andrew Spencer
Affiliations:
Alfred Health-Monash University,Melbourne, Victoria,Canada
,
Robert Orlowski
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston, Texas,United States
,
Karim Iskander
Affiliations:
Amgen, Inc.,Thousand Oaks,United States
,
Shibao Feng
Affiliations:
Amgen, Inc.,Thousand Oaks,United States
,
Sanjay Aggarwal
Affiliations:
Amgen, Inc.,Thousand Oaks,United States
,
Wee-Joo Chng
Affiliations:
National University Cancer Institute, National University Health System, Singapore and Cancer Science Institute of Singapore, National University of Singapore,Singapore,Singapore
Meletios A Dimopoulos
Affiliations:
School of Medicine, National and Kapodistrian University of Athens,Athens,Greece
EHA Learning Center. Goldschmidt H. Jun 11, 2016; 133547
Prof. Dr. Hartmut Goldschmidt
Prof. Dr. Hartmut Goldschmidt

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Abstract: P659

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
Subcutaneous (SC) delivery of bortezomib (BTZ) has been shown non-inferior to intravenous (IV) delivery in terms of efficacy while offering improved safety (Moreau, et al. Lancet Oncol 2011;12:431-40).  The phase 3 ENDEAVOR study demonstrated a significant improvement in progression-free survival (PFS) for carfilzomib and dexamethasone (Kd) vs IV/SC BTZ and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM) (Dimopoulos, et al. Lancet Oncol 2016;17:27-38).  Currently, most BTZ use in MM is SC, and most relapsed MM patients had prior exposure to BTZ.

Aims
We present results of a subset analysis of the efficacy and safety of Kd vs SC Vd in the ENDEAVOR study consistent with current standard of care; the effect of prior exposure to BTZ was also investigated.

Methods
After providing informed consent, patients with RRMM (1-3 lines of therapy) were randomized 1:1 to Kd or Vd.  The analysis compared Kd patients who had selected SC BTZ delivery pre-randomization if randomized to Vd arm with Vd patients who used SC BTZ.  Kd arm received carfilzomib (30-min IV infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) and dexamethasone (d) 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle.  Vd arm received BTZ 1.3 mg/m2 on days 1, 4, 8 and 11 and d (20 mg) on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. The primary endpoint was PFS.  Secondary endpoints included overall survival (OS), overall response rate (ORR), rate of grade ≥2 peripheral neuropathy (PN), and safety. 

Results
A total of 929 patients were randomized to Kd (n=464) or Vd (n=465); of these, 360 Vd patients received SC BTZ.  Among 464 Kd patients, 356 patients selected SC route of BTZ administration if randomized to Vd arm.  Median PFS has not been reached for Kd but was 9.5 months (mo) for Vd patients treated with SC BTZ (hazard ratio [HR]: 0.58; 95% confidence interval [CI], 0.46–0.72).  Median PFS for Kd vs SC Vd was 13.4 mo vs 8.4 mo for patients with prior BTZ exposure (HR: 0.66; 95% CI, 0.50–0.87).  Median OS has not been reached for Kd but was 24.3 mo for SC Vd (HR: 0.75; CI, 0.53–1.08).  ORR was 76.1% (Kd) vs 64.4% (SC Vd), and 70.4% (Kd) vs 62.1% (SC Vd) for patients with prior BTZ use.  Grade ≥2 PN rates were 6.5% (Kd) vs 33.3% (SC Vd), and 6.2% (Kd) vs 29.1% (SC Vd) for patients with prior BTZ.  Grade ≥ 3 adverse events (AEs) were 74.4% (Kd) vs 67.5% (SC Vd), and 71.8% (Kd) vs 64.5% (SC Vd) for patients with prior BTZ.  Results are shown in Table.  Figure shows Kaplan‒Meier PFS curves. Table. Outcomes
   Prior BTZ
 Kd (n=356)SC Vd (n=360)Kd (n=196)SC Vd (n=203)
Median PFS, moNot reached9.513.48.4
HR for Kd vs SC Vd   (95% CI)0.58 (0.46–0.72)0.66 (0.50–0.87)
ORR, % (95% CI)76.1 (71.3–80.4)64.4 (59.3–69.4)70.4 (63.5–76.7)62.1 (55.0–68.8)
Grade ≥2 PN rate, %6.533.36.229.1
Odds ratio (95% CI)0.139 (0.09–0.22)0.160 (0.08–0.31)
Grade ≥3 AEsa, %74.467.571.864.5
aSafety population was 355 (Kd) and 360 (SC Vd), and 195 (Kd) and 203 (SC Vd) in the prior BTZ group

Conclusion
Treatment with Kd led to prolonged progression-free survival vs Vd patients who were administered SC BTZ.  The use of Kd also led to higher response rates, a trend for prolonged OS, and lower rate of grade ≥2 PN vs SC Vd.  In patients with prior BTZ exposure, Kd treatment resulted in longer PFS, greater ORR, and decreased PN vs SC Vd.  These results suggest that Kd has a favorable benefit-risk profile and delivers superior efficacy and improved clinical outcomes compared with SC Vd for RRMM regardless of prior BTZ treatment.



Session topic: Innovative therapies for MM 4

Keyword(s): Multiple myeloma, Proteasome inhibitor
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