ENDEAVOR: Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01568866
• Collaborator: (none)
• Enrollment: 929
• Locations: 241
• Arms: 2
• Actual Duration (Months): 67.5
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Carfilzomib; Drug: Bortezomib; Drug: Dexamethasone	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 929 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Phase 3 Study of Carfilzomib Plus Dexamethasone vs. Bortezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma
• Actual Study Start Date: Jun 20, 2012
• Actual Primary Completion Date: Nov 10, 2014
• Actual Study Completion Date: Feb 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
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.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [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 [From randomization until the data cut-off date of 03 January 2017; median follow-up time for OS was 36.9 and 37.5 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 [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 [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 [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) [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) [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) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

1. 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.

2. 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).

3. 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).

4. 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.

5. Males and females ≥ 18 years of age.

6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2.

7. 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.

8. Left ventricular ejection fraction (LVEF) ≥ 40%.

9. Absolute neutrophil count (ANC) ≥ 1000/mm³ within 21 days prior to randomization. Screening ANC should be independent of growth factor support for ≥ 1 week.

10. 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.

11. 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.

1. 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.

1. Written informed consent in accordance with federal, local, and institutional guidelines.

2. 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).

3. 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

1. Patients with myelodysplastic syndrome.

2. Significant neuropathy (Grades 3 to 4, or Grade 2 with pain) within 14 days prior to randomization.

3. Female patients who are pregnant or lactating.

4. Known history of allergy to Captisol(a cyclodextrin derivative used to solubilize carfilzomib).

5. Patients with hypersensitivity to carfilzomib, Velcade, boron, or mannitol.

6. Patients with contraindication to dexamethasone.

7. 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.

8. Ongoing graft-vs-host disease.

9. Patients with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence St. Joseph Medical Center	Burbank	California	United States
2	UCSD Moore Cancer Center	La Jolla	California	United States
3	UCLA Medical Center	Los Angeles	California	United States
4	Central Coast Medical Oncology Group	Santa Maria	California	United States
5	Colorado Blood Cancer Institute	Denver	Colorado	United States
6	MAB Oncology/Hematology	Melbourne	Florida	United States
7	Palm Beach Cancer Institute	West Palm Beach	Florida	United States
8	Winship Cancer Institute	Atlanta	Georgia	United States
9	Hematology Oncology of Indiana, PC	Indianapolis	Indiana	United States
10	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States
11	Associates in Oncology/Hematology PC	Rockville	Maryland	United States
12	University of Michigan	Ann Arbor	Michigan	United States
13	University of Kansas	Kansas City	Missouri	United States
14	Hackensack University Medical Ctr	Hackensack	New Jersey	United States
15	Montefiore Medical Center	Bronx	New York	United States
16	Clinical Research Alliance Inc.	New York	New York	United States
17	Weill Cornell Medical College	New York	New York	United States
18	Wake Forest University Health Sciences, Section on Hematology and Oncology	Winston-Salem	North Carolina	United States
19	Gabrail Cancer Center	Canton	Ohio	United States
20	The Christ Hospital	Cincinnati	Ohio	United States
21	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania	United States
22	Hematology/Oncology Associates of SC	Greenville	South Carolina	United States
23	Vanderbilt Ingram Cancer Center	Nashville	Tennessee	United States
24	MD Anderson	Houston	Texas	United States
25	The Methodist Cancer Center	Houston	Texas	United States
26	Scott & White Memorial Hospital	Temple	Texas	United States
27	University of Utah School of Medicine	Salt Lake City	Utah	United States
28	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia
29	St. Vincent's Public Hospital Sydney	Darlinghurst	New South Wales	Australia
30	Saint George Hospital	Kogarah	New South Wales	Australia
31	Liverpool Hospital	Liverpool	New South Wales	Australia
32	Royal North Shore Hospital	Saint Leonards	New South Wales	Australia
33	Calvary Mater Newcastle	Waratah	New South Wales	Australia
34	Westmead Hospital	Westmead	New South Wales	Australia
35	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia
36	Haematology & Oncology Clinics of Australia	South Brisbane	Queensland	Australia
37	Haematology and Oncology Clinics of Australia at Chermside	South Brisbane	Queensland	Australia
38	Haematology and Oncology Clinics of Australia at Wesley	South Brisbane	Queensland	Australia
39	Royal Adelaide Hospital	Adelaide	South Australia	Australia
40	The Queen Elizabeth Hospital	Woodville	South Australia	Australia
41	Box Hill Hospital	Box Hill	Victoria	Australia
42	Monash Medical Centre	Clayton	Victoria	Australia
43	Saint Vincent's Hospital	East Melbourne	Victoria	Australia
44	Western Hospital	Footscray	Victoria	Australia
45	The Alfred Hospital	Melbourne	Victoria	Australia
46	Sunshine Hospital	St. Albans	Victoria	Australia
47	Fremantle Hospital	Fremantle	Western Australia	Australia
48	Royal Perth Hospital	Perth	Western Australia	Australia
49	Medizinische Universität Innsbruck	Innsbruck	Tyrol	Austria
50	Krankenhaus der Elisabethinen Linz, I Interne Abteilung	Linz	Upper Austria	Austria
51	Wilhelminenspital der Stadt Wien	Wien	Vienna	Austria
52	Universitair Ziekenhuis Leuven	Leuven	Flemish Brabant	Belgium
53	Cliniques Universitaires UCL de Mont-Godinne	Yvoir	Namur	Belgium
54	Universitair Ziekenhuis Gent	Ghent	Oost-vlaanderen	Belgium
55	Ziekenhuis Netwerk Antwerpen	Antwerp		Belgium
56	Cliniques Universitaires Saint Luc	Brussels		Belgium
57	Universitair Ziekenhuis Brussel	Brussels		Belgium
58	Liga Norte Riograndense Contra o Câncer	Natal	RIO Grande DO Norte	Brazil
59	Clínica de Oncologia de Porto Alegre	Porto Alegre	RIO Grande DO SUL	Brazil
60	Hospital de Clínicas de Porto Alegre	Porto Alegre	RIO Grande DO SUL	Brazil
61	Hospital São Lucas da PUCRS	Porto Alegre	RIO Grande DO SUL	Brazil
62	Hemocentro Campinas-Unicamp	Campinas	SAO Paulo	Brazil
63	Hospital Universitário Clementino Fraga Filho da Universidade Federal do Rio de Janeiro	Rio de Janeiro		Brazil
64	Instituto Centros Oncológicos Integrados de Educação e Pesquisa	Rio de Janeiro		Brazil
65	Instituto Nacional do Câncer-INCA	Rio de Janeiro		Brazil
66	Irmandade da Santa Casa de Misericórdia de São Paulo	São Paulo		Brazil
67	Military Medical Academy Hospital for Active Treatment	Sofia	Sofiya	Bulgaria
68	Shato, Ead	Sofia	Sofiya	Bulgaria
69	University Multiprofile Hospital for Active Treatment "Sveti Georgi" EAD	Plovdiv		Bulgaria
70	Multiprofile Hospital for Active Treatment, "Sveta Marina''	Varna		Bulgaria
71	University of Alberta Hospital	Edmonton	Alberta	Canada
72	British Columbia Cancer Agency	Kelowna	British Columbia	Canada
73	Saint John Regional Hospital	Saint John	New Brunswick	Canada
74	Queen Elizabeth II Health Science Centre	Halifax	Nova Scotia	Canada
75	London Health Sciences Centre	London	Ontario	Canada
76	The Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario	Canada
77	Windsor Regional Hospital	Windsor	Ontario	Canada
78	Hopital Maisonneuve-Rosemont	Montréal	Quebec	Canada
79	Fakultní nemocnice Královské Vinohrady	Praha 10	Praha	Czechia
80	Fakultní nemocnice Olomouc	Olomouc	Severomoravsky KRAJ	Czechia
81	FN Ostrava	Ostrava	Severomoravsky KRAJ	Czechia
82	Fakultní nemocnice Hradec Králové	Hradec Kralové	Vychodocesky KRAJ	Czechia
83	Fakultní nemocnice Brno	Brno		Czechia
84	Všeobecná fakultní nemocnice v Praze	Praha		Czechia
85	Centre Hospitalier de la Cote Basque	Bayonne	Aquitaine	France
86	Centre Hospitalier Universitaire Brest	Brest Cedex	Bretagne	France
87	Centre Hospitalier Universitaire de Rennes, Hôpital Pontchaillou	Rennes Cedex 9	Bretagne	France
88	Hopital Hotel-Dieu - Service d'Hematologie	Nantes	Cedex 1	France
89	Centre Henri-Becquerel	Rouen Cedex 1	Haute-normandie	France
90	Centre Hospitalier de Versailles	Le Chesnay	Ile-de-france	France
91	Hôpital Saint Louis	Paris	Ile-de-france	France
92	Hôpital Saint-Antoine	Paris	Ile-de-france	France
93	Hôpital Claude Huriez	Lille Cedex	NORD Pas-de-calais	France
94	Hôpital Hôtel-Dieu	Nantes cedex 1	PAYS DE LA Loire	France
95	Institut Paoli Calmettes	Marseille Cedex 9	Provence Alpes COTE D'azur	France
96	Centre Hospitalier Lyon Sud	Pierre Bénite Cedex	Rhone-alpes	France
97	Universitätsklinik Heidelberg	Heidelberg	Baden-wuerttemberg	Germany
98	Universitätsklinikum Tübingen	Tübingen	Baden-wuerttemberg	Germany
99	Universitätsklinikum Ulm	Ulm	Baden-wuerttemberg	Germany
100	Medizinische Klinik der Universität Würzburg	Würzburg	Bayern	Germany
101	Medizinische Hochschule Hannover	Hannover	Niedersachsen	Germany
102	Universitätsklinikum Aachen	Aachen	Nordrhein-westfalen	Germany
103	Universitätsklinikum Münster	Münster	Nordrhein-westfalen	Germany
104	Universitätsmedizin der Johannes Gutenberg Universität	Mainz	Rheinland-pfalz	Germany
105	Universitätsklinikum des Saarlandes	Homburg / Saar	Saarland	Germany
106	Klinikum Chemnitz gGmbH	Chemnitz	Sachsen	Germany
107	Universitätsklinikum Carl Gustav Carus, Med. Klinik und Poliklinik I	Dresden	Sachsen	Germany
108	Universitätsklinikum Leipzig	Leipzig	Sachsen	Germany
109	Universitätsklinikum Jena	Jena	Thuringen	Germany
110	Universitatsklinikum Freiburg	Freiburg		Germany
111	Universitätsklinikum Hamburg Eppendorf	Hamburg		Germany
112	Alexandra General Hospital	Athens	Attica	Greece
113	Bács-Kiskun Megyei Kórház Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza	Kecskemét	Bacs-kiskun	Hungary
114	Pécsi Tudományegyetem	Pécs	Baranya	Hungary
115	Szegedi Tudományegyetem	Szeged	Csongrad	Hungary
116	Debreceni Egyetem Klinikai Központ	Debrecen	Hajdu-bihar	Hungary
117	Egyesített Szent István és Szent László Kórház-Rendelointézet	Budapest		Hungary
118	Somogy Megyei Kaposi Mac okato Korhoz	Kaposvár		Hungary
119	Somogy Megyei Kaposi Mór Oktató Kórház	Kaposvár		Hungary
120	Rambam Health Corp.	Haifa		Israel
121	Hadassah Medical Center	Jerusalem		Israel
122	Meir Medical Center	Kfar Saba		Israel
123	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel
124	The Chaim Sheba Medical Center at Tel Hashomer	Tel Hashomer		Israel
125	IRCCS Centro di Riferimento Oncologico di Basilicata di Rionero in Vulture	Rionero in Vulture	Potenza	Italy
126	Azienda Ospedaliero-Univesitaria San Luigi Gonzaga	Orbassano	Torino	Italy
127	Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona	Ancona		Italy
128	Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi	Bologna		Italy
129	Azienda Ospedaliera Spedali Civili di Brescia	Brescia		Italy
130	IRCCS Azienda Ospedaliera Universitaria San Martino	Genova		Italy
131	Azienda Ospedaliera Universitaria Maggiore della Carità	Novara		Italy
132	Azienda Unità Sanitaria Locale di Piacenza-Ospedale Guglielmo da Saliceto	Piacenza		Italy
133	Azienda Ospedaliera Pisana Ospedale Santa Chiara	Pisa		Italy
134	Aienda Policknico Umberto I di Roma	Roma		Italy
135	Azienda Policknico Umberto l di Roma	Roma		Italy
136	Università Tor Vergata Ospedale Sant Eugenio	Roma		Italy
137	Azienda Ospedaliera Universitaria Senese - Policlinico S. Maria alle Scotte	Siena		Italy
138	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino		Italy
139	Nagoya City University Hospital	Nagoya City	Aichi	Japan
140	Toyohashi Municipal Hospital	Toyohashi	Aichi	Japan
141	National Hospital Organization Kyushu Cancer Center	Fukuoka-city	Fukuoka	Japan
142	Ogaki Municipal Hospital	Ogaki City	Gifu	Japan
143	Gunma University Hospital	Maebashi	Gunma	Japan
144	National Hospital Organization Nishigunma National Hospital	Shibukawa	Gunma	Japan
145	Sapporo Medical University Hospital	Sapporo	Hokkaido	Japan
146	Kobe City Medical Center General Hospital	Kobe	Hyogo	Japan
147	Tokai University Hospital	Isehara	Kanagawa	Japan
148	Niigata Cancer Center Hospital	Niigata-city	Niigata	Japan
149	Osaka University Hospital	Suita	Osaka	Japan
150	Saitama Medical Center	Kawagoe	Saitama	Japan
151	Tochigi Cancer Center	Utsunomiya	Tochigi	Japan
152	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan
153	The Cancer Institute Hospital Of Japanese Foundation For Cancer Research	Koto-ku	Tokyo	Japan
154	Toranornon Hospital	Shinagawa	Tokyo	Japan
155	Tokyo Medical University Hospital	Shinjuku	Tokyo	Japan
156	National Hospital Organization Disaster Medical Center	Tachikawa	Tokyo	Japan
157	Kyushu University Hospital	Fukuoka		Japan
158	Social Insurance Kyoto Hospital of All Japan Federation of Social Insurance Associations	Kyoto		Japan
159	University Hospital, Kyoto Prefectural University of Medicine	Kyoto		Japan
160	National Hospital Organization Okayama Medical Center	Okayama		Japan
161	Tokushima Prefectural Central Hospital	Tokushima		Japan
162	Japanese Red Cross Medical Center	Tokyo		Japan
163	Gachon University Gil Medical Center	Incheon	Gyeonggi-Do	Korea, Republic of
164	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of
165	Pusan National University Hospital	Busan	Gyeongsangnam-Do	Korea, Republic of
166	Kyungpook National University Hospital	Daegu		Korea, Republic of
167	Asan Medical Center	Seoul		Korea, Republic of
168	Samsung Medical Center	Seoul		Korea, Republic of
169	Seoul National University Hospital	Seoul		Korea, Republic of
170	Seoul Saint Mary's Hospital	Seoul		Korea, Republic of
171	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of
172	North Shore Hospital	North Shore City	Auckland	New Zealand
173	Middlemore Hospital	Otahuhu	Auckland	New Zealand
174	Auckland City Hospital	Grafton	Aukland	New Zealand
175	Christchurch Hospital	Christchurch		New Zealand
176	Dunedin Hospital	Dunedin		New Zealand
177	Specjalistyczny Szpital Miejski im. Mikolaja Kopernika	Torun	Kujawsko-Pomorskie	Poland
178	Zamojski Szpital Niepubliczny Sp. z o.o.	Zamosc	Lubelskie	Poland
179	Szpital Uniwersytecki w Krakowie	Krakow	Malopolskie	Poland
180	Instytut Hematologii i Transfuzjologii	Warszawa	Mazowieckie	Poland
181	Uniwersyteckie Centrum Kliniczne	Gdansk	Pomorskie	Poland
182	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespól Szpitali Miejskich	Chorzów	Slaskie	Poland
183	Szpital Kliniczny Przemienienia Panskiego Uniwersytetu Medycznego im K. Marcinkowskiego w Poznaniu	Poznan	Wielkopolskie	Poland
184	Spitalul Universitar de Urgenta Bucuresti	Bucharest	Bucuresti	Romania
185	Policlinica de Diagnostic Rapid SA, Compartiment Medical Oncologie-Hematologie	Brasov		Romania
186	Spitalul Clinic Judetean de Urgenta Brasov (Bumbea, Horia)	Brasov		Romania
187	Institutul Clinic Fundeni	Bucuresti		Romania
188	Institutul Regional de Oncologie Iasi	Iasi		Romania
189	Republican Clinical Hospital #1	Izhevsk		Russian Federation
190	City Clinical Hospital n.a. S. P. Botkin	Moscow		Russian Federation
191	Non-state Healthcare Institution "N.A. Semashko Central Clinical Hospital #2 of JSC "Russian Railway	Moscow		Russian Federation
192	Ryazan Regional Clinical Hospital	Ryazan		Russian Federation
193	Clinical Hospital Number 31	Saint Petersburg		Russian Federation
194	Federal Almazov Medical Research Centre	Saint Petersburg		Russian Federation
195	FGU Russian Scientific Research Institute of Hematology and Transfusiology	Saint Petersburg		Russian Federation
196	First Saint Petersburg I.P. Pavlov State Medical University	Saint Petersburg		Russian Federation
197	GUZ Samara Regional Clinical Hospital n.a. M.I. Kalinin	Samara		Russian Federation
198	National University Cancer Institute	Singapore		Singapore
199	Singapore General Hospital	Singapore		Singapore
200	Singapore Oncology Consultants	Singapore		Singapore
201	Univerzitná nemocnica Bratislava	Bratislava		Slovakia
202	Hospital Son Llàtzer	Palma de Mallorca	Baleares	Spain
203	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain
204	Hospital Clinic I Provincial de Barcelona	Barcelona		Spain
205	Institut Universitari Dexeus	Barcelona		Spain
206	Centro Integral Oncológico Clara Campal, Hospital de Madrid Norte-San Chinarro	Madrid		Spain
207	Hospital Universitario 12 de Octubre	Madrid		Spain
208	Hospital Universitario La Princesa	Madrid		Spain
209	Hospital Clínico Universitario de Salamanca	Salamanca		Spain
210	Hospital Universitario Virgen del Rocio	Sevilla		Spain
211	Hospital Universitari i Politecnic La Fé de Valencia	Valencia		Spain
212	Chang Gung Memorial Hospital	Kaohsiung		Taiwan
213	China Medical University Hospital	Taichung		Taiwan
214	National Cheng-Kung University Hospital	Tainan		Taiwan
215	National Taiwan University Hospital	Taipei		Taiwan
216	Taipei Veterans General Hospital	Taipei		Taiwan
217	Chang Gung Medical Foundation-LinKou Branch	Tao-Yuan		Taiwan
218	King Chulalongkorn Memorial Hospital	Bangkok	Bangkok Metropolis	Thailand
219	Ramathibodi Hospital	Bangkok	Bangkok Metropolis	Thailand
220	Srinagarind Hospital	Khon Kaen		Thailand
221	City Hematology Center	Dnepropetrovsk	Dnipropretrovsk	Ukraine
222	Municipal Institution of Health Protection "Clinical Hospital #8"	Kharkov	Kharkiv	Ukraine
223	Cherkassy Regional Oncology Center	Cherkassy		Ukraine
224	MI "Dnipropetrovsk City Multifield Clinical Hospital #4" of Dnipropetrovsk Regional Council", City Hematology Center	Dnipropetrovsk		Ukraine
225	Institute of Urgent and Reparative Surgury of Ukraine Academy of Medical Sciences	Donetsk		Ukraine
226	Khmelnytsky Regional Clinical Hospital	Khmelnytsky		Ukraine
227	Khmelnytsky Regional Hospital, Department of Hematology	Khmelnytsky		Ukraine
228	National Institute of Cancer, Oncohematology Department	Kiev		Ukraine
229	Kyiv Bone Marrow Transplantation Center	Kyiv		Ukraine
230	Lviv Regional Oncology Dispensary	Lviv		Ukraine
231	Lviv State Oncology Regional Treatment-Prophylactic Center, Department of Chemotherapy	Lviv		Ukraine
232	Regional Clinical Hospital	Mykolayiv		Ukraine
233	Royal Free Hospital	London	England	United Kingdom
234	University College Hospital	London	England	United Kingdom
235	Manchester Royal Infirmary	Manchester	England	United Kingdom
236	Nottingham University Hospitals NHS Trust	Nottingham	England	United Kingdom
237	Churchill Hospital	Oxford	England	United Kingdom
238	Derriford Hospital	Plymouth	England	United Kingdom
239	Royal Hallamshire Hospital	Sheffield	England	United Kingdom
240	Royal Marsden Hospital	Surrey	England	United Kingdom
241	Royal Wolverhampton Hospitals Trust	Wolverhampton	England	United Kingdom

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Chari A, Stewart AK, Russell SD, Moreau P, Herrmann J, Banchs J, Hajek R, Groarke J, Lyon AR, Batty GN, Ro S, Huang M, Iskander KS, Lenihan D. Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials. Blood Adv. 2018 Jul 10;2(13):1633-1644. doi: 10.1182/bloodadvances.2017015545. Review.
• Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. doi: 10.1038/leu.2016.390. Epub 2016 Dec 27.
• Dimopoulos M, Siegel D, White DJ, Boccia R, Iskander KS, Yang Z, Kimball AS, Mezzi K, Ludwig H, Niesvizky R. Carfilzomib vs bortezomib in patients with multiple myeloma and renal failure: a subgroup analysis of ENDEAVOR. Blood. 2019 Jan 10;133(2):147-155. doi: 10.1182/blood-2018-06-860015. Epub 2018 Nov 26.
• Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. doi: 10.1016/S1470-2045(17)30578-8. Epub 2017 Aug 23. Erratum in: Lancet Oncol. 2017 Oct;18(10):e562.
• Hari P, Mateos MV, Abonour R, Knop S, Bensinger W, Ludwig H, Song K, Hajek R, Moreau P, Siegel DS, Feng S, Obreja M, Aggarwal SK, Iskander K, Goldschmidt H. Efficacy and safety of carfilzomib regimens in multiple myeloma patients relapsing after autologous stem cell transplant: ASPIRE and ENDEAVOR outcomes. Leukemia. 2017 Dec;31(12):2630-2641. doi: 10.1038/leu.2017.122. Epub 2017 Apr 25.
• Ludwig H, Dimopoulos MA, Moreau P, Chng WJ, Goldschmidt H, Hájek R, Facon T, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Palumbo A, Gillenwater HH, Mohamed N, Aggarwal S, Feng S, Joshua D. Carfilzomib and dexamethasone vs bortezomib and dexamethasone in patients with relapsed multiple myeloma: results of the phase 3 study ENDEAVOR (NCT01568866) according to age subgroup. Leuk Lymphoma. 2017 Oct;58(10):2501-2504. doi: 10.1080/10428194.2017.1298755. Epub 2017 Mar 17.
• Ludwig H, Moreau P, Dimopoulos MA, Mateos MV, Kaiser M, Hajek R, Feng S, Cocks K, Buchanan J, Weisel K. Health-related quality of life in the ENDEAVOR study: carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed/refractory multiple myeloma. Blood Cancer J. 2019 Feb 22;9(3):23. doi: 10.1038/s41408-019-0181-0.
• Mateos MV, Goldschmidt H, San-Miguel J, Mikhael J, DeCosta L, Zhou L, Obreja M, Blaedel J, Szabo Z, Leleu X. Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: A subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials. Hematol Oncol. 2018 Apr;36(2):463-470. doi: 10.1002/hon.2499. Epub 2018 Feb 15.
• Moreau P, Joshua D, Chng WJ, Palumbo A, Goldschmidt H, Hájek R, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Aggarwal S, Feng S, Dimopoulos MA. Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study. Leukemia. 2017 Jan;31(1):115-122. doi: 10.1038/leu.2016.186. Epub 2016 Jul 4.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01568866
• Other Study ID Numbers: 2011-003; 2012-000128-16
• First Posted: Apr 2, 2012
• Last Update Posted: Apr 10, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by Amgen: multiple myeloma; relapsed multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Bortezomib

Study Results

Participant Flow

Recruitment Details	Adults with relapsed multiple myeloma were enrolled between 20 June 2012 and 30 June 2014 at 198 centers in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Results are reported as of the data cut-off date of 03 January 2017, the pre-specified 2nd interim analysis of the secondary endpoint of overall survival.
Pre-assignment Detail	Randomization was stratified by previous proteasome inhibitor therapy (yes vs no), previous lines of treatment (1 vs 2 or 3), International Staging System stage (I vs II-III), and planned route of bortezomib administration (intravenous vs subcutaneous) if randomly assigned to the bortezomib group.

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	27	48
NOT COMPLETED	438	416

Baseline Characteristics

Arm/Group Title	Bortezomib + DEX	Carfilzomib + DEX	Total
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.	Total of all reporting groups
Overall Participants	465	464	929
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65.0	65.0	65.0
Age, Customized (Count of Participants)
< 65 years	210 45.2%	223 48.1%	433 46.6%
65 -74 years	189 40.6%	164 35.3%	353 38%
≥ 75 years	66 14.2%	77 16.6%	143 15.4%
Sex: Female, Male (Count of Participants)
Female	236 50.8%	224 48.3%	460 49.5%
Male	229 49.2%	240 51.7%	469 50.5%
Race/Ethnicity, Customized (Count of Participants)
White	353 75.9%	348 75%	701 75.5%
Black	9 1.9%	8 1.7%	17 1.8%
Asian	57 12.3%	56 12.1%	113 12.2%
Native Hawaiian/Other Pacific Islander	0 0%	2 0.4%	2 0.2%
Not Reported	45 9.7%	50 10.8%	95 10.2%
Multiple	1 0.2%	0 0%	1 0.1%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 (Fully active)	232 49.9%	221 47.6%	453 48.8%
1 (Restrictive but ambulatory)	203 43.7%	211 45.5%	414 44.6%
2 (Ambulatory but unable to work)	30 6.5%	32 6.9%	62 6.7%
Stratification Factor: Prior Proteasome Inhibitor Treatment (Count of Participants)
Carfilzomib or bortezomib	253 54.4%	252 54.3%	505 54.4%
No prior carfilzomib or bortezomib	212 45.6%	212 45.7%	424 45.6%
Stratification Factor: Lines of Prior Treatment (Count of Participants)
1 line	229 49.2%	231 49.8%	460 49.5%
2 or 3 lines	236 50.8%	233 50.2%	469 50.5%
Stratification Factor: International Staging System (ISS) Stage (Count of Participants)
Stage I	204 43.9%	205 44.2%	409 44%
Stage II or III	261 56.1%	259 55.8%	520 56%
Stratification Factor: Route of Bortezomib Administration (Count of Participants)
Intravenous	108 23.2%	108 23.3%	216 23.3%
Subcutaneous	357 76.8%	356 76.7%	713 76.7%

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 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.
Measure Participants	465	464
Median (95% Confidence Interval) [months]	9.4	18.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib + 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 Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Stratified Log Rank
	Comments	Log rank test stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.533
	Confidence Interval	(2-Sided) 95%; 0.437 to 0.651
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 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 03 January 2017; median follow-up time for OS was 36.9 and 37.5 months for each treatment group respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

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.
Measure Participants	465	464
Median (95% Confidence Interval) [months]	40.0	47.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib + DEX, Carfilzomib + DEX
	Comments	The second interim analysis of overall survival was to be conducted after 394 events had been reached. A one-sided significance level was determined using the O'Brien-Fleming-type α spending function based on the actual number of events (α=0.0123).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0100
	Comments	The multiplicity in testing secondary endpoints was adjusted per group using the sequential Holm procedure to preserve the family-wise error rate at 0.025.
	Method	Stratified Log Rank
	Comments	Log rank test stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.791
	Confidence Interval	(2-Sided) 95%; 0.648 to 0.964
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 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 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.
Measure Participants	465	464
Number (95% Confidence Interval) [percentage of participants]	62.6 13.5%	76.9 16.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib + DEX, Carfilzomib + DEX
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	The multiplicity in testing secondary endpoints was adjusted per group using the sequential Holm procedure to preserve the family-wise error rate at 0.025.
	Method	Stratified Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test stratified by the randomization stratification factors.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.032
	Confidence Interval	(2-Sided) 95%; 1.519 to 2.718
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 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 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.
Measure Participants	291	357
Median (95% Confidence Interval) [months]	10.4	21.3

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 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.
Measure Participants	456	463
Number (95% Confidence Interval) [percentage of participants]	32.0 6.9%	6.0 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib + DEX, Carfilzomib + DEX
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The multiplicity in testing secondary endpoints was adjusted per group using the sequential Holm procedure to preserve the family-wise error rate at 0.025.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.137
	Confidence Interval	(2-Sided) 95%; 0.089 to 0.210
	Parameter Dispersion	Type: Value:
	Estimation Comments	The 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 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.
Measure Participants	40	48
Number [percentage of participants]	2.6 0.6%	0.0 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 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.
Measure Participants	52	55
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 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.
Measure Participants	52	45
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)

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 03 January 2017; median duration of treatment was 27 weeks in the bortezomib group and 48 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		Carfilzomib
Arm/Group Description
All Cause Mortality
	Bortezomib		Carfilzomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bortezomib		Carfilzomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	182/456 (39.9%)		272/463 (58.7%)
Blood and lymphatic system disorders
ANAEMIA	1/456 (0.2%)		4/463 (0.9%)
FEBRILE NEUTROPENIA	3/456 (0.7%)		3/463 (0.6%)
HAEMORRHAGIC ANAEMIA	0/456 (0%)		1/463 (0.2%)
NEUTROPENIA	0/456 (0%)		1/463 (0.2%)
PLASMACYTOSIS	0/456 (0%)		1/463 (0.2%)
THROMBOCYTOPENIA	6/456 (1.3%)		4/463 (0.9%)
THROMBOTIC MICROANGIOPATHY	0/456 (0%)		2/463 (0.4%)
THROMBOTIC THROMBOCYTOPENIC PURPURA	0/456 (0%)		1/463 (0.2%)
Cardiac disorders
ACUTE CORONARY SYNDROME	0/456 (0%)		2/463 (0.4%)
ACUTE LEFT VENTRICULAR FAILURE	0/456 (0%)		1/463 (0.2%)
ACUTE MYOCARDIAL INFARCTION	2/456 (0.4%)		1/463 (0.2%)
ANGINA PECTORIS	0/456 (0%)		3/463 (0.6%)
AORTIC VALVE INCOMPETENCE	1/456 (0.2%)		0/463 (0%)
ATRIAL FIBRILLATION	4/456 (0.9%)		6/463 (1.3%)
ATRIAL FLUTTER	1/456 (0.2%)		0/463 (0%)
BIFASCICULAR BLOCK	1/456 (0.2%)		0/463 (0%)
CARDIAC ARREST	1/456 (0.2%)		2/463 (0.4%)
CARDIAC FAILURE	3/456 (0.7%)		9/463 (1.9%)
CARDIAC FAILURE ACUTE	1/456 (0.2%)		2/463 (0.4%)
CARDIAC FAILURE CONGESTIVE	0/456 (0%)		1/463 (0.2%)
CARDIAC HYPERTROPHY	0/456 (0%)		1/463 (0.2%)
CARDIOMYOPATHY	0/456 (0%)		2/463 (0.4%)
LEFT VENTRICULAR DYSFUNCTION	0/456 (0%)		1/463 (0.2%)
LEFT VENTRICULAR FAILURE	1/456 (0.2%)		0/463 (0%)
MYOCARDIAL INFARCTION	2/456 (0.4%)		5/463 (1.1%)
PERICARDIAL EFFUSION	0/456 (0%)		1/463 (0.2%)
PLEUROPERICARDITIS	1/456 (0.2%)		0/463 (0%)
RIGHT VENTRICULAR FAILURE	1/456 (0.2%)		1/463 (0.2%)
SINUS TACHYCARDIA	0/456 (0%)		1/463 (0.2%)
STRESS CARDIOMYOPATHY	1/456 (0.2%)		0/463 (0%)
SUPRAVENTRICULAR TACHYCARDIA	0/456 (0%)		2/463 (0.4%)
Ear and labyrinth disorders
HEARING IMPAIRED	1/456 (0.2%)		0/463 (0%)
Endocrine disorders
INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION	1/456 (0.2%)		0/463 (0%)
Eye disorders
CATARACT	1/456 (0.2%)		0/463 (0%)
RETINAL TEAR	1/456 (0.2%)		0/463 (0%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	1/456 (0.2%)		0/463 (0%)
ABDOMINAL PAIN	2/456 (0.4%)		2/463 (0.4%)
ABDOMINAL PAIN UPPER	1/456 (0.2%)		0/463 (0%)
ABDOMINAL STRANGULATED HERNIA	0/456 (0%)		1/463 (0.2%)
COLITIS	1/456 (0.2%)		0/463 (0%)
CONSTIPATION	2/456 (0.4%)		1/463 (0.2%)
DIARRHOEA	11/456 (2.4%)		5/463 (1.1%)
DIVERTICULUM	0/456 (0%)		1/463 (0.2%)
ENTEROCOLITIS	0/456 (0%)		1/463 (0.2%)
GASTRIC HAEMORRHAGE	1/456 (0.2%)		0/463 (0%)
GASTROINTESTINAL DISORDER	0/456 (0%)		1/463 (0.2%)
GASTROINTESTINAL HAEMORRHAGE	2/456 (0.4%)		1/463 (0.2%)
ILEUS	1/456 (0.2%)		0/463 (0%)
ILEUS PARALYTIC	3/456 (0.7%)		0/463 (0%)
INTESTINAL OBSTRUCTION	1/456 (0.2%)		0/463 (0%)
INTESTINAL POLYP HAEMORRHAGE	1/456 (0.2%)		0/463 (0%)
LARGE INTESTINE PERFORATION	0/456 (0%)		1/463 (0.2%)
LOWER GASTROINTESTINAL HAEMORRHAGE	0/456 (0%)		1/463 (0.2%)
MELAENA	1/456 (0.2%)		0/463 (0%)
NAUSEA	3/456 (0.7%)		2/463 (0.4%)
PANCREATITIS	0/456 (0%)		1/463 (0.2%)
PARAESTHESIA ORAL	0/456 (0%)		1/463 (0.2%)
SMALL INTESTINAL OBSTRUCTION	0/456 (0%)		1/463 (0.2%)
SUBILEUS	1/456 (0.2%)		1/463 (0.2%)
VOMITING	2/456 (0.4%)		5/463 (1.1%)
General disorders
ASTHENIA	1/456 (0.2%)		0/463 (0%)
CARDIAC DEATH	0/456 (0%)		1/463 (0.2%)
CHEST PAIN	4/456 (0.9%)		3/463 (0.6%)
DEATH	0/456 (0%)		1/463 (0.2%)
DEVICE OCCLUSION	1/456 (0.2%)		0/463 (0%)
DISEASE PROGRESSION	6/456 (1.3%)		8/463 (1.7%)
FATIGUE	1/456 (0.2%)		3/463 (0.6%)
GENERAL PHYSICAL HEALTH DETERIORATION	0/456 (0%)		4/463 (0.9%)
GENERALISED OEDEMA	1/456 (0.2%)		0/463 (0%)
HYPERPYREXIA	1/456 (0.2%)		0/463 (0%)
HYPERTHERMIA	0/456 (0%)		1/463 (0.2%)
MALAISE	1/456 (0.2%)		0/463 (0%)
NON-CARDIAC CHEST PAIN	0/456 (0%)		1/463 (0.2%)
OEDEMA PERIPHERAL	0/456 (0%)		1/463 (0.2%)
PAIN	1/456 (0.2%)		0/463 (0%)
PYREXIA	3/456 (0.7%)		19/463 (4.1%)
SUDDEN DEATH	1/456 (0.2%)		3/463 (0.6%)
THROMBOSIS IN DEVICE	1/456 (0.2%)		0/463 (0%)
Hepatobiliary disorders
BILE DUCT STONE	0/456 (0%)		1/463 (0.2%)
CHOLECYSTITIS ACUTE	1/456 (0.2%)		0/463 (0%)
CHOLELITHIASIS	2/456 (0.4%)		0/463 (0%)
HEPATIC FAILURE	0/456 (0%)		2/463 (0.4%)
HEPATOCELLULAR INJURY	0/456 (0%)		1/463 (0.2%)
JAUNDICE CHOLESTATIC	0/456 (0%)		1/463 (0.2%)
LIVER DISORDER	0/456 (0%)		1/463 (0.2%)
Immune system disorders
HYPERSENSITIVITY	1/456 (0.2%)		0/463 (0%)
HYPOGAMMAGLOBULINAEMIA	0/456 (0%)		1/463 (0.2%)
Infections and infestations
ABDOMINAL INFECTION	0/456 (0%)		1/463 (0.2%)
ABSCESS LIMB	0/456 (0%)		1/463 (0.2%)
ACUTE SINUSITIS	0/456 (0%)		1/463 (0.2%)
APPENDICITIS	0/456 (0%)		1/463 (0.2%)
BACTERAEMIA	0/456 (0%)		1/463 (0.2%)
BACTERIAL DIARRHOEA	0/456 (0%)		1/463 (0.2%)
BACTERIAL INFECTION	2/456 (0.4%)		1/463 (0.2%)
BREAST ABSCESS	1/456 (0.2%)		0/463 (0%)
BRONCHIOLITIS	0/456 (0%)		2/463 (0.4%)
BRONCHITIS	2/456 (0.4%)		8/463 (1.7%)
BRONCHOPNEUMONIA	1/456 (0.2%)		7/463 (1.5%)
BRONCHOPULMONARY ASPERGILLOSIS	0/456 (0%)		1/463 (0.2%)
BURSITIS INFECTIVE	1/456 (0.2%)		1/463 (0.2%)
CATHETER SITE INFECTION	0/456 (0%)		1/463 (0.2%)
CELLULITIS	1/456 (0.2%)		3/463 (0.6%)
CLOSTRIDIAL INFECTION	0/456 (0%)		1/463 (0.2%)
CLOSTRIDIUM DIFFICILE SEPSIS	1/456 (0.2%)		0/463 (0%)
CORONA VIRUS INFECTION	1/456 (0.2%)		0/463 (0%)
DEVICE RELATED INFECTION	0/456 (0%)		2/463 (0.4%)
DIVERTICULITIS	0/456 (0%)		3/463 (0.6%)
ENCEPHALITIC INFECTION	0/456 (0%)		1/463 (0.2%)
ENCEPHALITIS HERPES	0/456 (0%)		1/463 (0.2%)
ENTERITIS INFECTIOUS	0/456 (0%)		1/463 (0.2%)
ERYSIPELAS	0/456 (0%)		1/463 (0.2%)
ESCHERICHIA BACTERAEMIA	0/456 (0%)		1/463 (0.2%)
ESCHERICHIA URINARY TRACT INFECTION	0/456 (0%)		1/463 (0.2%)
FEBRILE INFECTION	0/456 (0%)		2/463 (0.4%)
GASTROENTERITIS	4/456 (0.9%)		5/463 (1.1%)
GASTROENTERITIS VIRAL	1/456 (0.2%)		1/463 (0.2%)
H1N1 INFLUENZA	0/456 (0%)		1/463 (0.2%)
HAEMOPHILUS SEPSIS	0/456 (0%)		1/463 (0.2%)
HERPES ZOSTER	1/456 (0.2%)		0/463 (0%)
INFECTION	0/456 (0%)		4/463 (0.9%)
INFECTIOUS PLEURAL EFFUSION	0/456 (0%)		1/463 (0.2%)
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE	1/456 (0.2%)		1/463 (0.2%)
INFLUENZA	1/456 (0.2%)		3/463 (0.6%)
LISTERIOSIS	0/456 (0%)		1/463 (0.2%)
LOBAR PNEUMONIA	1/456 (0.2%)		2/463 (0.4%)
LOWER RESPIRATORY TRACT INFECTION	5/456 (1.1%)		7/463 (1.5%)
LOWER RESPIRATORY TRACT INFECTION VIRAL	0/456 (0%)		1/463 (0.2%)
LUNG INFECTION	3/456 (0.7%)		5/463 (1.1%)
NECROTISING ULCERATIVE PERIODONTITIS	0/456 (0%)		1/463 (0.2%)
ORAL FUNGAL INFECTION	0/456 (0%)		1/463 (0.2%)
OSTEOMYELITIS	0/456 (0%)		1/463 (0.2%)
PARAINFLUENZAE VIRUS INFECTION	0/456 (0%)		2/463 (0.4%)
PHARYNGITIS	1/456 (0.2%)		0/463 (0%)
PNEUMOCOCCAL INFECTION	0/456 (0%)		1/463 (0.2%)
PNEUMOCYSTIS JIROVECI PNEUMONIA	1/456 (0.2%)		0/463 (0%)
PNEUMONIA	42/456 (9.2%)		39/463 (8.4%)
PNEUMONIA BACTERIAL	1/456 (0.2%)		1/463 (0.2%)
PNEUMONIA INFLUENZAL	0/456 (0%)		1/463 (0.2%)
PNEUMONIA MORAXELLA	1/456 (0.2%)		0/463 (0%)
PNEUMONIA PNEUMOCOCCAL	1/456 (0.2%)		1/463 (0.2%)
PSEUDOMEMBRANOUS COLITIS	1/456 (0.2%)		0/463 (0%)
PULMONARY SEPSIS	1/456 (0.2%)		0/463 (0%)
PYELONEPHRITIS ACUTE	0/456 (0%)		1/463 (0.2%)
RESPIRATORY SYNCYTIAL VIRUS INFECTION	2/456 (0.4%)		0/463 (0%)
RESPIRATORY TRACT INFECTION	5/456 (1.1%)		10/463 (2.2%)
RESPIRATORY TRACT INFECTION VIRAL	1/456 (0.2%)		2/463 (0.4%)
SEPSIS	4/456 (0.9%)		7/463 (1.5%)
SEPTIC SHOCK	3/456 (0.7%)		4/463 (0.9%)
SINUSITIS	0/456 (0%)		1/463 (0.2%)
STREPTOCOCCAL BACTERAEMIA	0/456 (0%)		1/463 (0.2%)
TRACHEOBRONCHITIS	0/456 (0%)		1/463 (0.2%)
UPPER RESPIRATORY TRACT INFECTION	3/456 (0.7%)		7/463 (1.5%)
URINARY TRACT INFECTION	4/456 (0.9%)		6/463 (1.3%)
UROSEPSIS	3/456 (0.7%)		0/463 (0%)
VIRAL INFECTION	0/456 (0%)		1/463 (0.2%)
VIRAL UPPER RESPIRATORY TRACT INFECTION	0/456 (0%)		1/463 (0.2%)
Injury, poisoning and procedural complications
CHEST INJURY	0/456 (0%)		1/463 (0.2%)
COMPRESSION FRACTURE	0/456 (0%)		1/463 (0.2%)
FACIAL BONES FRACTURE	1/456 (0.2%)		1/463 (0.2%)
FEMORAL NECK FRACTURE	1/456 (0.2%)		0/463 (0%)
FEMUR FRACTURE	1/456 (0.2%)		0/463 (0%)
FOOT FRACTURE	0/456 (0%)		1/463 (0.2%)
FRACTURE	1/456 (0.2%)		0/463 (0%)
HEAD INJURY	1/456 (0.2%)		1/463 (0.2%)
HIP FRACTURE	0/456 (0%)		1/463 (0.2%)
HUMERUS FRACTURE	0/456 (0%)		3/463 (0.6%)
INFUSION RELATED REACTION	0/456 (0%)		3/463 (0.6%)
LIGAMENT SPRAIN	1/456 (0.2%)		0/463 (0%)
OPEN WOUND	1/456 (0.2%)		0/463 (0%)
PUBIS FRACTURE	1/456 (0.2%)		0/463 (0%)
SPINAL COMPRESSION FRACTURE	1/456 (0.2%)		1/463 (0.2%)
ULNA FRACTURE	1/456 (0.2%)		0/463 (0%)
UPPER LIMB FRACTURE	0/456 (0%)		1/463 (0.2%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/456 (0%)		1/463 (0.2%)
ASPARTATE AMINOTRANSFERASE INCREASED	0/456 (0%)		1/463 (0.2%)
BLOOD CORTISOL DECREASED	0/456 (0%)		1/463 (0.2%)
BLOOD CREATININE INCREASED	0/456 (0%)		2/463 (0.4%)
INFLUENZA B VIRUS TEST POSITIVE	0/456 (0%)		1/463 (0.2%)
LYMPHOCYTE COUNT DECREASED	1/456 (0.2%)		0/463 (0%)
PLATELET COUNT DECREASED	3/456 (0.7%)		2/463 (0.4%)
TROPONIN T INCREASED	1/456 (0.2%)		1/463 (0.2%)
Metabolism and nutrition disorders
DECREASED APPETITE	2/456 (0.4%)		0/463 (0%)
DEHYDRATION	3/456 (0.7%)		0/463 (0%)
DIABETES MELLITUS	1/456 (0.2%)		2/463 (0.4%)
DIABETES MELLITUS INADEQUATE CONTROL	1/456 (0.2%)		0/463 (0%)
HYPERCALCAEMIA	5/456 (1.1%)		0/463 (0%)
HYPERGLYCAEMIA	1/456 (0.2%)		4/463 (0.9%)
HYPERKALAEMIA	1/456 (0.2%)		1/463 (0.2%)
HYPOGLYCAEMIA	0/456 (0%)		3/463 (0.6%)
HYPONATRAEMIA	1/456 (0.2%)		2/463 (0.4%)
HYPOVOLAEMIA	0/456 (0%)		1/463 (0.2%)
TUMOUR LYSIS SYNDROME	0/456 (0%)		1/463 (0.2%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	3/456 (0.7%)		1/463 (0.2%)
BACK PAIN	3/456 (0.7%)		6/463 (1.3%)
BONE PAIN	0/456 (0%)		4/463 (0.9%)
FLANK PAIN	0/456 (0%)		1/463 (0.2%)
INTERVERTEBRAL DISC PROTRUSION	0/456 (0%)		1/463 (0.2%)
LUMBAR SPINAL STENOSIS	1/456 (0.2%)		2/463 (0.4%)
MOBILITY DECREASED	0/456 (0%)		1/463 (0.2%)
MUSCULAR WEAKNESS	1/456 (0.2%)		1/463 (0.2%)
MUSCULOSKELETAL CHEST PAIN	0/456 (0%)		1/463 (0.2%)
MUSCULOSKELETAL PAIN	1/456 (0.2%)		1/463 (0.2%)
MYALGIA	0/456 (0%)		1/463 (0.2%)
OSTEOARTHRITIS	0/456 (0%)		1/463 (0.2%)
OSTEONECROSIS OF JAW	0/456 (0%)		1/463 (0.2%)
PAIN IN EXTREMITY	1/456 (0.2%)		0/463 (0%)
PATHOLOGICAL FRACTURE	1/456 (0.2%)		0/463 (0%)
RHABDOMYOLYSIS	0/456 (0%)		1/463 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA	0/456 (0%)		1/463 (0.2%)
BASAL CELL CARCINOMA	0/456 (0%)		2/463 (0.4%)
BLADDER TRANSITIONAL CELL CARCINOMA	0/456 (0%)		1/463 (0.2%)
CANCER PAIN	0/456 (0%)		1/463 (0.2%)
CARCINOMA IN SITU	0/456 (0%)		1/463 (0.2%)
COLON CANCER	1/456 (0.2%)		1/463 (0.2%)
MENINGEAL NEOPLASM	0/456 (0%)		1/463 (0.2%)
METASTASES TO SPINE	0/456 (0%)		1/463 (0.2%)
MULTIPLE MYELOMA	1/456 (0.2%)		5/463 (1.1%)
OESOPHAGEAL SQUAMOUS CELL CARCINOMA	1/456 (0.2%)		0/463 (0%)
PLASMACYTOMA	0/456 (0%)		5/463 (1.1%)
PLEURAL MESOTHELIOMA	1/456 (0.2%)		0/463 (0%)
RECTAL CANCER	0/456 (0%)		1/463 (0.2%)
SQUAMOUS CELL CARCINOMA	1/456 (0.2%)		0/463 (0%)
TONGUE NEOPLASM MALIGNANT STAGE UNSPECIFIED	0/456 (0%)		1/463 (0.2%)
Nervous system disorders
ACQUIRED EPILEPTIC APHASIA	0/456 (0%)		1/463 (0.2%)
CENTRAL NERVOUS SYSTEM LESION	1/456 (0.2%)		0/463 (0%)
CEREBROVASCULAR ACCIDENT	0/456 (0%)		4/463 (0.9%)
COGNITIVE DISORDER	1/456 (0.2%)		0/463 (0%)
CONVULSION	1/456 (0.2%)		0/463 (0%)
DEPRESSED LEVEL OF CONSCIOUSNESS	1/456 (0.2%)		0/463 (0%)
DIZZINESS	1/456 (0.2%)		0/463 (0%)
ENCEPHALOPATHY	0/456 (0%)		1/463 (0.2%)
HEADACHE	0/456 (0%)		2/463 (0.4%)
HYPERCAPNIC COMA	0/456 (0%)		1/463 (0.2%)
HYPERTENSIVE ENCEPHALOPATHY	1/456 (0.2%)		0/463 (0%)
ISCHAEMIC STROKE	0/456 (0%)		3/463 (0.6%)
LETHARGY	0/456 (0%)		1/463 (0.2%)
LOSS OF CONSCIOUSNESS	1/456 (0.2%)		0/463 (0%)
METABOLIC ENCEPHALOPATHY	1/456 (0.2%)		0/463 (0%)
NEURALGIA	1/456 (0.2%)		1/463 (0.2%)
NEUROPATHY PERIPHERAL	2/456 (0.4%)		1/463 (0.2%)
PARAPARESIS	1/456 (0.2%)		0/463 (0%)
PARAPLEGIA	0/456 (0%)		1/463 (0.2%)
POLYNEUROPATHY	1/456 (0.2%)		0/463 (0%)
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME	0/456 (0%)		2/463 (0.4%)
RADICULITIS BRACHIAL	0/456 (0%)		1/463 (0.2%)
RADICULOPATHY	0/456 (0%)		1/463 (0.2%)
SCIATICA	1/456 (0.2%)		0/463 (0%)
SPINAL CORD COMPRESSION	2/456 (0.4%)		4/463 (0.9%)
SYNCOPE	4/456 (0.9%)		1/463 (0.2%)
TRANSIENT ISCHAEMIC ATTACK	2/456 (0.4%)		0/463 (0%)
Psychiatric disorders
COMPLETED SUICIDE	0/456 (0%)		1/463 (0.2%)
CONFUSIONAL STATE	4/456 (0.9%)		4/463 (0.9%)
DEPRESSION	1/456 (0.2%)		1/463 (0.2%)
DYSTHYMIC DISORDER	1/456 (0.2%)		0/463 (0%)
MENTAL DISORDER	0/456 (0%)		1/463 (0.2%)
PSYCHOTIC DISORDER	0/456 (0%)		1/463 (0.2%)
Renal and urinary disorders
ALBUMINURIA	0/456 (0%)		1/463 (0.2%)
ANURIA	0/456 (0%)		1/463 (0.2%)
NEPHROPATHY	1/456 (0.2%)		1/463 (0.2%)
NEPHROTIC SYNDROME	0/456 (0%)		1/463 (0.2%)
PROTEINURIA	0/456 (0%)		1/463 (0.2%)
RENAL FAILURE	0/456 (0%)		5/463 (1.1%)
RENAL FAILURE ACUTE	7/456 (1.5%)		11/463 (2.4%)
RENAL IMPAIRMENT	2/456 (0.4%)		1/463 (0.2%)
URINARY RETENTION	1/456 (0.2%)		0/463 (0%)
Reproductive system and breast disorders
PROSTATOMEGALY	1/456 (0.2%)		0/463 (0%)
UTERINE HAEMORRHAGE	0/456 (0%)		1/463 (0.2%)
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA	1/456 (0.2%)		3/463 (0.6%)
ACUTE RESPIRATORY DISTRESS SYNDROME	1/456 (0.2%)		1/463 (0.2%)
ACUTE RESPIRATORY FAILURE	1/456 (0.2%)		0/463 (0%)
ASTHMA	1/456 (0.2%)		3/463 (0.6%)
BRONCHOPNEUMOPATHY	1/456 (0.2%)		0/463 (0%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	1/456 (0.2%)		2/463 (0.4%)
DYSPNOEA	1/456 (0.2%)		18/463 (3.9%)
EPISTAXIS	1/456 (0.2%)		1/463 (0.2%)
HYPOXIA	1/456 (0.2%)		0/463 (0%)
INTERSTITIAL LUNG DISEASE	0/456 (0%)		2/463 (0.4%)
LUNG DISORDER	1/456 (0.2%)		3/463 (0.6%)
PLEURAL EFFUSION	1/456 (0.2%)		2/463 (0.4%)
PNEUMONITIS	1/456 (0.2%)		2/463 (0.4%)
PULMONARY ARTERIAL HYPERTENSION	0/456 (0%)		1/463 (0.2%)
PULMONARY EMBOLISM	3/456 (0.7%)		10/463 (2.2%)
PULMONARY HYPERTENSION	0/456 (0%)		3/463 (0.6%)
PULMONARY OEDEMA	1/456 (0.2%)		2/463 (0.4%)
RESPIRATORY FAILURE	0/456 (0%)		4/463 (0.9%)
Skin and subcutaneous tissue disorders
DRUG ERUPTION	0/456 (0%)		1/463 (0.2%)
ECZEMA	0/456 (0%)		1/463 (0.2%)
ERYTHEMA MULTIFORME	1/456 (0.2%)		0/463 (0%)
PRURITUS GENERALISED	1/456 (0.2%)		0/463 (0%)
PURPURA	0/456 (0%)		1/463 (0.2%)
Surgical and medical procedures
COLOSTOMY CLOSURE	0/456 (0%)		1/463 (0.2%)
HAEMORRHOID OPERATION	0/456 (0%)		1/463 (0.2%)
REMOVAL OF INTERNAL FIXATION	1/456 (0.2%)		0/463 (0%)
Vascular disorders
AORTIC ANEURYSM	0/456 (0%)		1/463 (0.2%)
AORTIC EMBOLUS	0/456 (0%)		1/463 (0.2%)
CIRCULATORY COLLAPSE	1/456 (0.2%)		1/463 (0.2%)
DEEP VEIN THROMBOSIS	3/456 (0.7%)		5/463 (1.1%)
HAEMATOMA	0/456 (0%)		1/463 (0.2%)
HYPERTENSION	0/456 (0%)		3/463 (0.6%)
HYPERTENSIVE CRISIS	0/456 (0%)		1/463 (0.2%)
HYPOTENSION	4/456 (0.9%)		1/463 (0.2%)
MALIGNANT HYPERTENSION	0/456 (0%)		1/463 (0.2%)
ORTHOSTATIC HYPOTENSION	4/456 (0.9%)		0/463 (0%)
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE	0/456 (0%)		2/463 (0.4%)
THROMBOPHLEBITIS	0/456 (0%)		1/463 (0.2%)
VENA CAVA THROMBOSIS	0/456 (0%)		1/463 (0.2%)
VENOUS THROMBOSIS LIMB	0/456 (0%)		1/463 (0.2%)
Other (Not Including Serious) Adverse Events
	Bortezomib		Carfilzomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	435/456 (95.4%)		446/463 (96.3%)
Blood and lymphatic system disorders
ANAEMIA	129/456 (28.3%)		196/463 (42.3%)
LYMPHOPENIA	25/456 (5.5%)		31/463 (6.7%)
NEUTROPENIA	26/456 (5.7%)		27/463 (5.8%)
THROMBOCYTOPENIA	83/456 (18.2%)		100/463 (21.6%)
Eye disorders
CATARACT	17/456 (3.7%)		32/463 (6.9%)
CONJUNCTIVITIS	36/456 (7.9%)		22/463 (4.8%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	26/456 (5.7%)		20/463 (4.3%)
ABDOMINAL PAIN	38/456 (8.3%)		32/463 (6.9%)
ABDOMINAL PAIN UPPER	35/456 (7.7%)		24/463 (5.2%)
CONSTIPATION	126/456 (27.6%)		75/463 (16.2%)
DIARRHOEA	184/456 (40.4%)		167/463 (36.1%)
DYSPEPSIA	25/456 (5.5%)		35/463 (7.6%)
NAUSEA	89/456 (19.5%)		108/463 (23.3%)
VOMITING	44/456 (9.6%)		75/463 (16.2%)
General disorders
ASTHENIA	78/456 (17.1%)		107/463 (23.1%)
CHEST PAIN	19/456 (4.2%)		42/463 (9.1%)
CHILLS	12/456 (2.6%)		26/463 (5.6%)
FATIGUE	140/456 (30.7%)		149/463 (32.2%)
INFLUENZA LIKE ILLNESS	10/456 (2.2%)		24/463 (5.2%)
MALAISE	8/456 (1.8%)		24/463 (5.2%)
OEDEMA PERIPHERAL	87/456 (19.1%)		116/463 (25.1%)
PYREXIA	68/456 (14.9%)		144/463 (31.1%)
Infections and infestations
BRONCHITIS	46/456 (10.1%)		103/463 (22.2%)
NASOPHARYNGITIS	61/456 (13.4%)		81/463 (17.5%)
PNEUMONIA	18/456 (3.9%)		24/463 (5.2%)
RESPIRATORY TRACT INFECTION	29/456 (6.4%)		47/463 (10.2%)
RHINITIS	10/456 (2.2%)		29/463 (6.3%)
UPPER RESPIRATORY TRACT INFECTION	80/456 (17.5%)		116/463 (25.1%)
URINARY TRACT INFECTION	28/456 (6.1%)		34/463 (7.3%)
Injury, poisoning and procedural complications
CONTUSION	25/456 (5.5%)		19/463 (4.1%)
FALL	23/456 (5%)		18/463 (3.9%)
Investigations
BLOOD CREATININE INCREASED	28/456 (6.1%)		52/463 (11.2%)
CREATININE RENAL CLEARANCE DECREASED	18/456 (3.9%)		29/463 (6.3%)
LYMPHOCYTE COUNT DECREASED	18/456 (3.9%)		42/463 (9.1%)
PLATELET COUNT DECREASED	41/456 (9%)		57/463 (12.3%)
Metabolism and nutrition disorders
DECREASED APPETITE	61/456 (13.4%)		50/463 (10.8%)
HYPERGLYCAEMIA	42/456 (9.2%)		53/463 (11.4%)
HYPERURICAEMIA	8/456 (1.8%)		31/463 (6.7%)
HYPOCALCAEMIA	19/456 (4.2%)		27/463 (5.8%)
HYPOKALAEMIA	51/456 (11.2%)		60/463 (13%)
HYPOPHOSPHATAEMIA	28/456 (6.1%)		32/463 (6.9%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	51/456 (11.2%)		60/463 (13%)
BACK PAIN	81/456 (17.8%)		105/463 (22.7%)
BONE PAIN	40/456 (8.8%)		55/463 (11.9%)
MUSCLE SPASMS	28/456 (6.1%)		92/463 (19.9%)
MUSCULAR WEAKNESS	47/456 (10.3%)		44/463 (9.5%)
MUSCULOSKELETAL CHEST PAIN	20/456 (4.4%)		39/463 (8.4%)
MUSCULOSKELETAL PAIN	23/456 (5%)		24/463 (5.2%)
MYALGIA	18/456 (3.9%)		28/463 (6%)
PAIN IN EXTREMITY	50/456 (11%)		55/463 (11.9%)
Nervous system disorders
DIZZINESS	69/456 (15.1%)		42/463 (9.1%)
DYSGEUSIA	27/456 (5.9%)		16/463 (3.5%)
HEADACHE	49/456 (10.7%)		95/463 (20.5%)
HYPOAESTHESIA	14/456 (3.1%)		24/463 (5.2%)
NEURALGIA	72/456 (15.8%)		11/463 (2.4%)
NEUROPATHY PERIPHERAL	130/456 (28.5%)		49/463 (10.6%)
PARAESTHESIA	76/456 (16.7%)		43/463 (9.3%)
PERIPHERAL SENSORY NEUROPATHY	70/456 (15.4%)		29/463 (6.3%)
POLYNEUROPATHY	26/456 (5.7%)		6/463 (1.3%)
TREMOR	23/456 (5%)		10/463 (2.2%)
Psychiatric disorders
ANXIETY	33/456 (7.2%)		19/463 (4.1%)
INSOMNIA	122/456 (26.8%)		125/463 (27%)
Respiratory, thoracic and mediastinal disorders
COUGH	72/456 (15.8%)		128/463 (27.6%)
DYSPNOEA	62/456 (13.6%)		144/463 (31.1%)
EPISTAXIS	14/456 (3.1%)		24/463 (5.2%)
OROPHARYNGEAL PAIN	19/456 (4.2%)		28/463 (6%)
PRODUCTIVE COUGH	15/456 (3.3%)		27/463 (5.8%)
Skin and subcutaneous tissue disorders
PRURITUS	29/456 (6.4%)		34/463 (7.3%)
RASH	35/456 (7.7%)		41/463 (8.9%)
Vascular disorders
FLUSHING	7/456 (1.5%)		24/463 (5.2%)
HYPERTENSION	45/456 (9.9%)		148/463 (32%)
HYPOTENSION	37/456 (8.1%)		29/463 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.