CLARION: Phase 3 Study of Carfilzomib, Melphalan, Prednisone vs Bortezomib, Melphalan, Prednisone in Newly Diagnosed Multiple Myeloma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01818752
• Collaborator: (none)
• Enrollment: 955
• Locations: 213
• Arms: 2
• Actual Duration (Months): 39.9
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective was to compare the progression-free survival of transplant ineligible patients newly diagnosed with multiple myeloma who were treated with carfilzomib, melphalan and prednisone (CMP) or with Velcade® (bortezomib), melphalan and prednisone (VMP).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 955 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, Melphalan, and Prednisone Versus Bortezomib, Melphalan, and Prednisone in Transplant-ineligible Patients With Newly Diagnosed Multiple Myeloma
• Actual Study Start Date: Jul 8, 2013
• Actual Primary Completion Date: Jul 15, 2016
• Actual Study Completion Date: Nov 4, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Carfilzomib, Melphalan, Prednisone Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Drug: Carfilzomib; Carfilzomib was administered over 30 minutes on days 1, 2, 8, 9, 22, 23, 29, and 30 for nine 42-day cycles. Carfilzomib 20 mg/m² IV was administered on days 1 and 2 of cycle 1, followed by escalation to 36 mg/m² IV starting on day 8 of cycle 1.; Other Names: Krypolis® ; Drug: Melphalan; Melphalan 9 mg/m² was taken orally on days 1 to 4 of all cycles.; Drug: Prednisone; Prednisone 60 mg/m² was taken orally on days 1 to 4 of all cycles.
Active Comparator: Bortezomib, Melphalan, Prednisone Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Drug: Bortezomib; Bortezomib 1.3 mg/m² was administered as a bolus IV injection or as a subcutaneous injection (per investigator's choice, dose modification, or regulatory approval) on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycles 1 to 4, and on days 1, 8, 22, and 29 of cycles 5 to 9.; Other Names: Velcade® ; Drug: Melphalan; Melphalan 9 mg/m² was taken orally on days 1 to 4 of all cycles.; Drug: Prednisone; Prednisone 60 mg/m² was taken orally on days 1 to 4 of all cycles.

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [From randomization until the data cut-off date of 15 July 2016; median follow-up time for PFS was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively.]

   Progression-free survival was defined as the time from randomization to the earlier of documented disease progression or death due to any cause. PFS was analyzed using Kaplan-Meier methods. The duration of PFS was censored for participants with no baseline and/or post-baseline disease assessments, who started a new anti-cancer therapy before documentation of disease progression or death, death or disease progression after missed disease assessment of 100 consecutive days or longer, or who were alive without documentation of disease progression before the data cutoff date, including lost to follow-up prior to disease progression. Participants were evaluated for disease response and progression according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC), determined centrally using a validated computer algorithm in a blinded manner.

Secondary Outcome Measures

1. Overall Survival (OS) [From randomization until the data cut-off date of 15 July 2016; median follow-up time for OS was 22.2 and 22.5 months in the bortezomib and carfilzomib arms respectively.]

   Overall survival (OS) was 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 on the date the patient was last known to be alive. Median overall survival was estimated using the Kaplan-Meier method.

2. Overall Response Rate [Disease response was assessed every 3 weeks during the first 54 weeks and every 6 weeks thereafter until PD or the data cut-off date of 15 July 2016; median follow-up time was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively.]

   Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). 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. Complete Response Rate [Disease response was assessed every 3 weeks during the first 54 weeks and every 6 weeks thereafter until PD or the data cut-off date of 15 July 2016; median follow-up time was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively.]

   Complete response rate was defined as the percentage of participants in each treatment group who achieved a sCR or CR per the IMWG-URC as their best response. 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.

4. Percentage of Participants With ≥ Grade 2 Peripheral Neuropathy [From the first dose of any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups.]

   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. European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status/Quality of Life (QOL) Scores [Baseline, weeks 6, 12, 18, 24, 30, 36, 42 and 48]

   The EORTC QLQ-C30 is a validated self-rating questionnaire including 30 items used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with higher scores indicating better Global Health Status/QOL.

6. Number of Participants With Adverse Events [From the first dose of any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups.]

   Adverse events (AEs)were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where GRADE 1 = Mild; GRADE 2 = Moderate; GRADE 3 = Severe; GRADE 4 = Life-threatening; GRADE 5 = Fatal. A serious adverse event is an adverse event that met 1 or more of the following criteria: Death Life-threatening Required inpatient hospitalization or prolongation of an existing hospitalization Resulted in persistent or significant disability/incapacity Congenital anomaly/birth defect Important medical event that jeopardized the participant and may have required medical or surgical intervention to prevent 1 of the outcomes listed above. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Newly diagnosed symptomatic multiple myeloma (per International Myeloma Working Group [IMWG] diagnostic criteria)

2. Transplant ineligibility

3. Measurable disease, as defined by 1 or more of the following (assessed within 21 days prior to randomization):

• Serum M-protein ≥ 0.5 g/dL, or

• Urine M-protein ≥ 200 mg/24 hours, or

• In subjects without detectable serum or urine M-protein, serum free light chain (SFLC) > 100 mg/L (involved light chain) and an abnormal kappa lambda ratio (SFLC kappa lambda ratio < 0.26 or > 1.65)

1. No prior treatment for multiple myeloma

2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

Exclusion Criteria:

1. Multiple myeloma of IgM (immunoglobulin M) subtype

2. Glucocorticoid therapy within 14 days prior to randomization that equals or exceeds a cumulative dose of 160 mg of dexamethasone

3. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

4. Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)

5. Waldenström macroglobulinemia (WM)

6. Known amyloidosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Cancer Associates for Research & Excellence, Inc. (cCARE)	Fresno	California	United States	93720
2	Marin Cancer Care	Greenbrae	California	United States	94904
3	Sutter Gould Medical Foundation	Modesto	California	United States	95357
4	Innovative Clinical Research Institute	Whittier	California	United States	90603
5	UF Health Shands Cancer Hospital	Gainesville	Florida	United States
6	Evanston KelIogg Cancer Center	Evanston	Illinois	United States
7	Billings Clinic Cancer Center	Billings	Montana	United States	59101
8	Maimonides Cancer Center	Brooklyn	New York	United States
9	Weill Cornell Medical Center	New York	New York	United States	10021
10	Gabrail Cancer Center Research	Canton	Ohio	United States	44718
11	Saint Francis Health System	Greenville	South Carolina	United States	29601
12	Spartanburg Regional Healthcare System	Spartanburg	South Carolina	United States	29303
13	Santee Hematology Oncology	Sumter	South Carolina	United States	29150
14	Seattle Cancer Care Alliance	Seattle	Washington	United States
15	Centro de educacion medica c investigacioncs clinicas "Norberto Quimo' (CEMIC)	Buenos Aires		Argentina
16	Sanatorio Britanico S.A.	Santa Fe		Argentina
17	Royal Prince Alfred Hospital	Camperdown	New South Wales	Australia	2050
18	St. Vincent's Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
19	Central Coast Local Health District	North Gosford	New South Wales	Australia	2250
20	Calvary Mater Newcastle	Waratah	New South Wales	Australia	2298
21	Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
22	Eastern Health - Box Hill Hospital	Box Hill	Victoria	Australia	3128
23	St. Vincent's Hospital Melbourne	Fitzroy	Victoria	Australia
24	The Alfred Hospital	Melbourne	Victoria	Australia	3004
25	Border Medical Oncology	Wodonga	Victoria	Australia	3690
26	Royal North Shore Hospital, Haematology Department	New South Wales		Australia
27	Medical University of Innsbruck, University Clinic for Internal Medicine V	Innsbruck		Austria	6020
28	Elisabeth Linz Hospital	Linz		Austria	4020
29	Vienna Wilhelminen Hospital	Vienna		Austria	1160
30	ZNA, Stuivenberg	Antwerp	Antwerpen	Belgium	2060
31	Saint Joseph Clinic Arlon, Department of Hematology	Arlon	Luxembourg	Belgium	6700
32	CHR de La Citadelle (ENG: Citadelle Regional Hospital Center)	Liège		Belgium	4000
33	CHU Mont-Godinne	Yvoir		Belgium	5530
34	University Multiprofile Hospital for Active Treatment "Sveti Georgi", Plovdiv, Hematology Clinic	Plovdiv		Bulgaria	4002
35	University Multiprofile Hospital for Active Treatment "Sveti Georgi", Plovdiv, Oncology and Hematology Clinic	Plovdiv		Bulgaria	4002
36	Military Medical Academy - Multiprofile Hospital for Active Treatment, Sofia, Hematology and Oncology Clinic	Sofia		Bulgaria	1606
37	Specialized Hospital for Active Treatment of Hematological Diseases, Sofia, Hematology Clinic	Sofia		Bulgaria	1756
38	Multiprofile Hospital for Active Treatment "Sveta Marina", Varna	Varna		Bulgaria	9010
39	CSSS-Champlain-Charles LeMoyne	Greenfield Park	Quebec	Canada
40	Fujian Medical University Union Hospital	Fuzhou City	Fujian	China
41	Guangdong General Hospital	Guangzhou	Guangdong	China
42	Guangzhou First People's Hospital	Guangzhou	Guangdong	China
43	The First Affiliated Hospital of Soochow University	Suzhou	Jiangsu	China
44	The First Hospital of Jilin University	Changchun	Jilin	China
45	The First Affiliated Hospital of the Fourth Military Medical University of PLA	Xi'an City	Shanxi	China
46	The First Affiliated Hospital of College of Medicine, Zhejiang University - Dr. Jie Jin	Hangzhou	Zhejiang	China
47	The First Affiliated Hospital of College of Medicine, Zhejiang University	Hangzhou	Zhejiang	China
48	307 Hospital of PLA	Beijing		China
49	Beijing Chao Yang Hospital, Capital Medical University	Beijing		China
50	Peking Union Medical College Hospital	Beijing		China
51	Peking University Third Hospital	Beijing		China
52	Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine	Shanghai		China
53	Shanghai Changzheng Hospital	Shanghai		China
54	Institute on Hematology & Blood Diseases Hospital Chinese Academy of Medical Scicnces & Peking Union Medical University	Tianjin		China
55	Tianjin Medical University Cancer Institute and Hospital	Tianjin		China
56	University Hospital Brno, Department of Internal Hematology and Oncology	Brno		Czechia	625 00
57	University Hospital Brno, Hospital Pharmacy - Department of Dilution of Cytostasis	Brno		Czechia	625 00
58	University Hospital Hradec Kralove	Hradec Kralove		Czechia	500 05
59	University Hospital Olomouc, 3rd Clinic of Internal Medicine, Nephrology, Rheumatology and Endocrinology	Olomouc		Czechia	775 20
60	University Hospital Ostrava, Clinic of Hematooncology of UHO and MFUO	Ostrava		Czechia	708 52
61	University Hospital Kralovske Vinohrady - Internal Hematology Clinic	Prague		Czechia	10034
62	General University Hospital Prague, 1st Department of Medicine - Department of Hematology	Prague		Czechia	128 08
63	CHU de Caen, Côte de Nacre	Caen Cedex 9		France	14033
64	CHU Estaing	Clermont-Ferrand		France	63000
65	UHC Dijon, Children's Hospital	Dijon		France
66	CHRU Hopital Huriez, Departement of Hematology	Lille Cedex		France
67	CHRU Lille Hôpital Claude Huriez	Lille		France	59037
68	Paoli Calmettes Institute, Department ofHematology 2	Marseille cedex		France
69	Nantes University Hospital Center	Nantes Cedex 1		France	44093
70	Centre Hospitalier Regional Universitaire de Nimes, Groupe Hospitalo-Universitaire Caremeau	Nimes cedex 9		France
71	Hopital Saini Louis, Service d'immuno-Hematologie	Paris		France
72	Hopital Saint Antoine	Paris		France
73	Hospital Necker	Paris		France
74	South Lyon Hospital Center	Pierre Bénite, cedex		France	69310
75	Centre Hospitalier Lyon Sud, Service d'hématologie Clinique	Pierre Bénite, Cedex		France	69495
76	Hopital Pontchaillou	Rennes Cedex 9		France
77	Hospital Purpan	Toulouse Cedex 9		France
78	CHU de Tours Hopital Bretonneau	Tours Cedex 1		France
79	Freiburg University Medical Center	Freiburg	Baden-Wuerttemberg	Germany
80	Ulm University Hospital, Center for Internal Medicine, Clinic of Internal Medicine III	Ulm	Baden-Wuerttemberg	Germany
81	Ludwig Maximilians University Hospital - Medical Clinic III	Munich	Bavaria	Germany
82	University Hospital Cologne	Cologne	Nordrhein-Westfalen	Germany	50937
83	Johannes Gutenberg-University Mainz, Medical Clinic and Policlinic III	Mainz	Rhineland-Palatinate	Germany
84	Saarland University Hospital	Homburg / Saar	Saarland	Germany
85	Group Practice for Hematology and Oncology	Dresden		Germany	1307
86	Stiftungsklinikum Mittelrhein GmbH, Clinic of Internal Medicine	Koblenz		Germany	56068
87	Evangelismos Hospital	Athens	Attica	Greece	10676
88	University of Athens, Alexandra Hospital	Athens		Greece	11528
89	St. Istvan and St. Laszlo Hospital of Budapest, Department of Haematology and Stem-cell Transplant	Budapest		Hungary	1097
90	National Institute of Oncology, Department of Oncology, Internal Medicine "A" and Hematology	Budapest		Hungary	1122
91	University of Debrecen, Medical and Health Science Center, Institute for Medicine, Chair of Hematology	Debrecen		Hungary	4032
92	Bekes County Pandy Kalman Hospital 1st Department of Internal Medicine, Hematology	Gyula		Hungary	5700
93	Kaposi Mor County Teaching Hospital, 2nd Department of Internal Medicine, Hematology	Kaposvar		Hungary	7400
94	Bacs-Kiskun County Teaching Hospital, II. Department of Internal Medicine	Kecskemet		Hungary	6000
95	Medical Center of the University of Pecs, 1st Clinic for Internal Medicine	Pecs		Hungary	7624
96	Soroka University Medical Center	Beer-Sheva		Israel	P.O.B 151
97	Rambam Medical Center, Department of Hematology	Haifa		Israel	31096
98	Ein Kerem Hospital, Department of Hematology	Jerusalem		Israel	91120
99	The Chaim Sheba Medical Center	Tel Hashomer		Israel
100	UO Clinica Ematologica, IRCCS A.O.U. San Martino	Genova	GE	Italy
101	A.O.U. San Luigi Gonzaga	Orbassano	TO	Italy
102	Ospedali Riuniti di Ancona Umberto I, G.M. Lancisi, G. Salesi	Ancona		Italy
103	Maggiore della Carita Hospital of Novara	Novara		Italy
104	Local NHS of Piacenza Hospital Guglielmo da Saliceto Department Oncology-Hematology, Unit of Hema	Piacenza		Italy
105	Ospedale S. Eugenio	Roma		Italy
106	Policlinico Universitario "Umberto I"	Rome		Italy
107	AO Città della Salute e della Scienza di Torino, Division of Hematology	Torino		Italy	10126
108	Nagoya City University Hospital	Nagoya	Aichi	Japan
109	Toyohashi Municipal Hospital	Toyohashi	Aichi	Japan
110	Kyushu University Hospital	Fukuoka	Fukuoka-Ken	Japan
111	National Hospitalization Organization Kyushu Cancer Center	Minami-ku	Fukuoka	Japan
112	Ogaki Municipal Hospital	Ogaki	Gifu	Japan
113	Gunma University Hospital	Maebashi	Gunma	Japan
114	Sapporo Medical University Hospital	Sapporo-shi	Hokkaidou	Japan
115	National Hospital Organization Okayama Medical Center	Okayama-city	Okayama	Japan
116	Osaka University Hospital	Suita	Osaka	Japan
117	Japanese Red Cross Medical Center	Tokyo	Shibuya-ku	Japan
118	Tochigi Cancer Center	Utsunomiya	Tochigi	Japan
119	The Cancer Institute Hospital of Japanese Foundation For Cancer Research	Koto	Tokyo	Japan
120	National Center for Global Health and Medicine	Shinjuku	Tokyo	Japan
121	National Hospital Organization Disaster Medical Center	Tachikawa-city	Tokyo	Japan
122	University Hospital, Kyoto Prefectural University of Medicine	Kyoto		Japan
123	Tokushima Prefectural Central Hospital	Tokushima		Japan
124	National Cancer Center	Goyang-si	Gyeonggi-do	Korea, Republic of
125	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	463-707
126	Chonnam National University Hwasun Hospital	Hwasun-gun	Jeollanam-do	Korea, Republic of	519-763
127	Pusan National University Hospital	Busan		Korea, Republic of	602-739
128	Inje University Busan Paik Hospital	Busan		Korea, Republic of	614-735
129	Kyungpook National University Hospital	Daegu		Korea, Republic of	700-721
130	Gachon University Gil Medical Center	Incheon		Korea, Republic of	405-760
131	Seoul National University Hospital	Seoul		Korea, Republic of	110-774
132	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	120-752
133	Samsung Medical Center	Seoul		Korea, Republic of	135-710
134	The Catholic University of Korea, Seoul St. Mary's Hospital	Seoul		Korea, Republic of	137-701
135	Asan Medical Center	Seoul		Korea, Republic of	138-736
136	Hospital Universitario "Dr. Jose Eleuterio Gonzalez"	Monterrey	Nuevo Leon	Mexico
137	Fundacion Centro Oncologieo de Integracion Regional - COIR	Mendoza		Mexico
138	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran	Mexico City		Mexico
139	Consultorio Privado del Dr. Guillermo Jose Ruiz y Arguelles	Puebla		Mexico
140	Vrije Universiteit Medisch Centrum (VUMC), Department of Hematology	Amsterdam		Netherlands
141	St. Antonius Ziekenhuis, Department of Hematology	Nieuwegein		Netherlands
142	Erasmus Medical Center	Rotterdam		Netherlands
143	Isala Clinics in Zwolle, Department of Oncology	Zwolle		Netherlands
144	North Shore Hospital	Auckland		New Zealand	0622
145	Auckland City Hospital	Auckland		New Zealand	1023
146	Canterbury Health Laboratories	Christchurch		New Zealand	8011
147	Wellington Hospital	Wellington		New Zealand	6021
148	Independent Public Healthcare Facility of the Ministry of Internal Affairs & Warminsko-Mazurskie Oncology Centre in Olsztyn	Olsztyn	OIsztyn	Poland
149	Independent Public Healthcare Facility Municipal Hospital Group, Department of Hematology	Chorzow	Slaskie	Poland	41-500
150	Andrzej Mielecki Independent Public Clinical Hospital of Medical University of Silesia in Katowice	Katowice		Poland	40-032
151	Independent Public Healthcare Facility University Hospital	Krakow		Poland
152	Nicolaus Copernicus Memorial Provincial Specialist Hospital	Lodz		Poland
153	Independent Public Teaching Hospital No.1 in Lublin, Dept. of Hematology-Oncology	Lublin		Poland
154	Nicolaus Copernicus Municipal Specialist Hospital, Department of Hematology	Torun		Poland	87-100
155	Maria Sklodowska-Curie Institute of Oncology	Warsaw		Poland	02-781
156	"Prof. Dr. Ion Chiricuta" Institut of Oncology, Hematology Department	Cluj-Napoca	Cluj County	Romania	400124
157	Iasi Regional Institute for Oncology, Medical Hematology Department	Iasi	Iasi County	Romania	700483
158	Brasov County Emergency Clinical Hospital, Hematology Department	Brasov		Romania	500326
159	Fundeni Clinical Institute, Hematology Department	Bucharest		Romania	022 328
160	Coltea Clinical Hospital, Hematology Department	Bucharest		Romania	030 171
161	Bucharest Emergency University Hospital, Hematology Department	Bucharest		Romania	50098
162	Targu-Mures County Emergency Clinical Hospital, Clinic of Hematology and Bone Marrow Transplantation	Targu-Mures		Romania	540042
163	State Medical Institution: Republican Hospital n a.V.A. Baranov, Department of Hematology	Petrozavodsk	Republic Of Karelia	Russian Federation	185019
164	Arkhangelsk Regional Clinical Hospital, Department of internal diseases #2	Arkhangelsk		Russian Federation
165	State Medical Institution: First Republican Clinical Hospital under the Ministry of Healthcare of the Republic of Udmurtia	Izhevsk		Russian Federation	426039
166	Institution of the Russian Academy of Medical Sciences Russian Oncological Research Center n.a. N.N.Blokhin under the Russian Academy of Medical Sciences	Moscow		Russian Federation	115478
167	City Clinical Hospital N.A.S.P. Botkin, Department of Bone Marrow Transplantation and Intensive Chemotherapy for Patients with Myeloproliferative Disorders	Moscow		Russian Federation	125284
168	State Higher Educational Institution St. Petersburg Pavlov State Medical University	Saint Petersburg		Russian Federation
169	The Federal State Budget Institute The Nikiforov Russian Center of Emergency and Radiation Medicine the Ministry of Russian	Saint Petersburg		Russian Federation
170	Federal State Institution: Russian Research Institute of Hematology and Blood Transfusion under the Federal Agency for High-Tech Medical Care	St. Petersburg		Russian Federation	191024
171	City Clinical Hospital #31, Department of Bone Marrow Transplantation and Intensive Chemotherapy for Patients with Myeloproliferative Disorders	St. Petersburg		Russian Federation	197110
172	National University Hospital	Singapore		Singapore	119228
173	Singapore General Hospital	Singapore		Singapore	169608
174	Singapore Oncology Consultants, Gleneagles Hospital	Singapore		Singapore	258500
175	OncoCare Cancer Center	Singapore		Singapore
176	Singapore General Hospital	Singapore		Singapore
177	Hospital Universitari Germans Trias i Pujol	Badalona	Barselona	Spain	8916
178	University Hospital of Navarra	Pamplona	Navarra	Spain
179	Hospital Clinic i Provincial Barcelona	Barcelona		Spain
180	Hospital Universitario 12 De Octubre	Madrid		Spain	28041
181	Hospital Universitario, Salamanca	Salamanca		Spain	37007
182	Hospital Virgen del Rocio University	Sevilla		Spain	41013
183	Universitari i Politècnic la Fe de Valencia Consulta Externa de Hematología	Valencia		Spain	46026
184	Hospital Quiron Zaragoza	Zaragoza		Spain
185	University Hospital Center Vaudois	Lausanne		Switzerland
186	County Hospital Saint Gallen	Saint Gallen		Switzerland
187	Changhua Christian Hospital	Changhua		Taiwan
188	Kuohsiung Chang Gung Memorial Hospital	Kaohsiung		Taiwan
189	China Medical University Hospital	Taichung		Taiwan	40447
190	National Taiwan University Hospital	Taipei		Taiwan	100
191	Taipei Veterans General Hospital	Taipei		Taiwan
192	Chang-Gung Memorial Hospital, Linkou	Tapei		Taiwan
193	Ege University Medical Faculty	Izmir	Bornova	Turkey
194	Ankara University Medical Faculty, Cebeci Research and Application Hospital, Hematology Department	Ankara	Cebeci	Turkey	06590
195	Marmara University Pendik Training and Research Hospital	Istanbul	Pendik	Turkey
196	Cherkasy Regional Oncology Center	Cherkasy		Ukraine	18009
197	Dnipropetrovsk City Multispecialty Clinical Hospital #4, Hematology Centre	Dnipropetrovsk		Ukraine	49102
198	Kharkiv Regional Clinical Oncology Center, Department of Hematology	Kharkiv		Ukraine	61070
199	Khmelnytskyi Regional Hospital, Hematology Department	Khmelnytskyi		Ukraine	29000
200	Kyiv Center for Bone Marrow Transplantation	Kyiv		Ukraine	03 115
201	Institute of Blood Pathology and Transfusion Medicine	Lviv		Ukraine	79044
202	Poltava M.V. Sklifosovskyi Regional Clinical-Hospital	Poltava		Ukraine
203	A. Novak Zakarpattia Regional Clinical Hospital	Uzhgorod		Ukraine
204	M.I. Pyrohov Vinnytsya Regional Clinical Hospital, Hematology Department	Vinnitsya		Ukraine	21018
205	O.F. Herbachevskyi Regional Clinical Hospital, Hematology Center	Zhytomyr		Ukraine	10002
206	Kent and Canterbury Hospital	Canterbury	Kent	United Kingdom	CTI 3NG
207	Maidstone Hospital, Kent Oncology Centre	Maidstone	Kent	United Kingdom	ME16 9QQ
208	Northwick Park Hospital	Harrow	Middlesex	United Kingdom
209	Raigmore Hospital	Inverness		United Kingdom	IV2 3UJ
210	University College London, Cancer Centre	London		United Kingdom	NW1 2PG
211	Guy's and St. Thomas' NHS Foundation Trust	London		United Kingdom	SE1 9RT
212	Oxford University Hospitals NHS Trust, Churchill Hospital	Oxford		United Kingdom	OX3 7LE
213	The Royal Wolverhampton Hospitals NHS Trust, New Cross Hospital	Wolverhampton		United Kingdom	WV10 0QP

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.
• Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. doi: 10.1182/blood-2018-09-874396. Epub 2019 Feb 28.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01818752
• Other Study ID Numbers: 2012-005; 2012-005283-97; 20130397
• First Posted: Mar 26, 2013
• Last Update Posted: Aug 26, 2019
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Prednisone; Bortezomib; Melphalan

Study Results

Participant Flow

Recruitment Details	This study was conducted at 183 centers in Argentina, Australia, Austria, Belgium, Bulgaria, Canada, China, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Poland, Romania, Russia, Singapore, South Korea, Spain, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, and United States.
Pre-assignment Detail	Eligible participants were randomized in a 1:1 ratio. Randomization was stratified by International Staging System (ISS) stage (stage 1 versus stages 2 or 3), choice of route of bortezomib administration (intravenous [IV] versus subcutaneous [SC]), region (North America, Europe, Asia Pacific, or other), and age (< 75 years versus ≥ 75 years).

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Period Title: Overall Study
STARTED	477	478
Received Treatment	470	474
COMPLETED	290	280
NOT COMPLETED	187	198

Baseline Characteristics

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone	Total
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Total of all reporting groups
Overall Participants	477	478	955
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	71.5 (6.5)	72.0 (5.7)	71.7 (6.1)
Sex: Female, Male (Count of Participants)
Female	238 49.9%	235 49.2%	473 49.5%
Male	239 50.1%	243 50.8%	482 50.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 3.1%	18 3.8%	33 3.5%
Not Hispanic or Latino	443 92.9%	427 89.3%	870 91.1%
Unknown or Not Reported	19 4%	33 6.9%	52 5.4%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	2 0.4%	1 0.2%	3 0.3%
Asian	121 25.4%	123 25.7%	244 25.5%
Black or African American	0 0%	3 0.6%	3 0.3%
White	339 71.1%	329 68.8%	668 69.9%
Other	3 0.6%	1 0.2%	4 0.4%
Multiple	0 0%	2 0.4%	2 0.2%
Not Reported	12 2.5%	19 4%	31 3.2%
Stratification Factor: International Staging System (ISS) Stage (participants) [Number]
Stage I	99 20.8%	95 19.9%	194 20.3%
Stage II or III	378 79.2%	383 80.1%	761 79.7%
Stratification Factor: Route of Bortezomib Administration (participants) [Number]
Intravenous	123 25.8%	123 25.7%	246 25.8%
Subcutaneous	354 74.2%	355 74.3%	709 74.2%
Stratification Factor: Region of Enrollment (participants) [Number]
Asia Pacific	141 29.6%	140 29.3%	281 29.4%
North America	12 2.5%	8 1.7%	20 2.1%
Europe	317 66.5%	320 66.9%	637 66.7%
Other	7 1.5%	10 2.1%	17 1.8%
Stratification Factor: Age (participants) [Number]
< 75 years	329 69%	327 68.4%	656 68.7%
≥ 75 years	148 31%	151 31.6%	299 31.3%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0 (Fully active)	125 26.2%	129 27%	254 26.6%
1 (Restrictive but ambulatory)	250 52.4%	260 54.4%	510 53.4%
2 (Ambulatory but unable to work)	101 21.2%	89 18.6%	190 19.9%
Missing	1 0.2%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	Progression-free survival was defined as the time from randomization to the earlier of documented disease progression or death due to any cause. PFS was analyzed using Kaplan-Meier methods. The duration of PFS was censored for participants with no baseline and/or post-baseline disease assessments, who started a new anti-cancer therapy before documentation of disease progression or death, death or disease progression after missed disease assessment of 100 consecutive days or longer, or who were alive without documentation of disease progression before the data cutoff date, including lost to follow-up prior to disease progression. Participants were evaluated for disease response and progression according to the International Myeloma Working Group Uniform Response Criteria (IMWG-URC), determined centrally using a validated computer algorithm in a blinded manner.
Time Frame	From randomization until the data cut-off date of 15 July 2016; median follow-up time for PFS was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively.

Outcome Measure Data

Analysis Population Description

The intent-to-treat population included all randomized participants.

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	477	478
Median (95% Confidence Interval) [months]	22.1	22.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib, Melphalan, Prednisone, Carfilzomib, Melphalan, Prednisone
	Comments	The inferential test associated with the primary analysis of PFS was assessed against an overall 1-sided significance level of α=0.025.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1590
	Comments	The p-value boundary for PFS analysis was 0.02141.
	Method	Log Rank
	Comments	Log-rank p-value (1-sided) stratified by ISS stage, choice of route of bortezomib administration, region and age.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.906
	Confidence Interval	(2-Sided) 95%; 0.746 to 1.101
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Carfilzomib/Bortezomib) was estimated using a Cox proportional hazards model stratified by ISS stage, choice of route of bortezomib administration, region and age.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) was 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 on the date the patient was 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 15 July 2016; median follow-up time for OS was 22.2 and 22.5 months in the bortezomib and carfilzomib arms respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	477	478
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib, Melphalan, Prednisone, Carfilzomib, Melphalan, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8934
	Comments	Based on the pre-specified multiplicity adjustment method, secondary endpoints were to be tested only if the results of the primary endpoint were significant. The p-values for all secondary endpoints are descriptive only.
	Method	Log Rank
	Comments	Log-rank p-value (1-sided) stratified by ISS stage, choice of route of bortezomib administration, region and age.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.211
	Confidence Interval	(2-Sided) 95%; 0.896 to 1.637
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio (Carfilzomib/Bortezomib) was estimated using a Cox proportional hazards model stratified by ISS stage, choice of route of bortezomib administration, region and age.

3. Secondary Outcome

Title	Overall Response Rate
Description	Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). 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 3 weeks during the first 54 weeks and every 6 weeks thereafter until PD or the data cut-off date of 15 July 2016; median follow-up time was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	477	478
Number (95% Confidence Interval) [percentage of participants]	78.8 16.5%	84.3 17.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib, Melphalan, Prednisone, Carfilzomib, Melphalan, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0218
	Comments	Based on the pre-specified multiplicity adjustment method, secondary endpoints were to be tested only if the results of the primary endpoint were significant. The p-values for all secondary endpoints are descriptive only.
	Method	Stratified Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel Chi-square test stratified by ISS stage, choice of route of bortezomib administration, region and age.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.412
	Confidence Interval	(2-Sided) 95%; 1.010 to 1.973
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (Carfilzomib/Bortezomib) was estimated using the Mantel-Haenszel method stratified by ISS stage, choice of route of bortezomib administration, region and age.

4. Secondary Outcome

Title	Complete Response Rate
Description	Complete response rate was defined as the percentage of participants in each treatment group who achieved a sCR or CR per the IMWG-URC as their best response. 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.
Time Frame	Disease response was assessed every 3 weeks during the first 54 weeks and every 6 weeks thereafter until PD or the data cut-off date of 15 July 2016; median follow-up time was 21.6.and 22.2 months in the bortezomib and carfilzomib arms respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	477	478
Number (95% Confidence Interval) [percentage of participants]	23.1 4.8%	25.9 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib, Melphalan, Prednisone, Carfilzomib, Melphalan, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1388
	Comments	Based on the pre-specified multiplicity adjustment method, secondary endpoints were to be tested only if the results of the primary endpoint were significant. The p-values for all secondary endpoints are descriptive only.
	Method	Stratified Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel Chi-square test stratified by ISS stage, choice of route of bortezomib administration, region and age.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.179
	Confidence Interval	(2-Sided) 95%; 0.875 to 1.589
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (Carfilzomib/Bortezomib) was estimated using the Mantel-Haenszel method stratified by ISS stage, choice of route of bortezomib administration, region and age.

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 any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups.

Outcome Measure Data

Analysis Population Description

The safety population included all randomized participants who received at least 1 dose of any study treatment (i.e., carfilzomib, bortezomib, melphalan, or prednisone).

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	470	474
Number (95% Confidence Interval) [percentage of participants]	35.1 7.4%	2.5 0.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib, Melphalan, Prednisone, Carfilzomib, Melphalan, Prednisone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Based on the pre-specified multiplicity adjustment method, secondary endpoints were to be tested only if the results of the primary endpoint were significant. The p-values for all secondary endpoints are descriptive only.
	Method	Pearson Chi-Square test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.048
	Confidence Interval	(2-Sided) 95%; 0.026 to 0.088
	Parameter Dispersion	Type: Value:
	Estimation Comments	Unstratified odds ratio (Carfilzomib/Bortezomib) was estimated.

6. Secondary Outcome

Title	European Organisation for Research and Treatment of Cancer Quality of Life Core Module (EORTC QLQ-C30) Global Health Status/Quality of Life (QOL) Scores
Description	The EORTC QLQ-C30 is a validated self-rating questionnaire including 30 items used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with higher scores indicating better Global Health Status/QOL.
Time Frame	Baseline, weeks 6, 12, 18, 24, 30, 36, 42 and 48

Outcome Measure Data

Analysis Population Description

Intent-to treat population with available data at each time point.

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	477	478
Baseline (n = 425, 425)	53.3 (21.9)	53.9 (22.5)
Week 6 (n = 412, 407)	56.2 (19.5)	61.1 (19.6)
Week 12 (n = 376, 389)	55.3 (19.8)	62.4 (17.7)
Week 18 (n = 341, 369)	55.7 (18.8)	63.2 (17.4)
Week 24 (n = 320, 345)	57.3 (17.6)	63.3 (17.1)
Week 30 (n = 298, 317)	61.6 (17.8)	63.0 (17.8)
Week 36 (n = 285, 308)	61.9 (17.5)	64.0 (18.1)
Week 42 (n = 275, 288)	63.3 (17.7)	65.0 (18.1)
Week 48 (n = 261, 265)	62.9 (18.4)	65.1 (17.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bortezomib, Melphalan, Prednisone, Carfilzomib, Melphalan, Prednisone
	Comments	Treatment groups were compared using a linear mixed model for repeated measures (MMRM). The model included the fixed, categorical effects of treatment (all baseline responses were modeled with a dummy treatment), the randomization stratification factors - ISS stage, choice of route of bortezomib administration, region, age, and random effects of subject intercept and coefficient on time.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Based on the pre-specified multiplicity adjustment method, secondary endpoints were to be tested only if the results of the primary endpoint were significant. The p-values for all secondary endpoints are descriptive only.
	Method	Mixed Effects Model for Repeated Measure
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	4.99
	Confidence Interval	(2-Sided) 95%; 3.48 to 6.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.773
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Adverse events (AEs)were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where GRADE 1 = Mild; GRADE 2 = Moderate; GRADE 3 = Severe; GRADE 4 = Life-threatening; GRADE 5 = Fatal. A serious adverse event is an adverse event that met 1 or more of the following criteria: Death Life-threatening Required inpatient hospitalization or prolongation of an existing hospitalization Resulted in persistent or significant disability/incapacity Congenital anomaly/birth defect Important medical event that jeopardized the participant and may have required medical or surgical intervention to prevent 1 of the outcomes listed above. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.
Time Frame	From the first dose of any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups.

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Bortezomib, Melphalan, Prednisone	Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².	Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
Measure Participants	470	474
All adverse events	454 95.2%	460 96.2%
AEs ≥ grade 3	358 75.1%	354 74.1%
Serious adverse events	198 41.5%	235 49.2%
Leading to discontinuation of study drug	73 15.3%	83 17.4%
Fatal adverse events	20 4.2%	31 6.5%
Treatment-related adverse events (TRAEs)	431 90.4%	408 85.4%
TRAEs ≥ grade 3	285 59.7%	268 56.1%
Treatment-related serious adverse events	102 21.4%	136 28.5%
TRAE leading to discontinuation of study drug	51 10.7%	54 11.3%
Treatment-related fatal adverse events	5 1%	10 2.1%

Adverse Events

Time Frame	From the first dose of any study drug up to 30 days after the last dose of any study drug as of the data cut-off date of 15 July 2016; median duration of treatment was 52 weeks in both treatment groups.
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, Melphalan, Prednisone		Carfilzomib, Melphalan, Prednisone
Arm/Group Description	Participants received bortezomib in combination with melphalan and prednisone for nine 42-day cycles. Bortezomib was administered either IV or subcutaneously at 1.3 mg/m² during cycles 1 to 4 on days 1, 4, 8, 11, 22, 25, 29, and 32 followed by 1.3 mg/m² during cycles 5 to 9 on days 1, 8, 22, and 29. On days 1 to 4 of each cycle, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².		Participants received carfilzomib administered in combination with melphalan and prednisone for nine 42-day cycles. Carfilzomib was administered as an intravenous (IV) infusion on days 1, 2, 8, 9, 22, 23, 29, and 30 of each 42-day cycle. The carfilzomib dose was at 20 mg/m² on cycle 1, days 1 and 2 followed by 36 mg/m² thereafter. On days 1 to 4, melphalan was administered at 9 mg/m² and prednisone was administered at 60 mg/m².
All Cause Mortality
	Bortezomib, Melphalan, Prednisone		Carfilzomib, Melphalan, Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bortezomib, Melphalan, Prednisone		Carfilzomib, Melphalan, Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	198/470 (42.1%)		235/474 (49.6%)
Blood and lymphatic system disorders
Anaemia	6/470 (1.3%)		11/474 (2.3%)
Bone marrow failure	2/470 (0.4%)		0/474 (0%)
Febrile neutropenia	5/470 (1.1%)		4/474 (0.8%)
Haemolytic uraemic syndrome	0/470 (0%)		1/474 (0.2%)
Neutropenia	4/470 (0.9%)		4/474 (0.8%)
Pancytopenia	0/470 (0%)		2/474 (0.4%)
Thrombocytopenia	11/470 (2.3%)		5/474 (1.1%)
Cardiac disorders
Acute coronary syndrome	0/470 (0%)		1/474 (0.2%)
Acute left ventricular failure	1/470 (0.2%)		1/474 (0.2%)
Acute myocardial infarction	0/470 (0%)		4/474 (0.8%)
Angina pectoris	0/470 (0%)		1/474 (0.2%)
Aortic valve incompetence	0/470 (0%)		1/474 (0.2%)
Arrhythmia	1/470 (0.2%)		1/474 (0.2%)
Atrial fibrillation	4/470 (0.9%)		7/474 (1.5%)
Atrial flutter	1/470 (0.2%)		2/474 (0.4%)
Atrial tachycardia	0/470 (0%)		1/474 (0.2%)
Atrioventricular block	0/470 (0%)		1/474 (0.2%)
Atrioventricular block second degree	0/470 (0%)		1/474 (0.2%)
Cardiac amyloidosis	0/470 (0%)		1/474 (0.2%)
Cardiac arrest	1/470 (0.2%)		0/474 (0%)
Cardiac failure	7/470 (1.5%)		21/474 (4.4%)
Cardiac failure acute	1/470 (0.2%)		0/474 (0%)
Cardiac failure chronic	0/470 (0%)		1/474 (0.2%)
Cardiac failure congestive	0/470 (0%)		8/474 (1.7%)
Cardiopulmonary failure	1/470 (0.2%)		0/474 (0%)
Coronary artery disease	1/470 (0.2%)		0/474 (0%)
Coronary artery occlusion	0/470 (0%)		1/474 (0.2%)
Hypertensive cardiomegaly	0/470 (0%)		1/474 (0.2%)
Left ventricular dysfunction	0/470 (0%)		2/474 (0.4%)
Left ventricular failure	0/470 (0%)		1/474 (0.2%)
Myocardial infarction	2/470 (0.4%)		3/474 (0.6%)
Supraventricular tachycardia	1/470 (0.2%)		0/474 (0%)
Tachycardia	0/470 (0%)		1/474 (0.2%)
Ventricular extrasystoles	1/470 (0.2%)		1/474 (0.2%)
Ear and labyrinth disorders
Vertigo	1/470 (0.2%)		0/474 (0%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	2/470 (0.4%)		0/474 (0%)
Eye disorders
Diplopia	0/470 (0%)		1/474 (0.2%)
Retinopathy	0/470 (0%)		1/474 (0.2%)
Gastrointestinal disorders
Abdominal pain	1/470 (0.2%)		0/474 (0%)
Abdominal pain upper	1/470 (0.2%)		1/474 (0.2%)
Colitis	2/470 (0.4%)		1/474 (0.2%)
Constipation	1/470 (0.2%)		1/474 (0.2%)
Diarrhoea	7/470 (1.5%)		3/474 (0.6%)
Duodenal ulcer	0/470 (0%)		1/474 (0.2%)
Dyspepsia	0/470 (0%)		1/474 (0.2%)
Dysphagia	1/470 (0.2%)		0/474 (0%)
Faecaloma	1/470 (0.2%)		0/474 (0%)
Gastric haemorrhage	0/470 (0%)		1/474 (0.2%)
Gastritis	1/470 (0.2%)		0/474 (0%)
Gastrointestinal haemorrhage	2/470 (0.4%)		1/474 (0.2%)
Ileus	5/470 (1.1%)		0/474 (0%)
Ileus paralytic	1/470 (0.2%)		0/474 (0%)
Inguinal hernia	1/470 (0.2%)		1/474 (0.2%)
Intestinal haemorrhage	1/470 (0.2%)		0/474 (0%)
Intestinal obstruction	3/470 (0.6%)		0/474 (0%)
Large intestine perforation	1/470 (0.2%)		0/474 (0%)
Melaena	0/470 (0%)		1/474 (0.2%)
Nausea	2/470 (0.4%)		2/474 (0.4%)
Small intestinal haemorrhage	1/470 (0.2%)		0/474 (0%)
Small intestinal obstruction	1/470 (0.2%)		0/474 (0%)
Subileus	1/470 (0.2%)		0/474 (0%)
Vomiting	6/470 (1.3%)		3/474 (0.6%)
General disorders
Adverse drug reaction	1/470 (0.2%)		0/474 (0%)
Asthenia	6/470 (1.3%)		4/474 (0.8%)
Chest pain	1/470 (0.2%)		2/474 (0.4%)
Death	1/470 (0.2%)		0/474 (0%)
Disease progression	0/470 (0%)		1/474 (0.2%)
Fatigue	1/470 (0.2%)		1/474 (0.2%)
General physical health deterioration	5/470 (1.1%)		2/474 (0.4%)
Generalised oedema	1/470 (0.2%)		0/474 (0%)
Infusion site extravasation	0/470 (0%)		1/474 (0.2%)
Infusion site pain	0/470 (0%)		1/474 (0.2%)
Malaise	1/470 (0.2%)		0/474 (0%)
Mucosal inflammation	1/470 (0.2%)		0/474 (0%)
Multiple organ dysfunction syndrome	0/470 (0%)		2/474 (0.4%)
Non-cardiac chest pain	2/470 (0.4%)		0/474 (0%)
Oedema peripheral	0/470 (0%)		1/474 (0.2%)
Pain	1/470 (0.2%)		0/474 (0%)
Peripheral swelling	0/470 (0%)		1/474 (0.2%)
Pyrexia	9/470 (1.9%)		16/474 (3.4%)
Sudden death	1/470 (0.2%)		2/474 (0.4%)
Hepatobiliary disorders
Bile duct stone	0/470 (0%)		2/474 (0.4%)
Cholangitis acute	1/470 (0.2%)		0/474 (0%)
Cholecystitis acute	1/470 (0.2%)		1/474 (0.2%)
Cholestasis	1/470 (0.2%)		0/474 (0%)
Drug-induced liver injury	1/470 (0.2%)		0/474 (0%)
Hepatic failure	0/470 (0%)		1/474 (0.2%)
Hepatic function abnormal	0/470 (0%)		1/474 (0.2%)
Hepatitis toxic	1/470 (0.2%)		1/474 (0.2%)
Hepatocellular injury	0/470 (0%)		1/474 (0.2%)
Hepatotoxicity	0/470 (0%)		1/474 (0.2%)
Jaundice cholestatic	1/470 (0.2%)		0/474 (0%)
Immune system disorders
Hypersensitivity	0/470 (0%)		1/474 (0.2%)
Infections and infestations
Abdominal infection	0/470 (0%)		1/474 (0.2%)
Abscess limb	0/470 (0%)		1/474 (0.2%)
Bacteraemia	0/470 (0%)		1/474 (0.2%)
Bacterial infection	1/470 (0.2%)		2/474 (0.4%)
Bronchitis	3/470 (0.6%)		8/474 (1.7%)
Cellulitis	0/470 (0%)		1/474 (0.2%)
Clostridium colitis	1/470 (0.2%)		0/474 (0%)
Clostridium difficile colitis	2/470 (0.4%)		1/474 (0.2%)
Device related infection	0/470 (0%)		1/474 (0.2%)
Ear infection	0/470 (0%)		1/474 (0.2%)
Erysipelas	0/470 (0%)		1/474 (0.2%)
Escherichia infection	0/470 (0%)		1/474 (0.2%)
Gastroenteritis	2/470 (0.4%)		1/474 (0.2%)
Gastroenteritis norovirus	0/470 (0%)		1/474 (0.2%)
Gastrointestinal infection	0/470 (0%)		2/474 (0.4%)
Hepatitis C	0/470 (0%)		1/474 (0.2%)
Hepatitis viral	0/470 (0%)		1/474 (0.2%)
Infection	2/470 (0.4%)		3/474 (0.6%)
Influenza	0/470 (0%)		2/474 (0.4%)
Legionella infection	1/470 (0.2%)		0/474 (0%)
Lower respiratory tract infection	2/470 (0.4%)		1/474 (0.2%)
Lung infection	6/470 (1.3%)		5/474 (1.1%)
Otitis media	0/470 (0%)		1/474 (0.2%)
Pneumonia	31/470 (6.6%)		46/474 (9.7%)
Postoperative wound infection	0/470 (0%)		1/474 (0.2%)
Pseudomonas bronchitis	0/470 (0%)		1/474 (0.2%)
Pulmonary tuberculosis	0/470 (0%)		1/474 (0.2%)
Pyelonephritis chronic	0/470 (0%)		1/474 (0.2%)
Respiratory tract infection	1/470 (0.2%)		2/474 (0.4%)
Respiratory tract infection bacterial	1/470 (0.2%)		0/474 (0%)
Respiratory tract infection viral	0/470 (0%)		1/474 (0.2%)
Rhinovirus infection	0/470 (0%)		1/474 (0.2%)
Sepsis	7/470 (1.5%)		8/474 (1.7%)
Sepsis syndrome	0/470 (0%)		1/474 (0.2%)
Septic shock	2/470 (0.4%)		2/474 (0.4%)
Sinusitis	0/470 (0%)		2/474 (0.4%)
Tonsillitis	1/470 (0.2%)		0/474 (0%)
Tooth infection	0/470 (0%)		1/474 (0.2%)
Upper respiratory tract infection	4/470 (0.9%)		3/474 (0.6%)
Urinary tract infection	3/470 (0.6%)		5/474 (1.1%)
Urosepsis	1/470 (0.2%)		2/474 (0.4%)
Viral infection	1/470 (0.2%)		1/474 (0.2%)
Injury, poisoning and procedural complications
Ankle fracture	0/470 (0%)		1/474 (0.2%)
Cervical vertebral fracture	1/470 (0.2%)		0/474 (0%)
Fall	1/470 (0.2%)		0/474 (0%)
Femoral neck fracture	2/470 (0.4%)		4/474 (0.8%)
Femur fracture	3/470 (0.6%)		2/474 (0.4%)
Head injury	1/470 (0.2%)		1/474 (0.2%)
Heat illness	0/470 (0%)		1/474 (0.2%)
Hip fracture	1/470 (0.2%)		0/474 (0%)
Humerus fracture	1/470 (0.2%)		0/474 (0%)
Infusion related reaction	0/470 (0%)		2/474 (0.4%)
Joint dislocation	1/470 (0.2%)		0/474 (0%)
Lower limb fracture	1/470 (0.2%)		0/474 (0%)
Lumbar vertebral fracture	4/470 (0.9%)		1/474 (0.2%)
Pneumoconiosis	1/470 (0.2%)		0/474 (0%)
Radius fracture	1/470 (0.2%)		0/474 (0%)
Rib fracture	1/470 (0.2%)		0/474 (0%)
Spinal compression fracture	0/470 (0%)		2/474 (0.4%)
Spinal cord injury cervical	1/470 (0.2%)		0/474 (0%)
Spinal fracture	2/470 (0.4%)		1/474 (0.2%)
Wrist fracture	1/470 (0.2%)		0/474 (0%)
Investigations
Blood creatinine increased	2/470 (0.4%)		2/474 (0.4%)
Blood uric acid increased	0/470 (0%)		1/474 (0.2%)
C-reactive protein increased	0/470 (0%)		1/474 (0.2%)
Creatinine renal clearance decreased	0/470 (0%)		1/474 (0.2%)
Haemoglobin decreased	1/470 (0.2%)		1/474 (0.2%)
Platelet count decreased	3/470 (0.6%)		2/474 (0.4%)
Urine output decreased	1/470 (0.2%)		0/474 (0%)
Metabolism and nutrition disorders
Acidosis	1/470 (0.2%)		0/474 (0%)
Decreased appetite	2/470 (0.4%)		0/474 (0%)
Dehydration	5/470 (1.1%)		1/474 (0.2%)
Diabetes mellitus	0/470 (0%)		1/474 (0.2%)
Electrolyte imbalance	1/470 (0.2%)		1/474 (0.2%)
Hypercalcaemia	1/470 (0.2%)		1/474 (0.2%)
Hyperkalaemia	1/470 (0.2%)		2/474 (0.4%)
Hyperproteinaemia	1/470 (0.2%)		0/474 (0%)
Hypocalcaemia	1/470 (0.2%)		1/474 (0.2%)
Hypokalaemia	2/470 (0.4%)		1/474 (0.2%)
Hyponatraemia	2/470 (0.4%)		1/474 (0.2%)
Hypophosphataemia	0/470 (0%)		1/474 (0.2%)
Malnutrition	0/470 (0%)		1/474 (0.2%)
Tetany	0/470 (0%)		1/474 (0.2%)
Tumour lysis syndrome	0/470 (0%)		3/474 (0.6%)
Musculoskeletal and connective tissue disorders
Back pain	4/470 (0.9%)		6/474 (1.3%)
Bone pain	1/470 (0.2%)		3/474 (0.6%)
Bursitis	1/470 (0.2%)		0/474 (0%)
Myalgia	0/470 (0%)		1/474 (0.2%)
Pathological fracture	2/470 (0.4%)		0/474 (0%)
Polyarthritis	0/470 (0%)		1/474 (0.2%)
Spinal pain	3/470 (0.6%)		1/474 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric	0/470 (0%)		2/474 (0.4%)
Breast cancer stage I	1/470 (0.2%)		0/474 (0%)
Lung neoplasm malignant	0/470 (0%)		1/474 (0.2%)
Oesophageal adenocarcinoma	1/470 (0.2%)		0/474 (0%)
Paraneoplastic syndrome	1/470 (0.2%)		0/474 (0%)
Plasma cell myeloma	2/470 (0.4%)		0/474 (0%)
Prostate cancer	0/470 (0%)		1/474 (0.2%)
Squamous cell carcinoma of skin	0/470 (0%)		1/474 (0.2%)
Nervous system disorders
Amnesia	1/470 (0.2%)		0/474 (0%)
Aphasia	0/470 (0%)		1/474 (0.2%)
Autonomic nervous system imbalance	1/470 (0.2%)		0/474 (0%)
Autonomic neuropathy	1/470 (0.2%)		0/474 (0%)
Brain oedema	0/470 (0%)		1/474 (0.2%)
Cauda equina syndrome	1/470 (0.2%)		0/474 (0%)
Cerebral infarction	1/470 (0.2%)		2/474 (0.4%)
Cerebrovascular accident	2/470 (0.4%)		1/474 (0.2%)
Coma	0/470 (0%)		1/474 (0.2%)
Dementia	1/470 (0.2%)		0/474 (0%)
Encephalopathy	0/470 (0%)		1/474 (0.2%)
Facial paresis	1/470 (0.2%)		0/474 (0%)
Haemorrhage intracranial	0/470 (0%)		1/474 (0.2%)
Headache	0/470 (0%)		2/474 (0.4%)
Hypotonia	1/470 (0.2%)		0/474 (0%)
Ischaemic stroke	0/470 (0%)		1/474 (0.2%)
Lacunar infarction	0/470 (0%)		1/474 (0.2%)
Loss of consciousness	1/470 (0.2%)		0/474 (0%)
Memory impairment	1/470 (0.2%)		0/474 (0%)
Myoclonus	0/470 (0%)		1/474 (0.2%)
Neuralgia	1/470 (0.2%)		0/474 (0%)
Neuropathy peripheral	3/470 (0.6%)		0/474 (0%)
Peripheral motor neuropathy	1/470 (0.2%)		0/474 (0%)
Peripheral sensory neuropathy	1/470 (0.2%)		0/474 (0%)
Polyneuropathy	1/470 (0.2%)		0/474 (0%)
Presyncope	1/470 (0.2%)		0/474 (0%)
Seizure	0/470 (0%)		1/474 (0.2%)
Somnolence	0/470 (0%)		1/474 (0.2%)
Spinal cord compression	1/470 (0.2%)		0/474 (0%)
Subarachnoid haemorrhage	2/470 (0.4%)		0/474 (0%)
Syncope	5/470 (1.1%)		4/474 (0.8%)
Toxic encephalopathy	1/470 (0.2%)		0/474 (0%)
Transient ischaemic attack	0/470 (0%)		1/474 (0.2%)
Trigeminal neuralgia	1/470 (0.2%)		0/474 (0%)
VIth nerve paralysis	1/470 (0.2%)		0/474 (0%)
Psychiatric disorders
Confusional state	1/470 (0.2%)		3/474 (0.6%)
Hallucination	1/470 (0.2%)		0/474 (0%)
Illusion	1/470 (0.2%)		0/474 (0%)
Psychiatric decompensation	0/470 (0%)		1/474 (0.2%)
Renal and urinary disorders
Acute kidney injury	10/470 (2.1%)		19/474 (4%)
Chronic kidney disease	1/470 (0.2%)		3/474 (0.6%)
Prerenal failure	1/470 (0.2%)		0/474 (0%)
Renal failure	3/470 (0.6%)		14/474 (3%)
Renal impairment	1/470 (0.2%)		1/474 (0.2%)
Renal injury	1/470 (0.2%)		1/474 (0.2%)
Ureterolithiasis	1/470 (0.2%)		0/474 (0%)
Urinary retention	2/470 (0.4%)		3/474 (0.6%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/470 (0.2%)		0/474 (0%)
Pelvic pain	0/470 (0%)		1/474 (0.2%)
Prostatomegaly	0/470 (0%)		1/474 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/470 (0%)		1/474 (0.2%)
Acute respiratory distress syndrome	1/470 (0.2%)		0/474 (0%)
Asthma	0/470 (0%)		1/474 (0.2%)
Bronchitis chronic	1/470 (0.2%)		0/474 (0%)
Bronchospasm	1/470 (0.2%)		1/474 (0.2%)
Chronic obstructive pulmonary disease	1/470 (0.2%)		0/474 (0%)
Dyspnoea	3/470 (0.6%)		9/474 (1.9%)
Dyspnoea exertional	1/470 (0.2%)		0/474 (0%)
Epistaxis	0/470 (0%)		1/474 (0.2%)
Hydrothorax	0/470 (0%)		1/474 (0.2%)
Hypoxia	0/470 (0%)		1/474 (0.2%)
Interstitial lung disease	0/470 (0%)		1/474 (0.2%)
Lung disorder	0/470 (0%)		1/474 (0.2%)
Mediastinal haematoma	0/470 (0%)		1/474 (0.2%)
Pleural effusion	0/470 (0%)		1/474 (0.2%)
Pleurisy	2/470 (0.4%)		0/474 (0%)
Pneumonitis	3/470 (0.6%)		2/474 (0.4%)
Pneumothorax	0/470 (0%)		1/474 (0.2%)
Pulmonary congestion	0/470 (0%)		1/474 (0.2%)
Pulmonary embolism	1/470 (0.2%)		7/474 (1.5%)
Pulmonary fibrosis	0/470 (0%)		1/474 (0.2%)
Pulmonary hypertension	0/470 (0%)		1/474 (0.2%)
Pulmonary oedema	1/470 (0.2%)		1/474 (0.2%)
Respiratory failure	4/470 (0.9%)		6/474 (1.3%)
Respiratory tract congestion	0/470 (0%)		1/474 (0.2%)
Upper respiratory tract inflammation	0/470 (0%)		1/474 (0.2%)
Wheezing	1/470 (0.2%)		0/474 (0%)
Skin and subcutaneous tissue disorders
Diabetic foot	0/470 (0%)		1/474 (0.2%)
Erythema multiforme	1/470 (0.2%)		0/474 (0%)
Rash	3/470 (0.6%)		0/474 (0%)
Rash maculo-papular	1/470 (0.2%)		1/474 (0.2%)
Stevens-Johnson syndrome	1/470 (0.2%)		0/474 (0%)
Social circumstances
Immobile	1/470 (0.2%)		0/474 (0%)
Surgical and medical procedures
Aortic aneurysm repair	1/470 (0.2%)		0/474 (0%)
Bone operation	1/470 (0.2%)		0/474 (0%)
Vertebroplasty	0/470 (0%)		2/474 (0.4%)
Vascular disorders
Aortic dissection	1/470 (0.2%)		0/474 (0%)
Circulatory collapse	1/470 (0.2%)		0/474 (0%)
Deep vein thrombosis	0/470 (0%)		1/474 (0.2%)
Haematoma	0/470 (0%)		1/474 (0.2%)
Hypertension	2/470 (0.4%)		8/474 (1.7%)
Hypertensive crisis	0/470 (0%)		2/474 (0.4%)
Hypotension	7/470 (1.5%)		3/474 (0.6%)
Hypovolaemic shock	1/470 (0.2%)		0/474 (0%)
Orthostatic hypotension	2/470 (0.4%)		0/474 (0%)
Peripheral artery occlusion	0/470 (0%)		1/474 (0.2%)
Peripheral artery stenosis	0/470 (0%)		1/474 (0.2%)
Peripheral ischaemia	0/470 (0%)		1/474 (0.2%)
Phlebitis	0/470 (0%)		1/474 (0.2%)
Shock haemorrhagic	0/470 (0%)		1/474 (0.2%)
Other (Not Including Serious) Adverse Events
	Bortezomib, Melphalan, Prednisone		Carfilzomib, Melphalan, Prednisone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	437/470 (93%)		437/474 (92.2%)
Blood and lymphatic system disorders
Anaemia	143/470 (30.4%)		168/474 (35.4%)
Leukopenia	39/470 (8.3%)		34/474 (7.2%)
Neutropenia	121/470 (25.7%)		121/474 (25.5%)
Thrombocytopenia	91/470 (19.4%)		84/474 (17.7%)
Gastrointestinal disorders
Abdominal distension	27/470 (5.7%)		10/474 (2.1%)
Abdominal pain	27/470 (5.7%)		12/474 (2.5%)
Abdominal pain upper	32/470 (6.8%)		21/474 (4.4%)
Constipation	114/470 (24.3%)		65/474 (13.7%)
Diarrhoea	132/470 (28.1%)		95/474 (20%)
Nausea	132/470 (28.1%)		167/474 (35.2%)
Vomiting	88/470 (18.7%)		116/474 (24.5%)
General disorders
Asthenia	67/470 (14.3%)		70/474 (14.8%)
Chest pain	11/470 (2.3%)		24/474 (5.1%)
Chills	14/470 (3%)		44/474 (9.3%)
Fatigue	85/470 (18.1%)		78/474 (16.5%)
Oedema peripheral	54/470 (11.5%)		84/474 (17.7%)
Pyrexia	80/470 (17%)		168/474 (35.4%)
Infections and infestations
Bronchitis	39/470 (8.3%)		40/474 (8.4%)
Nasopharyngitis	33/470 (7%)		31/474 (6.5%)
Pneumonia	27/470 (5.7%)		30/474 (6.3%)
Upper respiratory tract infection	50/470 (10.6%)		49/474 (10.3%)
Urinary tract infection	26/470 (5.5%)		29/474 (6.1%)
Investigations
Alanine aminotransferase increased	16/470 (3.4%)		28/474 (5.9%)
Blood creatinine increased	22/470 (4.7%)		35/474 (7.4%)
Neutrophil count decreased	71/470 (15.1%)		55/474 (11.6%)
Platelet count decreased	61/470 (13%)		48/474 (10.1%)
Weight decreased	24/470 (5.1%)		15/474 (3.2%)
White blood cell count decreased	58/470 (12.3%)		51/474 (10.8%)
Metabolism and nutrition disorders
Decreased appetite	88/470 (18.7%)		67/474 (14.1%)
Hyperglycaemia	37/470 (7.9%)		30/474 (6.3%)
Hyperuricaemia	22/470 (4.7%)		28/474 (5.9%)
Hypocalcaemia	41/470 (8.7%)		47/474 (9.9%)
Hypokalaemia	63/470 (13.4%)		53/474 (11.2%)
Hyponatraemia	24/470 (5.1%)		16/474 (3.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	33/470 (7%)		32/474 (6.8%)
Back pain	56/470 (11.9%)		53/474 (11.2%)
Bone pain	29/470 (6.2%)		31/474 (6.5%)
Pain in extremity	46/470 (9.8%)		30/474 (6.3%)
Nervous system disorders
Dizziness	39/470 (8.3%)		45/474 (9.5%)
Headache	23/470 (4.9%)		44/474 (9.3%)
Hypoaesthesia	26/470 (5.5%)		14/474 (3%)
Neuralgia	45/470 (9.6%)		2/474 (0.4%)
Neuropathy peripheral	154/470 (32.8%)		29/474 (6.1%)
Paraesthesia	32/470 (6.8%)		24/474 (5.1%)
Peripheral sensory neuropathy	64/470 (13.6%)		8/474 (1.7%)
Polyneuropathy	36/470 (7.7%)		5/474 (1.1%)
Psychiatric disorders
Insomnia	65/470 (13.8%)		49/474 (10.3%)
Respiratory, thoracic and mediastinal disorders
Cough	63/470 (13.4%)		63/474 (13.3%)
Dyspnoea	34/470 (7.2%)		72/474 (15.2%)
Skin and subcutaneous tissue disorders
Pruritus	22/470 (4.7%)		41/474 (8.6%)
Rash	47/470 (10%)		26/474 (5.5%)
Vascular disorders
Hypertension	32/470 (6.8%)		102/474 (21.5%)
Hypotension	37/470 (7.9%)		17/474 (3.6%)

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.