ClinicalTrials.gov
History of Changes for Study: NCT01568866
Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR)
Latest version (submitted November 10, 2022) on ClinicalTrials.gov
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Study Record Versions
Version A B Submitted Date Changes
1 March 30, 2012 None (earliest Version on record)
2 April 2, 2012 Study Status, Arms and Interventions and Outcome Measures
3 July 2, 2012 Recruitment Status, Study Status, Contacts/Locations and Oversight
4 July 3, 2012 Contacts/Locations and Study Status
5 July 13, 2012 Contacts/Locations and Study Status
6 September 14, 2012 Study Status and Contacts/Locations
7 October 3, 2012 Study Status and Contacts/Locations
8 October 11, 2012 Oversight and Study Status
9 November 2, 2012 Study Status and Contacts/Locations
10 December 3, 2012 Study Status and Contacts/Locations
11 February 6, 2013 Study Status, Contacts/Locations and Eligibility
12 March 19, 2013 Study Status and Contacts/Locations
13 May 9, 2013 Contacts/Locations and Study Status
14 June 11, 2013 Study Status and Contacts/Locations
15 June 17, 2013 Study Status
16 October 28, 2013 Study Status and Contacts/Locations
17 January 6, 2014 Contacts/Locations and Study Status
18 January 22, 2014 Study Status
19 January 28, 2014 Contacts/Locations and Study Status
20 March 3, 2014 Study Status and Contacts/Locations
21 March 31, 2014 Study Status and Contacts/Locations
22 April 28, 2014 Study Status, Contacts/Locations and Study Design
23 June 13, 2014 Recruitment Status, Contacts/Locations and Study Status
24 June 27, 2014 Contacts/Locations and Study Status
25 February 3, 2015 Study Status
26 March 2, 2015 Study Status
27 March 31, 2015 Contacts/Locations and Study Status
28 June 25, 2015 Study Status and Contacts/Locations
29 August 4, 2015 Study Status and Contacts/Locations
30 November 6, 2015 Study Status, Arms and Interventions, Outcome Measures, Study Design, Results, Eligibility, Study Description and Study Identification
31 December 14, 2015 Arms and Interventions and Study Status
32 January 31, 2017 Study Status and Outcome Measures
33 April 18, 2017 Contacts/Locations, Study Status and Study Identification
34 December 14, 2017 Study Status, References and Contacts/Locations
35 February 14, 2018 Recruitment Status and Study Status
36 May 24, 2018 Adverse Events, Outcome Measures, Baseline Characteristics, Participant Flow, Study Status and More Information
37 August 1, 2018 Study Status and References
38 September 6, 2018 Study Status and References
39 April 1, 2019 References and Study Status
40 September 8, 2022 References, Study Status and Outcome Measures
41 November 10, 2022 Study Status and References
Comparison Format:
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Study NCT01568866
Submitted Date:  December 14, 2015 (v31)
Open or close this module Study Identification
Unique Protocol ID: 2011-003
Brief Title: Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients (ENDEAVOR)
Official Title: A Randomized, Open-label, Phase 3 Study of Carfilzomib Plus Dexamethasone vs. Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma
Secondary IDs: 2012-000128-16 [EudraCT Number]
Open or close this module Study Status
Record Verification: December 2015
Overall Status: Active, not recruiting
Study Start: June 2012
Primary Completion: November 2014 [Actual]
Study Completion: December 2018 [Anticipated]
First Submitted: March 28, 2012
First Submitted that
Met QC Criteria:		 March 30, 2012
First Posted: April 2, 2012 [Estimate]
Results First Submitted: November 6, 2015
Results First Submitted that
Met QC Criteria:		 November 6, 2015
Results First Posted: December 11, 2015 [Estimate]
Last Update Submitted that
Met QC Criteria:		 December 14, 2015
Last Update Posted: January 15, 2016 [Estimate]
Open or close this module Sponsor/Collaborators
Sponsor: Amgen
Responsible Party: Sponsor
Collaborators:
Open or close this module Oversight
U.S. FDA-regulated Drug:
U.S. FDA-regulated Device:
Data Monitoring: Yes
Open or close this module Study Description
Brief Summary: The primary objective of this study was to compare progression-free survival in patients with multiple myeloma who relapsed after 1 to 3 prior therapies treated with carfilzomib plus dexamethasone or bortezomib plus dexamethasone.
Detailed Description:
Open or close this module Conditions
Conditions: Multiple Myeloma
Keywords: multiple myeloma
relapsed multiple myeloma
Open or close this module Study Design
Study Type: Interventional
Primary Purpose: Treatment
Study Phase: Phase 3
Interventional Study Model: Parallel Assignment
Number of Arms: 2
Masking: None (Open Label)
Allocation: Randomized
Enrollment: 929 [Actual]
Open or close this module Arms and Interventions
Arms Assigned Interventions
Experimental: Carfilzomib plus Dexamethasone
Participants received 20 mg/m² carfilzomib administered by intravenous (IV) infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
 Drug: Carfilzomib
Carfilzomib is administered over 30 minutes as an infusion.
Other Names:
  • PR-171
  • Krypolis
Drug: Dexamethasone
Tablet for oral administration; On days when carfilzomib or bortezomib was administered, the dexamethasone was to be given 30 minutes to 4 hours prior to the carfilzomib or bortezomib dose.
Active Comparator: Bortezomib plus Dexamethasone
Participants received bortezomib 1.3 mg/m² administered IV or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.
 Drug: Bortezomib
Bortezomib is administered as a 3-5 second bolus IV injection or SC injection (in accordance with regulatory approval)
Other Names:
  • Velcade
Drug: Dexamethasone
Tablet for oral administration; On days when carfilzomib or bortezomib was administered, the dexamethasone was to be given 30 minutes to 4 hours prior to the carfilzomib or bortezomib dose.
Open or close this module Outcome Measures
[See Results Section.]
Primary Outcome Measures:
1. Progression Free Survival
[ Time Frame: From randomization until the data cut-off date of 10 November 2014; median follow-up time for PFS was 11.1.and 11.9 months in the bortezomib and carfilzomib arms respectively ]

Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC).

Median PFS was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
Secondary Outcome Measures:
1. Overall Survival
[ Time Frame: From randomization until the data cut-off date of 10 November 2014; median follow-up time for OS was 11.9 and 12.5 months for each treatment group respectively. ]

Overall survival (OS) is defined as the time from randomization to the date of death (whatever the cause). Participants who were alive or lost to follow-up as of the data analysis cut-off date were censored at the patient's date of last contact (last known to be alive).

Median overall survival was estimated using the Kaplan-Meier method.
2. Overall Response
[ Time Frame: Disease response was assessed every 28 days until end of treatment or the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group. ]

Disease response was evaluated according to the IMWG-URC by the IRC. Overall response was defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR) or stringent CR (sCR).

sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM).

CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.
3. Duration of Response
[ Time Frame: From randomization until the data cut-off date of 10 November 2014; median follow-up time for DOR was 9.4 and 10.4 months for each treatment group respectively. ]

Duration of response (DOR) was calculated for participants who achieved an sCR, CR, VGPR, or PR. Duration of response is defined as the time from first evidence of PR or better to confirmation of disease progression or death due to any cause. Median duration of response was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
4. Percentage of Participants With ≥ Grade 2 Peripheral Neuropathy
[ Time Frame: From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group. ]

Neuropathy events were defined as Grade 2 or higher peripheral neuropathy as specified by peripheral neuropathy Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query, narrow (scope) (SMQN) terms.

Peripheral neuropathy was assessed by neurologic exam and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03:

Grade 1: Asymptomatic; Grade 2: Moderate symptoms, limiting instrumental activities of daily living (ADL) Grade 3: Severe symptoms; limiting self-care ADL; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death.
5. Percentage of Participants With a Significant Reduction in Left Ventricular Ejection Fraction (LVEF)
[ Time Frame: Baseline and 24 weeks ]

A significant reduction in LVEF was defined as a ≥ 10% decrease (absolute change) from baseline in participants whose baseline LVEF is ≤ 55%.

For participants with LVEF > 55% at baseline, a significant change was defined as a decrease in LVEF to < 45%.
6. Change From Baseline in Right Ventricular Fractional Area Change (FAC)
[ Time Frame: Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group). ]

Right ventricular function was assessed by measuring fractional area change (FAC) on echocardiogram.
7. Change From Baseline in Pulmonary Artery Systolic Pressure (PASP)
[ Time Frame: Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group). ]

Pulmonary artery pressure was measured using transthoracic echocardiogram.
Open or close this module Eligibility
Minimum Age: 18 Years
Maximum Age:
Sex: All
Gender Based:
Accepts Healthy Volunteers: No
Criteria:

Inclusion Criteria:

  1. Multiple myeloma with relapsing or progressing disease at study entry.
  2. Patients must have evaluable multiple myeloma with, at least one of the following (assessed within 21 days prior to randomization):
    • Serum M-protein ≥ 0.5 g/dL, or
    • Urine M-protein ≥ 200 mg/24 hour, or
    • In patients without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal serum kappa/lamda ratio, or
    • For immunoglobulin (Ig) A patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL).
  3. Patients must have documented at least partial response (PR) to at least 1 line of prior therapy. PR documentation can be based on Investigator assessment.
  4. Received 1, but no more than 3 prior treatment regimens or lines of therapy for multiple myeloma. (Induction therapy followed by stem cell transplant and consolidation/maintenance therapy will be considered as one line of therapy).
  5. Prior therapy with Velcade is allowed as long as the patient had at least a PR to prior Velcade therapy, was not removed from Velcade therapy due to toxicity, and will have at least a 6 month Velcade treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month Velcade treatment-free interval).
  6. Prior therapy with carfilzomib is allowed as long as the patient had at least a PR to prior carfilzomib therapy, was not removed from carfilzomib therapy due to toxicity, and had at least a 6-month carfilzomib treatment-free interval from last dose received until first study treatment. (Patients may receive maintenance therapy with drugs that are not in the proteasome inhibitor class during this 6 month carfilzomib treatment-free interval). The exception to this is patients randomized or previously randomized in any other Onyx-Sponsored Phase 3 trial.
  7. Males and females ≥ 18 years of age.
  8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.
  9. Adequate hepatic function within 21 days prior to randomization, with bilirubin < 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN.
  10. Left ventricular ejection fraction (LVEF) ≥ 40%.
  11. Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to randomization. Screening ANC should be independent of growth factor support for ≥ 1 week.
  12. Hemoglobin ≥ 8.0 g/dL within 21 days prior to randomization. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.
  13. Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization. Patients should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.
  14. Calculated or measured creatinine clearance (CrCl) of ≥ 15 mL/min within 21 days prior to randomization. Calculation should be based on standard formula such as the Cockcroft and Gault:

    [(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL)]; multiply result by 0.85 if female.

  15. Written informed consent in accordance with federal, local, and institutional guidelines.
  16. Female patients of child-bearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to randomization and agree to use an effective method of contraception during and for 3 months following last dose of drug (more frequent pregnancy tests may be conducted if required per local regulations). FCBP is defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
  17. Male patients must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a FCBP.

Exclusion Criteria:

  1. Multiple Myeloma of IgM subtype.
  2. Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 14 days prior to randomization.
  3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
  4. Plasma cell leukemia or circulating plasma cells ≥ 2 × 10^9/L.
  5. Waldenstrom's Macroglobulinemia.
  6. Patients with known amyloidosis.
  7. Chemotherapy with approved or investigational anticancer therapeutics within 21 days prior to randomization.
  8. Patients randomized or previously randomized in any other Onyx-Sponsored Phase 3 trial.
  9. Focal radiation therapy within 7 days prior to randomization. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to randomization (i.e., prior radiation must have been to less than 30% of the bone marrow).
  10. Immunotherapy within 21 days prior to randomization.
  11. Major surgery (excluding kyphoplasty) within 28 days prior to randomization.
  12. Active congestive heart failure (New York Heart Association [NYHA] Class III to IV), symptomatic ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within four months prior to randomization.
  13. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to randomization.
  14. Known human immunodeficiency (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen [SAg] or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed).
  15. Patients with known cirrhosis.
  16. Second malignancy within the past 3 years except:
    • adequately treated basal cell or squamous cell skin cancer
    • carcinoma in situ of the cervix
    • prostate cancer < Gleason score 6 with stable prostate-specific antigen (PSA) over 12 months
    • breast carcinoma in situ with full surgical resection
    • treated medullary or papillary thyroid cancer
  17. Patients with myelodysplastic syndrome.
  18. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to randomization.
  19. Female patients who are pregnant or lactating.
  20. Known history of allergy to Captisol(a cyclodextrin derivative used to solubilize carfilzomib).
  21. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.
  22. Patients with contraindication to dexamethasone.
  23. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
  24. Ongoing graft-vs-host disease.
  25. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.
Open or close this module Contacts/Locations
Study Officials: Hartmut Goldschmidt, MD
Principal Investigator
Universitätsklinik Heidelberg, Heidelberg, Germany
Douglas Joshua, BSc, MBBS, DPhil (Oxon), FRACP
Principal Investigator
Royal Prince Alfred Hospital, Camperdown, Australia
Philippe Moreau, MD
Principal Investigator
Hôpital Hôtel-Dieu, NANTES Cedex 01, France
Robert Orlowski, PhD, MD
Principal Investigator
UT M.D. Anderson Cancer Center, MD Anderson Cancer Center, Houston, Texas
Locations: United States, California
Providence St. Joseph Medical Center
Burbank, California, United States
UCSD Moore Cancer Center
La Jolla, California, United States
UCLA Medical Center
Los Angeles, California, United States
Central Coast Medical Oncology Group
Santa Maria, California, United States
United States, Colorado
Colorado Blood Cancer Institute
Denver, Colorado, United States
United States, Florida
MAB Oncology/Hematology
Melbourne, Florida, United States
Palm Beach Cancer Institute
West Palm Beach, Florida, United States
United States, Georgia
Winship Cancer Institute
Atlanta, Georgia, United States
United States, Indiana
Hematology Oncology of Indiana, PC
Indianapolis, Indiana, United States
United States, Maryland
Center for Cancer and Blood Disorders
Bethesda, Maryland, United States
Associates in Oncology/Hematology PC
Rockville, Maryland, United States
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States
United States, Missouri
University of Kansas
Kansas City, Missouri, United States
United States, New Jersey
Hackensack University Medical Ctr
Hackensack, New Jersey, United States
United States, New York
Montefiore Medical Center
Bronx, New York, United States
Clinical Research Alliance Inc.
New York, New York, United States
Weill Cornell Medical College
New York, New York, United States
United States, North Carolina
Wake Forest University Health Sciences, Section on Hematology and Oncology
Winston-Salem, North Carolina, United States
United States, Ohio
Gabrail Cancer Center
Canton, Ohio, United States
The Christ Hospital
Cincinnati, Ohio, United States
United States, Pennsylvania
Western Pennsylvania Hospital
Pittsburgh, Pennsylvania, United States
United States, South Carolina
Hematology/Oncology Associates of SC
Greenville, South Carolina, United States
United States, Tennessee
Vanderbilt Ingram Cancer Center
Nashville, Tennessee, United States
United States, Texas
MD Anderson
Houston, Texas, United States
The Methodist Cancer Center
Houston, Texas, United States
Scott & White Memorial Hospital
Temple, Texas, United States
United States, Utah
University of Utah School of Medicine
Salt Lake City, Utah, United States
Australia, New South Wales
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
St. Vincent's Public Hospital Sydney
Darlinghurst, New South Wales, Australia
Saint George Hospital
Kogarah, New South Wales, Australia
Liverpool Hospital
Liverpool, New South Wales, Australia
Royal North Shore Hospital
Saint Leonards, New South Wales, Australia
Calvary Mater Newcastle
Waratah, New South Wales, Australia
Westmead Hospital
Westmead, New South Wales, Australia
Australia, Queensland
Royal Brisbane and Women's Hospital
Herston, Queensland, Australia
Haematology & Oncology Clinics of Australia
South Brisbane, Queensland, Australia
Haematology and Oncology Clinics of Australia at Chermside
South Brisbane, Queensland, Australia
Haematology and Oncology Clinics of Australia at Wesley
South Brisbane, Queensland, Australia
Australia, South Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia
The Queen Elizabeth Hospital
Woodville, South Australia, Australia
Australia, Victoria
Box Hill Hospital
Box Hill, Victoria, Australia
Monash Medical Centre
Clayton, Victoria, Australia
Saint Vincent's Hospital
East Melbourne, Victoria, Australia
Western Hospital
Footscray, Victoria, Australia
The Alfred Hospital
Melbourne, Victoria, Australia
Sunshine Hospital
St. Albans, Victoria, Australia
Australia, Western Australia
Fremantle Hospital
Fremantle, Western Australia, Australia
Royal Perth Hospital
Perth, Western Australia, Australia
Austria, Tyrol
Medizinische Universität Innsbruck
Innsbruck, Tyrol, Austria
Austria, Upper Austria
Krankenhaus der Elisabethinen Linz, I Interne Abteilung
Linz, Upper Austria, Austria
Austria, Vienna
Wilhelminenspital der Stadt Wien
Wien, Vienna, Austria
Belgium
Ziekenhuis Netwerk Antwerpen
Antwerp, Belgium
Cliniques Universitaires Saint Luc
Brussels, Belgium
Universitair Ziekenhuis Brussel
Brussels, Belgium
Belgium, Flemish Brabant
Universitair Ziekenhuis Leuven
Leuven, Flemish Brabant, Belgium
Belgium, Namur
Cliniques Universitaires UCL de Mont-Godinne
Yvoir, Namur, Belgium
Belgium, Oost-vlaanderen
Universitair Ziekenhuis Gent
Ghent, Oost-vlaanderen, Belgium
Brazil
Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro
Rio de Janeiro, Brazil
Instituto Centros Oncológicos Integrados de Educação e Pesquisa
Rio de Janeiro, Brazil
Instituto Nacional do Câncer-INCA
Rio de Janeiro, Brazil
Irmandade da Santa Casa de Misericórdia de São Paulo
São Paulo, Brazil
Brazil, Rio Grande Do Norte
Liga Norte Riograndense Contra o Câncer
Natal, Rio Grande Do Norte, Brazil
Brazil, Rio Grande Do Sul
Clínica de Oncologia de Porto Alegre
Porto Alegre, Rio Grande Do Sul, Brazil
Hospital de Clínicas de Porto Alegre
Porto Alegre, Rio Grande Do Sul, Brazil
Hospital São Lucas da PUCRS
Porto Alegre, Rio Grande Do Sul, Brazil
Brazil, Sao Paulo
Hemocentro Campinas-Unicamp
Campinas, Sao Paulo, Brazil
Bulgaria
University Multiprofile Hospital for Active Treatment "Sveti Georgi" EAD
Plovdiv, Bulgaria
Multiprofile Hospital for Active Treatment, "Sveta Marina''
Varna, Bulgaria
Bulgaria, Sofiya
Military Medical Academy Hospital for Active Treatment
Sofia, Sofiya, Bulgaria
Shato, Ead
Sofia, Sofiya, Bulgaria
Canada, Alberta
University of Alberta Hospital
Edmonton, Alberta, Canada
Canada, British Columbia
British Columbia Cancer Agency
Kelowna, British Columbia, Canada
Canada, New Brunswick
Saint John Regional Hospital
Saint John, New Brunswick, Canada
Canada, Nova Scotia
Queen Elizabeth II Health Science Centre
Halifax, Nova Scotia, Canada
Canada, Ontario
London Health Sciences Centre
London, Ontario, Canada
The Ottawa Hospital Regional Cancer Centre
Ottawa, Ontario, Canada
Windsor Regional Hospital
Windsor, Ontario, Canada
Canada, Quebec
Hopital Maisonneuve-Rosemont
Montréal, Quebec, Canada
Czech Republic
Fakultní nemocnice Brno
Brno, Czech Republic
Všeobecná fakultní nemocnice v Praze
Praha, Czech Republic
Czech Republic, Praha
Fakultní nemocnice Královské Vinohrady
Praha 10, Praha, Czech Republic
Czech Republic, Severomoravsky Kraj
Fakultní nemocnice Olomouc
Olomouc, Severomoravsky Kraj, Czech Republic
FN Ostrava
Ostrava, Severomoravsky Kraj, Czech Republic
Czech Republic, Vychodocesky Kraj
Fakultní nemocnice Hradec Králové
Hradec Kralové, Vychodocesky Kraj, Czech Republic
France, Aquitaine
Centre Hospitalier de la Cote Basque
Bayonne, Aquitaine, France
France, Bretagne
Centre Hospitalier Universitaire Brest
Brest Cedex, Bretagne, France
Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou
Rennes Cedex 9, Bretagne, France
France, Cedex 1
Hopital Hotel-Dieu - Service d'Hematologie
Nantes, Cedex 1, France
France, Haute-normandie
Centre Henri-Becquerel
Rouen Cedex 1, Haute-normandie, France
France, Ile-de-france
Centre Hospitalier de Versailles
Le Chesnay, Ile-de-france, France
Hôpital Saint Louis
Paris, Ile-de-france, France
Hôpital Saint-Antoine
Paris, Ile-de-france, France
France, Nord Pas-de-calais
Hôpital Claude Huriez
Lille Cedex, Nord Pas-de-calais, France
France, Pays de La Loire
Hôpital Hôtel-Dieu
Nantes cedex 1, Pays de La Loire, France
France, Provence Alpes Cote D'azur
Institut Paoli Calmettes
Marseille Cedex 9, Provence Alpes Cote D'azur, France
France, Rhone-alpes
Centre Hospitalier Lyon Sud
Pierre Bénite Cedex, Rhone-alpes, France
Germany
Universitatsklinikum Freiburg
Freiburg, Germany
Universitätsklinikum Hamburg Eppendorf
Hamburg, Germany
Germany, Baden-wuerttemberg
Universitätsklinik Heidelberg
Heidelberg, Baden-wuerttemberg, Germany
Universitätsklinikum Tübingen
Tübingen, Baden-wuerttemberg, Germany
Universitätsklinikum Ulm
Ulm, Baden-wuerttemberg, Germany
Germany, Bayern
Medizinische Klinik der Universität Würzburg
Würzburg, Bayern, Germany
Germany, Niedersachsen
Medizinische Hochschule Hannover
Hannover, Niedersachsen, Germany
Germany, Nordrhein-westfalen
Universitätsklinikum Aachen
Aachen, Nordrhein-westfalen, Germany
Universitätsklinikum Münster
Münster, Nordrhein-westfalen, Germany
Germany, Rheinland-pfalz
Universitätsmedizin der Johannes Gutenberg Universität
Mainz, Rheinland-pfalz, Germany
Germany, Saarland
Universitätsklinikum des Saarlandes
Homburg / Saar, Saarland, Germany
Germany, Sachsen
Klinikum Chemnitz gGmbH
Chemnitz, Sachsen, Germany
Universitätsklinikum Carl Gustav Carus, Med. Klinik und Poliklinik I
Dresden, Sachsen, Germany
Universitätsklinikum Leipzig
Leipzig, Sachsen, Germany
Germany, Thuringen
Universitätsklinikum Jena
Jena, Thuringen, Germany
Greece, Attica
Alexandra General Hospital
Athens, Attica, Greece
Hungary
Egyesített Szent István és Szent László Kórház-Rendelointézet
Budapest, Hungary
Somogy Megyei Kaposi Mac okato Korhoz
Kaposvár, Hungary
Somogy Megyei Kaposi Mór Oktató Kórház
Kaposvár, Hungary
Hungary, Bacs-kiskun
Bács-Kiskun Megyei Kórház Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza
Kecskemét, Bacs-kiskun, Hungary
Hungary, Baranya
Pécsi Tudományegyetem
Pécs, Baranya, Hungary
Hungary, Csongrad
Szegedi Tudományegyetem
Szeged, Csongrad, Hungary
Hungary, Hajdu-bihar
Debreceni Egyetem Klinikai Központ
Debrecen, Hajdu-bihar, Hungary
Israel
Rambam Health Corp.
Haifa, Israel
Hadassah Medical Center
Jerusalem, Israel
Meir Medical Center
Kfar Saba, Israel
Tel Aviv Sourasky Medical Center
Tel Aviv, Israel
The Chaim Sheba Medical Center at Tel Hashomer
Tel Hashomer, Israel
Italy
Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
Ancona, Italy
Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
Bologna, Italy
Azienda Ospedaliera Spedali Civili di Brescia
Brescia, Italy
IRCCS Azienda Ospedaliera Universitaria San Martino
Genova, Italy
Azienda Ospedaliera Universitaria Maggiore della Carità
Novara, Italy
Azienda Unità Sanitaria Locale di Piacenza-Ospedale Guglielmo da Saliceto
Piacenza, Italy
Azienda Ospedaliera Pisana Ospedale Santa Chiara
Pisa, Italy
Aienda Policknico Umberto I di Roma
Roma, Italy
Azienda Policknico Umberto l di Roma
Roma, Italy
Università Tor Vergata Ospedale Sant Eugenio
Roma, Italy
Azienda Ospedaliera Universitaria Senese - Policlinico S. Maria alle Scotte
Siena, Italy
Azienda Ospedaliera Città della Salute e della Scienza di Torino
Torino, Italy
Italy, Potenza
IRCCS Centro di Riferimento Oncologico di Basilicata di Rionero in Vulture
Rionero in Vulture, Potenza, Italy
Italy, Torino
Azienda Ospedaliero-Univesitaria San Luigi Gonzaga
Orbassano, Torino, Italy
Japan
Kyushu University Hospital
Fukuoka, Japan
Social Insurance Kyoto Hospital of All Japan Federation of Social Insurance Associations
Kyoto, Japan
University Hospital, Kyoto Prefectural University of Medicine
Kyoto, Japan
National Hospital Organization Okayama Medical Center
Okayama, Japan
Tokushima Prefectural Central Hospital
Tokushima, Japan
Japanese Red Cross Medical Center
Tokyo, Japan
Japan, Aichi
Nagoya City University Hospital
Nagoya City, Aichi, Japan
Toyohashi Municipal Hospital
Toyohashi, Aichi, Japan
Japan, Fukuoka
National Hospital Organization Kyushu Cancer Center
Fukuoka-city, Fukuoka, Japan
Japan, Gifu
Ogaki Municipal Hospital
Ogaki City, Gifu, Japan
Japan, Gunma
Gunma University Hospital
Maebashi, Gunma, Japan
National Hospital Organization Nishigunma National Hospital
Shibukawa, Gunma, Japan
Japan, Hokkaido
Sapporo Medical University Hospital
Sapporo, Hokkaido, Japan
Japan, Hyogo
Kobe City Medical Center General Hospital
Kobe, Hyogo, Japan
Japan, Kanagawa
Tokai University Hospital
Isehara, Kanagawa, Japan
Japan, Niigata
Niigata Cancer Center Hospital
Niigata-city, Niigata, Japan
Japan, Osaka
Osaka University Hospital
Suita, Osaka, Japan
Japan, Saitama
Saitama Medical Center
Kawagoe, Saitama, Japan
Japan, Tochigi
Tochigi Cancer Center
Utsunomiya, Tochigi, Japan
Japan, Tokyo
National Cancer Center Hospital
Chuo-ku, Tokyo, Japan
The Cancer Institute Hospital Of Japanese Foundation For Cancer Research
Koto-ku, Tokyo, Japan
Toranornon Hospital
Shinagawa, Tokyo, Japan
Tokyo Medical University Hospital
Shinjuku, Tokyo, Japan
National Hospital Organization Disaster Medical Center
Tachikawa, Tokyo, Japan
Korea, Republic of
Kyungpook National University Hospital
Daegu, Korea, Republic of
Asan Medical Center
Seoul, Korea, Republic of
Samsung Medical Center
Seoul, Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of
Seoul Saint Mary's Hospital
Seoul, Korea, Republic of
Severance Hospital, Yonsei University Health System
Seoul, Korea, Republic of
Korea, Republic of, Gyeonggi-Do
Gachon University Gil Medical Center
Incheon, Gyeonggi-Do, Korea, Republic of
Korea, Republic of, Gyeonggi-do
Seoul National University Bundang Hospital
Seongnam-si, Gyeonggi-do, Korea, Republic of
Korea, Republic of, Gyeongsangnam-Do
Pusan National University Hospital
Busan, Gyeongsangnam-Do, Korea, Republic of
New Zealand
Christchurch Hospital
Christchurch, New Zealand
Dunedin Hospital
Dunedin, New Zealand
New Zealand, Auckland
North Shore Hospital
North Shore City, Auckland, New Zealand
Middlemore Hospital
Otahuhu, Auckland, New Zealand
New Zealand, Aukland
Auckland City Hospital
Grafton, Aukland, New Zealand
Poland, Kujawsko-Pomorskie
Specjalistyczny Szpital Miejski im. Mikolaja Kopernika
Torun, Kujawsko-Pomorskie, Poland
Poland, Lubelskie
Zamojski Szpital Niepubliczny Sp. z o.o.
Zamosc, Lubelskie, Poland
Poland, Malopolskie
Szpital Uniwersytecki w Krakowie
Krakow, Malopolskie, Poland
Poland, Mazowieckie
Instytut Hematologii i Transfuzjologii
Warszawa, Mazowieckie, Poland
Poland, Pomorskie
Uniwersyteckie Centrum Kliniczne
Gdansk, Pomorskie, Poland
Poland, Slaskie
Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespól Szpitali Miejskich
Chorzów, Slaskie, Poland
Poland, Wielkopolskie
Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu
Poznan, Wielkopolskie, Poland
Romania
Policlinica de Diagnostic Rapid SA, Compartiment Medical Oncologie-Hematologie
Brasov, Romania
Spitalul Clinic Judetean de Urgenta Brasov (Bumbea, Horia)
Brasov, Romania
Institutul Clinic Fundeni
Bucuresti, Romania
Institutul Regional de Oncologie Iasi
Iasi, Romania
Romania, Bucuresti
Spitalul Universitar de Urgenta Bucuresti
Bucharest, Bucuresti, Romania
Russian Federation
Republican Clinical Hospital #1
Izhevsk, Russian Federation
City Clinical Hospital n.a. S. P. Botkin
Moscow, Russian Federation
Non-state Healthcare Institution "N.A. Semashko Central Clinical Hospital #2 of JSC "Russian Railway
Moscow, Russian Federation
Ryazan Regional Clinical Hospital
Ryazan, Russian Federation
Clinical Hospital Number 31
Saint Petersburg, Russian Federation
Federal Almazov Medical Research Centre
Saint Petersburg, Russian Federation
FGU Russian Scientific Research Institute of Hematology and Transfusiology
Saint Petersburg, Russian Federation
First Saint Petersburg I.P. Pavlov State Medical University
Saint Petersburg, Russian Federation
GUZ Samara Regional Clinical Hospital n.a. M.I. Kalinin
Samara, Russian Federation
Singapore
National University Cancer Institute
Singapore, Singapore
Singapore General Hospital
Singapore, Singapore
Singapore Oncology Consultants
Singapore, Singapore
Slovakia
Univerzitná nemocnica Bratislava
Bratislava, Slovakia
Spain
Hospital Clinic I Provincial de Barcelona
Barcelona, Spain
Institut Universitari Dexeus
Barcelona, Spain
Centro Integral Oncológico Clara Campal, Hospital de Madrid Norte-San Chinarro
Madrid, Spain
Hospital Universitario 12 de Octubre
Madrid, Spain
Hospital Universitario La Princesa
Madrid, Spain
Hospital Clínico Universitario de Salamanca
Salamanca, Spain
Hospital Universitario Virgen del Rocio
Sevilla, Spain
Hospital Universitari i Politecnic La Fé de Valencia
Valencia, Spain
Spain, Baleares
Hospital Son Llàtzer
Palma de Mallorca, Baleares, Spain
Spain, Barcelona
Hospital Universitari Germans Trias i Pujol
Badalona, Barcelona, Spain
Taiwan
Chang Gung Memorial Hospital
Kaohsiung, Taiwan
China Medical University Hospital
Taichung, Taiwan
National Cheng-Kung University Hospital
Tainan, Taiwan
National Taiwan University Hospital
Taipei, Taiwan
Taipei Veterans General Hospital
Taipei, Taiwan
Chang Gung Medical Foundation-LinKou Branch
Tao-Yuan, Taiwan
Thailand
Srinagarind Hospital
Khon Kaen, Thailand
Thailand, Bangkok Metropolis
King Chulalongkorn Memorial Hospital
Bangkok, Bangkok Metropolis, Thailand
Ramathibodi Hospital
Bangkok, Bangkok Metropolis, Thailand
Ukraine
Cherkassy Regional Oncology Center
Cherkassy, Ukraine
MI "Dnipropetrovsk City Multifield Clinical Hospital #4" of Dnipropetrovsk Regional Council", City Hematology Center
Dnipropetrovsk, Ukraine
Institute of Urgent and Reparative Surgury of Ukraine Academy of Medical Sciences
Donetsk, Ukraine
Khmelnytsky Regional Clinical Hospital
Khmelnytsky, Ukraine
Khmelnytsky Regional Hospital, Department of Hematology
Khmelnytsky, Ukraine
National Institute of Cancer, Oncohematology Department
Kiev, Ukraine
Kyiv Bone Marrow Transplantation Center
Kyiv, Ukraine
Lviv Regional Oncology Dispensary
Lviv, Ukraine
Lviv State Oncology Regional Treatment-Prophylactic Center, Department of Chemotherapy
Lviv, Ukraine
Regional Clinical Hospital
Mykolayiv, Ukraine
Ukraine, Dnipropretrovsk
City Hematology Center
Dnepropetrovsk, Dnipropretrovsk, Ukraine
Ukraine, Kharkiv
Municipal Institution of Health Protection "Clinical Hospital #8"
Kharkov, Kharkiv, Ukraine
United Kingdom, England
Royal Free Hospital
London, England, United Kingdom
University College Hospital
London, England, United Kingdom
Manchester Royal Infirmary
Manchester, England, United Kingdom
Nottingham University Hospitals NHS Trust
Nottingham, England, United Kingdom
Churchill Hospital
Oxford, England, United Kingdom
Derriford Hospital
Plymouth, England, United Kingdom
Royal Hallamshire Hospital
Sheffield, England, United Kingdom
Royal Marsden Hospital
Surrey, England, United Kingdom
Royal Wolverhampton Hospitals Trust
Wolverhampton, England, United Kingdom
Open or close this module IPDSharing
Plan to Share IPD:
Open or close this module References
Links:
Available IPD/Information:
Study Results
Open or close this module Participant Flow
Recruitment Details Adults with relapsed multiple myeloma were eligible to participate in this study. Participants were required to have relapsed or progressed multiple myeloma after at least 1, but no more than 3, prior multiple myeloma therapies.
Pre-assignment Details Results are reported as of the data cut-off date of 10 November 2014, at which time an interim analysis of the primary endpoint was performed after approximately 75% of the planned progression-free survival events had been observed. Monitoring for safety and long-term survival is continuing.
 
Arm/Group Title Bortezomib + DEX Carfilzomib + DEX
Arm/Group Description Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle. Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Period Title: Overall Study
Started 465 464
Received Treatment 456 463
Completed 105 [1] 200 [1]
Not Completed 360 264
Reason Not Completed
Disease Progression 168 117
Adverse Event 73 65
Patient Request 45 40
Physician Decision 35 18
Withdrawal by Subject 19 6
Death 9 13
Protocol Non-compliance 1 4
Lost to Follow-up 1 0
Randomized but Not Dosed 9 1
[1]Indicates participants still receiving treatment
Open or close this module Baseline Characteristics
Arm/Group TitleBortezomib + DEXCarfilzomib + DEXTotal
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.Total of all reporting groups
Overall Number of Baseline Participants 465 464 929
Baseline Analysis Population Description
Age, Continuous
Median (Full Range)
Unit of measure: years
Number Analyzed465 Participants464 Participants929 Participants
65.0(30.0 to 88.0)65.0(35.0 to 89.0)65.0(30.0 to 89.0)
Age, Customized
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
< 65 years
210223433
65 -74 years
189164353
≥ 75 years
6677143
Sex: Female, Male
Measure Type: Count of Participants
Unit of measure: Participants
Number Analyzed465 Participants464 Participants929 Participants
Female
236
50.75%
224
48.28%
460
49.52%
Male
229
49.25%
240
51.72%
469
50.48%
Race/Ethnicity, Customized
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
White
353348701
Black
9817
Asian
5756113
Native Hawaiian/Other Pacific Islander
022
Not Reported
455095
Multiple
101
Eastern Cooperative Oncology Group (ECOG) Performance Status [1]
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
0 (Fully active)
232221453
1 (Restrictive but ambulatory)
203211414
2 (Ambulatory but unable to work)
303262
 
[1]Measure Description: Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participants disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active; 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, no self-care, confined to bed or chair; 5 = Dead.
Stratification Factor: Prior Proteasome Inhibitor Treatment
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
Carfilzomib or bortezomib
253252505
No prior carfilzomib or bortezomib
212212424
Stratification Factor: Lines of Prior Treatment
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
1 line
229231460
2 or 3 lines
236233469
Stratification Factor: International Staging System (ISS) Stage [1]
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
Stage I
204205409
Stage II or III
261259520
 
[1]Measure Description: 

The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group:

  • Stage I: β2-microglobulin (β2M) < 3.5 mg/L, albumin >= 3.5 g/dL
  • Stage II: β2M < 3.5 mg/L and albumin < 3.5 g/dL; or β2M 3.5 mg/L - 5.5 mg/L irrespective of the serum albumin
  • Stage III: β2M ≥ 5.5 mg/L
Stratification Factor: Route of Bortezomib Administration [1]
Measure Type: Number
Unit of measure: participants
Number Analyzed465 Participants464 Participants929 Participants
Intravenous
108108216
Subcutaneous
357356713
 
[1]Measure Description: The route of bortezomib administration (IV versus SC) was made in accordance with local regulatory approved route of administration. The value for this variable was selected for all participants prior to randomization to treatment group in order to balance the baseline characteristics that led to the choice of the particular route of bortezomib administration between the 2 arms.
Open or close this module Outcome Measures
1. Primary Outcome:
Title Progression Free Survival
Description

Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC).

Median PFS was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.

Time Frame From randomization until the data cut-off date of 10 November 2014; median follow-up time for PFS was 11.1.and 11.9 months in the bortezomib and carfilzomib arms respectively
Outcome Measure Data
Analysis Population Description
Intent-to-Treat Population
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed465 464
Median (95% Confidence Interval)
Unit of Measure: months
9.4(8.4 to 10.4) 18.7(15.6 to NA) [1]
[1]NA Explanation: Could not be estimated due to the low number of events.
Statistical Analysis 1
Statistical Analysis OverviewComparison Group SelectionBortezomib + DEX, Carfilzomib + DEX
Comments

The PFS interim analysis was to be performed using a group sequential monitoring plan.

The monitoring plan included an O'Brien-Fleming type of efficacy stopping boundary constructed using the Lan-DeMets alpha spending function to ensure a 1-sided Type I error rate ≤ 0.025.

Type of Statistical TestSuperiority or Other (legacy)
Comments[Not specified]
Statistical Test of HypothesisP-Value< 0.0001
Comments[Not specified]
MethodStratified Log Rank
CommentsLog rank test stratified by the randomization stratification factors.
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value0.533
Confidence Interval(2-sided) 95%
0.437 to 0.651
Estimation CommentsThe hazard ratio (carfilzomib/bortezomib) was estimated using a Cox proportional hazards model stratified by prior proteasome inhibitor treatment, lines of prior treatment, ISS stage, and choice of route of bortezomib administration.
2. Secondary Outcome:
Title Overall Survival
Description

Overall survival (OS) is defined as the time from randomization to the date of death (whatever the cause). Participants who were alive or lost to follow-up as of the data analysis cut-off date were censored at the patient's date of last contact (last known to be alive).

Median overall survival was estimated using the Kaplan-Meier method.

Time Frame From randomization until the data cut-off date of 10 November 2014; median follow-up time for OS was 11.9 and 12.5 months for each treatment group respectively.
Outcome Measure Data
Analysis Population Description
Intent-to-treat population
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed465 464
Median (95% Confidence Interval)
Unit of Measure: months
24.3(24.3 to NA) [1] NA(NA to NA) [1]
[1]NA Explanation: Could not be estimated due to the low number of events
Statistical Analysis 1
Statistical Analysis OverviewComparison Group SelectionBortezomib + DEX, Carfilzomib + DEX
Comments

The OS analysis at the time of the primary analysis of PFS (data cut-off date 10 November 2014) was the first OS interim analysis.The significance level for the first OS interim analysis was 0.0001 regardless of the number of OS events.

The final analysis of OS will be performed after approximately 496 deaths have occurred.

Type of Statistical TestSuperiority or Other (legacy)
Comments[Not specified]
Statistical Test of HypothesisP-Value0.0650
CommentsThe multiplicity in testing secondary endpoints was adjusted per group using the sequential Holm procedure to preserve the family-wise error rate at 0.025.
MethodStratified Log Rank
CommentsLog rank test stratified by the randomization stratification factors.
Method of EstimationEstimation ParameterHazard Ratio (HR)
Estimated Value0.786
Confidence Interval(2-sided) 95%
0.575 to 1.075
Estimation CommentsThe hazard ratio (carfilzomib/bortezomib) was estimated using a Cox proportional hazards model stratified by prior proteasome inhibitor treatment, lines of prior treatment, ISS stage, and choice of route of bortezomib administration.
3. Secondary Outcome:
Title Overall Response
Description

Disease response was evaluated according to the IMWG-URC by the IRC. Overall response was defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR) or stringent CR (sCR).

sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM).

CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and < 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein <100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to < 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

Time Frame Disease response was assessed every 28 days until end of treatment or the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.
Outcome Measure Data
Analysis Population Description
Intent-to-treat population
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed465 464
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
62.6(58.0 to 67.0) 76.9(72.8 to 80.7)
Statistical Analysis 1
Statistical Analysis OverviewComparison Group SelectionBortezomib + DEX, Carfilzomib + DEX
Comments[Not specified]
Type of Statistical TestSuperiority or Other (legacy)
Comments[Not specified]
Statistical Test of HypothesisP-Value< 0.0001
CommentsThe multiplicity in testing secondary endpoints was adjusted per group using the sequential Holm procedure to preserve the family-wise error rate at 0.025.
MethodStratified Cochran-Mantel-Haenszel
CommentsCochran-Mantel-Haenszel test stratified by the randomization stratification factors.
Method of EstimationEstimation ParameterOdds Ratio (OR)
Estimated Value2.032
Confidence Interval(2-sided) 95%
1.519 to 2.718
Estimation CommentsThe odds ratio (carfilzomib/bortezomib) was calculated using the Cochran-Mantel-Haenszel method stratified by prior proteasome inhibitor treatment, lines of prior treatment, ISS stage, and choice of route of bortezomib administration.
4. Secondary Outcome:
Title Duration of Response
Description Duration of response (DOR) was calculated for participants who achieved an sCR, CR, VGPR, or PR. Duration of response is defined as the time from first evidence of PR or better to confirmation of disease progression or death due to any cause. Median duration of response was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.
Time Frame From randomization until the data cut-off date of 10 November 2014; median follow-up time for DOR was 9.4 and 10.4 months for each treatment group respectively.
Outcome Measure Data
Analysis Population Description
Intent-to-treat population with an overall response
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed291 357
Median (95% Confidence Interval)
Unit of Measure: months
10.4(9.3 to 13.8) 21.3(21.3 to NA) [1]
[1]NA Explanation: Could not be estimated due to the low number of events
5. Secondary Outcome:
Title Percentage of Participants With ≥ Grade 2 Peripheral Neuropathy
Description

Neuropathy events were defined as Grade 2 or higher peripheral neuropathy as specified by peripheral neuropathy Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query, narrow (scope) (SMQN) terms.

Peripheral neuropathy was assessed by neurologic exam and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03:

Grade 1: Asymptomatic; Grade 2: Moderate symptoms, limiting instrumental activities of daily living (ADL) Grade 3: Severe symptoms; limiting self-care ADL; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death.

Time Frame From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.
Outcome Measure Data
Analysis Population Description
Safety population (all participants who received at least 1 dose of study treatment)
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed456 463
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
32.0(27.7 to 36.3) 6.0(3.9 to 8.2)
Statistical Analysis 1
Statistical Analysis OverviewComparison Group SelectionBortezomib + DEX, Carfilzomib + DEX
Comments[Not specified]
Type of Statistical TestSuperiority or Other (legacy)
Comments[Not specified]
Statistical Test of HypothesisP-Value<0.0001
CommentsThe multiplicity in testing secondary endpoints was adjusted per group using the sequential Holm procedure to preserve the family-wise error rate at 0.025.
MethodCochran-Mantel-Haenszel
Comments[Not specified]
Method of EstimationEstimation ParameterOdds Ratio (OR)
Estimated Value0.137
Confidence Interval(2-sided) 95%
0.089 to 0.210
Estimation CommentsThe odds ratio (carfilzomib/bortezomib) was estimated using the unconditional Cochran-Mantel-Haenszel method.
6. Secondary Outcome:
Title Percentage of Participants With a Significant Reduction in Left Ventricular Ejection Fraction (LVEF)
Description

A significant reduction in LVEF was defined as a ≥ 10% decrease (absolute change) from baseline in participants whose baseline LVEF is ≤ 55%.

For participants with LVEF > 55% at baseline, a significant change was defined as a decrease in LVEF to < 45%.

Time Frame Baseline and 24 weeks
Outcome Measure Data
Analysis Population Description
Cardiopulmonary Safety Evaluable subgroup (all randomized participants who enrolled in the cardiopulmonary substudy with evaluable baseline echocardiogram scans per the central laboratory) and with both baseline and at least one post-baseline LVEF measurement within 24 weeks.
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed40 48
Measure Type: Number
Unit of Measure: percentage of participants
2.6 0.0
7. Secondary Outcome:
Title Change From Baseline in Right Ventricular Fractional Area Change (FAC)
Description Right ventricular function was assessed by measuring fractional area change (FAC) on echocardiogram.
Time Frame Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group).
Outcome Measure Data
Analysis Population Description
Cardiopulmonary Safety Evaluable subgroup with available FAC data at baseline; "n" indicates participants whose results were available at both the baseline and the specified post-baseline visit.
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed52 55
Mean (Standard Deviation)
Unit of Measure: percent fractional area change
Week 12 (n=40, 40)
-0.7(5.00) -1.1(5.36)
Week 24 (n=26, 31)
0.7(6.10) -1.0(5.03)
Week 36 (n=15, 18)
-0.5(7.27) -0.5(6.38)
End of Treatment (n=23, 18)
0.4(4.73) -1.9(5.47)
8. Secondary Outcome:
Title Change From Baseline in Pulmonary Artery Systolic Pressure (PASP)
Description Pulmonary artery pressure was measured using transthoracic echocardiogram.
Time Frame Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group).
Outcome Measure Data
Analysis Population Description
Cardiopulmonary Safety Evaluable subgroup with available PASP data at baseline; "n" indicates participants whose results were available at both the baseline and the specified post-baseline visit.
 
Arm/Group TitleBortezomib + DEXCarfilzomib + DEX
Arm/Group DescriptionParticipants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Number of Participants Analyzed52 45
Mean (Standard Deviation)
Unit of Measure: mmHg
Week 12 (n=34, 30)
0.3(11.72) 2.8(11.44)
Week 24 (n=22, 20)
1.7(8.47) 3.4(13.63)
Week 36 (n=12, 14)
4.0(7.24) 2.6(13.55)
End of Treatment (n=21, 14)
3.4(8.14) 0.9(11.40)
Open or close this module Adverse Events
 
Time Frame From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.
Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
 
Arm/Group Title Bortezomib + DEX Carfilzomib + DEX
Arm/Group Description Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle. Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
All-Cause Mortality
  Bortezomib + DEXCarfilzomib + DEX
 Affected / At Risk (%)Affected / At Risk (%)
Total / /
Serious Adverse Events
  Bortezomib + DEXCarfilzomib + DEX
 Affected / At Risk (%)Affected / At Risk (%)
Total 162 / 456 (35.53%)223 / 463 (48.16%)
Blood and lymphatic system disorders
Anaemia † A 1 / 456 (0.22%)4 / 463 (0.86%)
Febrile neutropenia † A 2 / 456 (0.44%)2 / 463 (0.43%)
Neutropenia † A 0 / 456 (0%)1 / 463 (0.22%)
Plasmacytosis † A 0 / 456 (0%)1 / 463 (0.22%)
Thrombocytopenia † A 6 / 456 (1.32%)4 / 463 (0.86%)
Thrombotic microangiopathy † A 0 / 456 (0%)2 / 463 (0.43%)
Thrombotic thrombocytopenic purpura † A 0 / 456 (0%)1 / 463 (0.22%)
Cardiac disorders
Acute coronary syndrome † A 0 / 456 (0%)2 / 463 (0.43%)
Acute left ventricular failure † A 0 / 456 (0%)1 / 463 (0.22%)
Acute myocardial infarction † A 2 / 456 (0.44%)0 / 463 (0%)
Angina pectoris † A 0 / 456 (0%)3 / 463 (0.65%)
Atrial fibrillation † A 4 / 456 (0.88%)5 / 463 (1.08%)
Atrial flutter † A 1 / 456 (0.22%)0 / 463 (0%)
Bifascicular block † A 1 / 456 (0.22%)0 / 463 (0%)
Cardiac arrest † A 1 / 456 (0.22%)2 / 463 (0.43%)
Cardiac failure † A 3 / 456 (0.66%)8 / 463 (1.73%)
Cardiac failure acute † A 1 / 456 (0.22%)2 / 463 (0.43%)
Cardiac failure congestive † A 0 / 456 (0%)1 / 463 (0.22%)
Cardiomyopathy † A 0 / 456 (0%)1 / 463 (0.22%)
Left ventricular dysfunction † A 0 / 456 (0%)1 / 463 (0.22%)
Left ventricular failure † A 1 / 456 (0.22%)0 / 463 (0%)
Myocardial infarction † A 2 / 456 (0.44%)2 / 463 (0.43%)
Pericardial effusion † A 0 / 456 (0%)1 / 463 (0.22%)
Right ventricular failure † A 1 / 456 (0.22%)1 / 463 (0.22%)
Sinus tachycardia † A 0 / 456 (0%)1 / 463 (0.22%)
Stress cardiomyopathy † A 1 / 456 (0.22%)0 / 463 (0%)
Supraventricular tachycardia † A 0 / 456 (0%)2 / 463 (0.43%)
Ear and labyrinth disorders
Hearing impaired † A 1 / 456 (0.22%)0 / 463 (0%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion † A 1 / 456 (0.22%)0 / 463 (0%)
Eye disorders
Retinal tear † A 1 / 456 (0.22%)0 / 463 (0%)
Gastrointestinal disorders
Abdominal distension † A 1 / 456 (0.22%)0 / 463 (0%)
Abdominal pain † A 2 / 456 (0.44%)2 / 463 (0.43%)
Abdominal pain upper † A 1 / 456 (0.22%)0 / 463 (0%)
Abdominal strangulated hernia † A 0 / 456 (0%)1 / 463 (0.22%)
Colitis † A 1 / 456 (0.22%)0 / 463 (0%)
Constipation † A 2 / 456 (0.44%)1 / 463 (0.22%)
Diarrhoea † A 9 / 456 (1.97%)5 / 463 (1.08%)
Diverticulum † A 0 / 456 (0%)1 / 463 (0.22%)
Enterocolitis † A 0 / 456 (0%)1 / 463 (0.22%)
Gastric haemorrhage † A 1 / 456 (0.22%)0 / 463 (0%)
Gastrointestinal haemorrhage † A 2 / 456 (0.44%)1 / 463 (0.22%)
Ileus paralytic † A 3 / 456 (0.66%)0 / 463 (0%)
Intestinal obstruction † A 1 / 456 (0.22%)0 / 463 (0%)
Large intestine perforation † A 0 / 456 (0%)1 / 463 (0.22%)
Melaena † A 1 / 456 (0.22%)0 / 463 (0%)
Nausea † A 3 / 456 (0.66%)2 / 463 (0.43%)
Pancreatitis † A 0 / 456 (0%)1 / 463 (0.22%)
Paraesthesia oral † A 0 / 456 (0%)1 / 463 (0.22%)
Small intestinal obstruction † A 0 / 456 (0%)1 / 463 (0.22%)
Subileus † A 1 / 456 (0.22%)1 / 463 (0.22%)
Upper gastrointestinal haemorrhage † A 0 / 456 (0%)1 / 463 (0.22%)
Vomiting † A 2 / 456 (0.44%)5 / 463 (1.08%)
General disorders
Asthenia † A 1 / 456 (0.22%)0 / 463 (0%)
Cardiac death † A 0 / 456 (0%)1 / 463 (0.22%)
Chest pain † A 2 / 456 (0.44%)3 / 463 (0.65%)
Device occlusion † A 1 / 456 (0.22%)0 / 463 (0%)
Disease progression † A 5 / 456 (1.1%)7 / 463 (1.51%)
Fatigue † A 1 / 456 (0.22%)2 / 463 (0.43%)
General physical health deterioration † A 0 / 456 (0%)4 / 463 (0.86%)
Generalised oedema † A 1 / 456 (0.22%)0 / 463 (0%)
Hyperpyrexia † A 1 / 456 (0.22%)0 / 463 (0%)
Hyperthermia † A 0 / 456 (0%)1 / 463 (0.22%)
Malaise † A 1 / 456 (0.22%)0 / 463 (0%)
Non-cardiac chest pain † A 0 / 456 (0%)1 / 463 (0.22%)
Oedema peripheral † A 0 / 456 (0%)1 / 463 (0.22%)
Pain † A 1 / 456 (0.22%)1 / 463 (0.22%)
Pyrexia † A 3 / 456 (0.66%)15 / 463 (3.24%)
Sudden death † A 1 / 456 (0.22%)2 / 463 (0.43%)
Thrombosis in device † A 1 / 456 (0.22%)0 / 463 (0%)
Hepatobiliary disorders
Bile duct stone † A 0 / 456 (0%)1 / 463 (0.22%)
Cholecystitis acute † A 1 / 456 (0.22%)0 / 463 (0%)
Cholelithiasis † A 2 / 456 (0.44%)0 / 463 (0%)
Hepatic failure † A 0 / 456 (0%)2 / 463 (0.43%)
Hepatocellular injury † A 0 / 456 (0%)1 / 463 (0.22%)
Jaundice cholestatic † A 0 / 456 (0%)1 / 463 (0.22%)
Liver disorder † A 0 / 456 (0%)1 / 463 (0.22%)
Immune system disorders
Hypersensitivity † A 1 / 456 (0.22%)0 / 463 (0%)
Hypogammaglobulinaemia † A 0 / 456 (0%)1 / 463 (0.22%)
Infections and infestations
Acute sinusitis † A 0 / 456 (0%)1 / 463 (0.22%)
Bacteraemia † A 0 / 456 (0%)1 / 463 (0.22%)
Bacterial infection † A 2 / 456 (0.44%)0 / 463 (0%)
Breast abscess † A 1 / 456 (0.22%)0 / 463 (0%)
Bronchiolitis † A 0 / 456 (0%)1 / 463 (0.22%)
Bronchitis † A 2 / 456 (0.44%)4 / 463 (0.86%)
Bronchopneumonia † A 0 / 456 (0%)6 / 463 (1.3%)
Bursitis infective † A 1 / 456 (0.22%)1 / 463 (0.22%)
Cardiac infection † A 0 / 456 (0%)1 / 463 (0.22%)
Cellulitis † A 1 / 456 (0.22%)2 / 463 (0.43%)
Clostridial infection † A 0 / 456 (0%)1 / 463 (0.22%)
Clostridium difficile sepsis † A 1 / 456 (0.22%)0 / 463 (0%)
Corona virus infection † A 1 / 456 (0.22%)0 / 463 (0%)
Device related infection † A 0 / 456 (0%)2 / 463 (0.43%)
Diverticulitis † A 0 / 456 (0%)2 / 463 (0.43%)
Encephalitic infection † A 0 / 456 (0%)1 / 463 (0.22%)
Erysipelas † A 0 / 456 (0%)1 / 463 (0.22%)
Escherichia bacteraemia † A 0 / 456 (0%)1 / 463 (0.22%)
Escherichia urinary tract infection † A 0 / 456 (0%)1 / 463 (0.22%)
Febrile infection † A 0 / 456 (0%)2 / 463 (0.43%)
Gastroenteritis † A 3 / 456 (0.66%)3 / 463 (0.65%)
Gastroenteritis viral † A 1 / 456 (0.22%)1 / 463 (0.22%)
H1N1 influenza † A 0 / 456 (0%)1 / 463 (0.22%)
Herpes zoster † A 1 / 456 (0.22%)0 / 463 (0%)
Infection † A 0 / 456 (0%)4 / 463 (0.86%)
Infective exacerbation of bronchiectasis † A 1 / 456 (0.22%)0 / 463 (0%)
Infective exacerbation of chronic obstructive airways disease † A 1 / 456 (0.22%)1 / 463 (0.22%)
Influenza † A 0 / 456 (0%)3 / 463 (0.65%)
Listeriosis † A 0 / 456 (0%)1 / 463 (0.22%)
Lobar pneumonia † A 0 / 456 (0%)1 / 463 (0.22%)
Lower respiratory tract infection † A 4 / 456 (0.88%)4 / 463 (0.86%)
Lower respiratory tract infection viral † A 0 / 456 (0%)1 / 463 (0.22%)
Lung infection † A 3 / 456 (0.66%)4 / 463 (0.86%)
Necrotising ulcerative periodontitis † A 0 / 456 (0%)1 / 463 (0.22%)
Oral fungal infection † A 0 / 456 (0%)1 / 463 (0.22%)
Parainfluenzae virus infection † A 0 / 456 (0%)2 / 463 (0.43%)
Pharyngitis † A 1 / 456 (0.22%)0 / 463 (0%)
Pneumococcal infection † A 0 / 456 (0%)1 / 463 (0.22%)
Pneumocystis jiroveci pneumonia † A 1 / 456 (0.22%)0 / 463 (0%)
Pneumonia † A 39 / 456 (8.55%)28 / 463 (6.05%)
Pneumonia bacterial † A 1 / 456 (0.22%)1 / 463 (0.22%)
Pneumonia moraxella † A 1 / 456 (0.22%)0 / 463 (0%)
Pneumonia pneumococcal † A 0 / 456 (0%)1 / 463 (0.22%)
Pseudomembranous colitis † A 1 / 456 (0.22%)0 / 463 (0%)
Pulmonary sepsis † A 1 / 456 (0.22%)0 / 463 (0%)
Respiratory syncytial virus infection † A 1 / 456 (0.22%)1 / 463 (0.22%)
Respiratory tract infection † A 5 / 456 (1.1%)5 / 463 (1.08%)
Respiratory tract infection viral † A 1 / 456 (0.22%)2 / 463 (0.43%)
Sepsis † A 3 / 456 (0.66%)6 / 463 (1.3%)
Septic shock † A 3 / 456 (0.66%)4 / 463 (0.86%)
Sinusitis † A 0 / 456 (0%)1 / 463 (0.22%)
Staphylococcal infection † A 0 / 456 (0%)1 / 463 (0.22%)
Streptococcal bacteraemia † A 0 / 456 (0%)1 / 463 (0.22%)
Tracheobronchitis † A 0 / 456 (0%)1 / 463 (0.22%)
Upper respiratory tract infection † A 3 / 456 (0.66%)7 / 463 (1.51%)
Urinary tract infection † A 4 / 456 (0.88%)5 / 463 (1.08%)
Urosepsis † A 3 / 456 (0.66%)0 / 463 (0%)
Viral infection † A 0 / 456 (0%)1 / 463 (0.22%)
Viral upper respiratory tract infection † A 0 / 456 (0%)1 / 463 (0.22%)
Injury, poisoning and procedural complications
Chest injury † A 0 / 456 (0%)1 / 463 (0.22%)
Compression fracture † A 0 / 456 (0%)1 / 463 (0.22%)
Facial bones fracture † A 1 / 456 (0.22%)1 / 463 (0.22%)
Femoral neck fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Femur fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Foot fracture † A 0 / 456 (0%)1 / 463 (0.22%)
Fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Head injury † A 1 / 456 (0.22%)0 / 463 (0%)
Hip fracture † A 0 / 456 (0%)1 / 463 (0.22%)
Humerus fracture † A 0 / 456 (0%)3 / 463 (0.65%)
Infusion related reaction † A 0 / 456 (0%)2 / 463 (0.43%)
Ligament sprain † A 1 / 456 (0.22%)0 / 463 (0%)
Pubis fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Spinal compression fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Ulna fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Upper limb fracture † A 0 / 456 (0%)1 / 463 (0.22%)
Investigations
Blood cortisol decreased † A 0 / 456 (0%)1 / 463 (0.22%)
Blood creatinine increased † A 0 / 456 (0%)2 / 463 (0.43%)
Lymphocyte count decreased † A 1 / 456 (0.22%)0 / 463 (0%)
Platelet count decreased † A 3 / 456 (0.66%)2 / 463 (0.43%)
Troponin T increased † A 1 / 456 (0.22%)1 / 463 (0.22%)
Metabolism and nutrition disorders
Decreased appetite † A 2 / 456 (0.44%)0 / 463 (0%)
Dehydration † A 3 / 456 (0.66%)0 / 463 (0%)
Diabetes mellitus † A 1 / 456 (0.22%)2 / 463 (0.43%)
Diabetes mellitus inadequate control † A 1 / 456 (0.22%)0 / 463 (0%)
Hypercalcaemia † A 5 / 456 (1.1%)0 / 463 (0%)
Hyperglycaemia † A 1 / 456 (0.22%)3 / 463 (0.65%)
Hyperkalaemia † A 1 / 456 (0.22%)0 / 463 (0%)
Hypoglycaemia † A 0 / 456 (0%)1 / 463 (0.22%)
Hyponatraemia † A 1 / 456 (0.22%)0 / 463 (0%)
Hypovolaemia † A 0 / 456 (0%)1 / 463 (0.22%)
Tumour lysis syndrome † A 0 / 456 (0%)1 / 463 (0.22%)
Musculoskeletal and connective tissue disorders
Arthralgia † A 3 / 456 (0.66%)1 / 463 (0.22%)
Back pain † A 2 / 456 (0.44%)5 / 463 (1.08%)
Bone pain † A 0 / 456 (0%)3 / 463 (0.65%)
Flank pain † A 0 / 456 (0%)1 / 463 (0.22%)
Lumbar spinal stenosis † A 0 / 456 (0%)1 / 463 (0.22%)
Mobility decreased † A 0 / 456 (0%)1 / 463 (0.22%)
Muscular weakness † A 1 / 456 (0.22%)1 / 463 (0.22%)
Musculoskeletal chest pain † A 0 / 456 (0%)1 / 463 (0.22%)
Musculoskeletal pain † A 1 / 456 (0.22%)1 / 463 (0.22%)
Myalgia † A 0 / 456 (0%)1 / 463 (0.22%)
Osteoarthritis † A 0 / 456 (0%)1 / 463 (0.22%)
Osteonecrosis of jaw † A 0 / 456 (0%)1 / 463 (0.22%)
Pain in extremity † A 1 / 456 (0.22%)0 / 463 (0%)
Pathological fracture † A 1 / 456 (0.22%)0 / 463 (0%)
Rhabdomyolysis † A 0 / 456 (0%)1 / 463 (0.22%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia † A 0 / 456 (0%)1 / 463 (0.22%)
Basal cell carcinoma † A 0 / 456 (0%)2 / 463 (0.43%)
Bladder transitional cell carcinoma † A 0 / 456 (0%)1 / 463 (0.22%)
Colon cancer † A 0 / 456 (0%)1 / 463 (0.22%)
Meningeal neoplasm † A 0 / 456 (0%)1 / 463 (0.22%)
Metastases to spine † A 0 / 456 (0%)1 / 463 (0.22%)
Multiple myeloma † A 1 / 456 (0.22%)5 / 463 (1.08%)
Oesophageal squamous cell carcinoma † A 1 / 456 (0.22%)0 / 463 (0%)
Plasmacytoma † A 0 / 456 (0%)5 / 463 (1.08%)
Pleural mesothelioma † A 1 / 456 (0.22%)0 / 463 (0%)
Rectal cancer † A 0 / 456 (0%)1 / 463 (0.22%)
Squamous cell carcinoma † A 1 / 456 (0.22%)0 / 463 (0%)
Tongue neoplasm malignant stage unspecified † A 0 / 456 (0%)1 / 463 (0.22%)
Nervous system disorders
Acquired epileptic aphasia † A 0 / 456 (0%)1 / 463 (0.22%)
Central nervous system lesion † A 1 / 456 (0.22%)0 / 463 (0%)
Cerebrovascular accident † A 0 / 456 (0%)3 / 463 (0.65%)
Convulsion † A 1 / 456 (0.22%)0 / 463 (0%)
Depressed level of consciousness † A 1 / 456 (0.22%)0 / 463 (0%)
Dizziness † A 1 / 456 (0.22%)0 / 463 (0%)
Headache † A 0 / 456 (0%)2 / 463 (0.43%)
Hypercapnic coma † A 0 / 456 (0%)1 / 463 (0.22%)
Ischaemic stroke † A 0 / 456 (0%)1 / 463 (0.22%)
Lethargy † A 0 / 456 (0%)1 / 463 (0.22%)
Neuralgia † A 1 / 456 (0.22%)1 / 463 (0.22%)
Neuropathy peripheral † A 2 / 456 (0.44%)1 / 463 (0.22%)
Paraparesis † A 1 / 456 (0.22%)0 / 463 (0%)
Paraplegia † A 0 / 456 (0%)1 / 463 (0.22%)
Posterior reversible encephalopathy syndrome † A 0 / 456 (0%)2 / 463 (0.43%)
Radiculopathy † A 0 / 456 (0%)1 / 463 (0.22%)
Spinal cord compression † A 2 / 456 (0.44%)3 / 463 (0.65%)
Syncope † A 4 / 456 (0.88%)0 / 463 (0%)
Transient ischaemic attack † A 2 / 456 (0.44%)0 / 463 (0%)
Psychiatric disorders
Confusional state † A 4 / 456 (0.88%)4 / 463 (0.86%)
Depression † A 1 / 456 (0.22%)1 / 463 (0.22%)
Dysthymic disorder † A 1 / 456 (0.22%)0 / 463 (0%)
Mental disorder † A 0 / 456 (0%)1 / 463 (0.22%)
Psychotic disorder † A 0 / 456 (0%)1 / 463 (0.22%)
Renal and urinary disorders
Albuminuria † A 0 / 456 (0%)1 / 463 (0.22%)
Anuria † A 0 / 456 (0%)1 / 463 (0.22%)
Nephropathy † A 1 / 456 (0.22%)1 / 463 (0.22%)
Nephrotic syndrome † A 0 / 456 (0%)1 / 463 (0.22%)
Renal failure † A 0 / 456 (0%)4 / 463 (0.86%)
Renal failure acute † A 5 / 456 (1.1%)8 / 463 (1.73%)
Renal impairment † A 1 / 456 (0.22%)1 / 463 (0.22%)
Urinary retention † A 1 / 456 (0.22%)0 / 463 (0%)
Reproductive system and breast disorders
Prostatomegaly † A 1 / 456 (0.22%)0 / 463 (0%)
Uterine haemorrhage † A 0 / 456 (0%)1 / 463 (0.22%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema † A 1 / 456 (0.22%)3 / 463 (0.65%)
Acute respiratory distress syndrome † A 1 / 456 (0.22%)1 / 463 (0.22%)
Acute respiratory failure † A 1 / 456 (0.22%)0 / 463 (0%)
Asthma † A 1 / 456 (0.22%)3 / 463 (0.65%)
Bronchopneumopathy † A 1 / 456 (0.22%)0 / 463 (0%)
Chronic obstructive pulmonary disease † A 1 / 456 (0.22%)2 / 463 (0.43%)
Dyspnoea † A 1 / 456 (0.22%)14 / 463 (3.02%)
Epistaxis † A 1 / 456 (0.22%)1 / 463 (0.22%)
Hypoxia † A 1 / 456 (0.22%)0 / 463 (0%)
Interstitial lung disease † A 0 / 456 (0%)1 / 463 (0.22%)
Lung disorder † A 1 / 456 (0.22%)1 / 463 (0.22%)
Pleural effusion † A 1 / 456 (0.22%)2 / 463 (0.43%)
Pneumonitis † A 1 / 456 (0.22%)2 / 463 (0.43%)
Pulmonary arterial hypertension † A 0 / 456 (0%)1 / 463 (0.22%)
Pulmonary embolism † A 3 / 456 (0.66%)10 / 463 (2.16%)
Pulmonary hypertension † A 0 / 456 (0%)3 / 463 (0.65%)
Pulmonary oedema † A 1 / 456 (0.22%)2 / 463 (0.43%)
Respiratory failure † A 0 / 456 (0%)4 / 463 (0.86%)
Skin and subcutaneous tissue disorders
Drug eruption † A 0 / 456 (0%)1 / 463 (0.22%)
Eczema † A 0 / 456 (0%)1 / 463 (0.22%)
Erythema multiforme † A 1 / 456 (0.22%)0 / 463 (0%)
Pruritus generalised † A 1 / 456 (0.22%)0 / 463 (0%)
Purpura † A 0 / 456 (0%)1 / 463 (0.22%)
Surgical and medical procedures
Colostomy closure † A 0 / 456 (0%)1 / 463 (0.22%)
Haemorrhoid operation † A 0 / 456 (0%)1 / 463 (0.22%)
Vascular disorders
Aortic aneurysm † A 0 / 456 (0%)1 / 463 (0.22%)
Circulatory collapse † A 1 / 456 (0.22%)1 / 463 (0.22%)
Deep vein thrombosis † A 2 / 456 (0.44%)4 / 463 (0.86%)
Haematoma † A 0 / 456 (0%)1 / 463 (0.22%)
Hypertension † A 0 / 456 (0%)1 / 463 (0.22%)
Hypertensive crisis † A 0 / 456 (0%)1 / 463 (0.22%)
Hypotension † A 4 / 456 (0.88%)0 / 463 (0%)
Orthostatic hypotension † A 3 / 456 (0.66%)0 / 463 (0%)
Thrombophlebitis † A 0 / 456 (0%)1 / 463 (0.22%)
Venous thrombosis limb † A 0 / 456 (0%)1 / 463 (0.22%)
†Indicates events were collected by systematic assessment.
ATerm from vocabulary, MedDRA 15.1
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
  Bortezomib + DEXCarfilzomib + DEX
 Affected / At Risk (%)Affected / At Risk (%)
Total 427 / 456 (93.64%)440 / 463 (95.03%)
Blood and lymphatic system disorders
Anaemia † A 123 / 456 (26.97%)181 / 463 (39.09%)
Lymphopenia † A 24 / 456 (5.26%)30 / 463 (6.48%)
Neutropenia † A 25 / 456 (5.48%)24 / 463 (5.18%)
Thrombocytopenia † A 77 / 456 (16.89%)95 / 463 (20.52%)
Eye disorders
Conjunctivitis † A 30 / 456 (6.58%)12 / 463 (2.59%)
Gastrointestinal disorders
Abdominal distension † A 26 / 456 (5.7%)19 / 463 (4.1%)
Abdominal pain † A 35 / 456 (7.68%)29 / 463 (6.26%)
Abdominal pain upper † A 35 / 456 (7.68%)18 / 463 (3.89%)
Constipation † A 122 / 456 (26.75%)68 / 463 (14.69%)
Diarrhoea † A 175 / 456 (38.38%)141 / 463 (30.45%)
Dyspepsia † A 24 / 456 (5.26%)31 / 463 (6.7%)
Nausea † A 80 / 456 (17.54%)89 / 463 (19.22%)
Vomiting † A 39 / 456 (8.55%)63 / 463 (13.61%)
General disorders
Asthenia † A 74 / 456 (16.23%)94 / 463 (20.3%)
Chest pain † A 17 / 456 (3.73%)37 / 463 (7.99%)
Fatigue † A 130 / 456 (28.51%)136 / 463 (29.37%)
Oedema peripheral † A 78 / 456 (17.11%)101 / 463 (21.81%)
Pyrexia † A 61 / 456 (13.38%)124 / 463 (26.78%)
Infections and infestations
Bronchitis † A 39 / 456 (8.55%)73 / 463 (15.77%)
Nasopharyngitis † A 51 / 456 (11.18%)66 / 463 (14.25%)
Respiratory tract infection † A 26 / 456 (5.7%)30 / 463 (6.48%)
Upper respiratory tract infection † A 64 / 456 (14.04%)91 / 463 (19.65%)
Urinary tract infection † A 25 / 456 (5.48%)28 / 463 (6.05%)
Investigations
Blood creatinine increased † A 26 / 456 (5.7%)47 / 463 (10.15%)
Creatinine renal clearance decreased † A 18 / 456 (3.95%)26 / 463 (5.62%)
Lymphocyte count decreased † A 18 / 456 (3.95%)39 / 463 (8.42%)
Platelet count decreased † A 39 / 456 (8.55%)54 / 463 (11.66%)
Metabolism and nutrition disorders
Decreased appetite † A 56 / 456 (12.28%)40 / 463 (8.64%)
Hyperglycaemia † A 40 / 456 (8.77%)48 / 463 (10.37%)
Hyperuricaemia † A 9 / 456 (1.97%)27 / 463 (5.83%)
Hypocalcaemia † A 18 / 456 (3.95%)24 / 463 (5.18%)
Hypokalaemia † A 45 / 456 (9.87%)50 / 463 (10.8%)
Hypophosphataemia † A 25 / 456 (5.48%)26 / 463 (5.62%)
Musculoskeletal and connective tissue disorders
Arthralgia † A 45 / 456 (9.87%)47 / 463 (10.15%)
Back pain † A 71 / 456 (15.57%)84 / 463 (18.14%)
Bone pain † A 38 / 456 (8.33%)47 / 463 (10.15%)
Muscle spasms † A 27 / 456 (5.92%)86 / 463 (18.57%)
Muscular weakness † A 43 / 456 (9.43%)36 / 463 (7.78%)
Musculoskeletal chest pain † A 17 / 456 (3.73%)37 / 463 (7.99%)
Pain in extremity † A 49 / 456 (10.75%)47 / 463 (10.15%)
Nervous system disorders
Dizziness † A 66 / 456 (14.47%)37 / 463 (7.99%)
Dysgeusia † A 25 / 456 (5.48%)14 / 463 (3.02%)
Headache † A 46 / 456 (10.09%)79 / 463 (17.06%)
Neuralgia † A 70 / 456 (15.35%)8 / 463 (1.73%)
Neuropathy peripheral † A 121 / 456 (26.54%)43 / 463 (9.29%)
Paraesthesia † A 74 / 456 (16.23%)36 / 463 (7.78%)
Peripheral sensory neuropathy † A 67 / 456 (14.69%)27 / 463 (5.83%)
Polyneuropathy † A 24 / 456 (5.26%)5 / 463 (1.08%)
Tremor † A 23 / 456 (5.04%)10 / 463 (2.16%)
Psychiatric disorders
Anxiety † A 31 / 456 (6.8%)17 / 463 (3.67%)
Insomnia † A 119 / 456 (26.1%)117 / 463 (25.27%)
Respiratory, thoracic and mediastinal disorders
Cough † A 64 / 456 (14.04%)115 / 463 (24.84%)
Dyspnoea † A 60 / 456 (13.16%)127 / 463 (27.43%)
Oropharyngeal pain † A 18 / 456 (3.95%)26 / 463 (5.62%)
Skin and subcutaneous tissue disorders
Pruritus † A 24 / 456 (5.26%)25 / 463 (5.4%)
Rash † A 27 / 456 (5.92%)27 / 463 (5.83%)
Vascular disorders
Flushing † A 7 / 456 (1.54%)24 / 463 (5.18%)
Hypertension † A 40 / 456 (8.77%)114 / 463 (24.62%)
Hypotension † A 36 / 456 (7.89%)23 / 463 (4.97%)
†Indicates events were collected by systematic assessment.
ATerm from vocabulary, MedDRA 15.1
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Certain Agreements:
Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between the Principal Investigator and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact:
Name/Official Title:
 Study Director
Organization:
 Amgen, Inc.
Phone:
 866-572-6436
Email:
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