ARROW: Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02412878
• Collaborator: (none)
• Enrollment: 478
• Locations: 140
• Arms: 2
• Actual Duration (Months): 40
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to compare the progression-free survival (PFS) of once-weekly carfilzomib dosing in combination with dexamethasone to twice-weekly carfilzomib dosing in combination with dexamethasone in adults with relapsed and refractory multiple myeloma, previously treated with bortezomib and an immunomodulatory agent (IMiD).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 478 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label, Phase 3 Study in Subjects With Relapsed and Refractory Multiple Myeloma Receiving Carfilzomib in Combination With Dexamethasone, Comparing Once-weekly Versus Twice-weekly Carfilzomib Dosing
• Actual Study Start Date: Sep 9, 2015
• Actual Primary Completion Date: Jun 15, 2017
• Actual Study Completion Date: Jan 7, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Drug: Carfilzomib; Carfilzomib was administered as an IV infusion; Other Names: PR-171 PR171 Kyprolis® (carfilzomib) for Injection ; Drug: Dexamethasone; Commercially available dexamethasone was obtained by the investigational site.
Experimental: Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone Participants received carfilzomib administered by IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Drug: Carfilzomib; Carfilzomib was administered as an IV infusion; Other Names: PR-171 PR171 Kyprolis® (carfilzomib) for Injection ; Drug: Dexamethasone; Commercially available dexamethasone was obtained by the investigational site.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively.]

   Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.

Secondary Outcome Measures

1. Overall Response Rate [Disease response was assessed every 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively.]

   Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate 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.

2. Overall Survival [From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively.]

   Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive.

3. Number of Participants With Adverse Events (AEs) [From first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.]

   The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. Treatment-related adverse events are adverse events considered related to at least 1 investigational product by the investigator, including those with unknown relationship.

4. Plasma Carfilzomib Concentration During Cycle 2 [Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion]

   Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL.

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

1. Relapsed multiple myeloma

2. Refractory multiple myeloma defined as meeting 1 or more of the following:

• Nonresponsive to most recent therapy (stable disease only or PD while on treatment), or

• Disease progression within 60 days of discontinuation from most recent therapy

1. At least 2 but no more than 3 prior therapies for multiple myeloma

2. Prior exposure to an immunomodulatory agent (IMiD)

3. Prior exposure to a proteasome inhibitor (PI)

4. Documented response of at least partial response (PR) to 1 line of prior therapy

5. Measurable disease with at least 1 of the following assessed within the 21 days prior to randomization:

• Serum M-protein ≥ 0.5 g/dL

• Urine M-protein ≥ 200 mg/24 hours

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

1. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1

2. Left ventricular ejection fraction (LVEF) ≥ 40% within the 21 days prior to randomization

3. Adequate organ and bone marrow function within the 21 days prior to randomization defined by:

• Bilirubin < 1.5 times the upper limit of normal (ULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times the ULN

• Absolute neutrophil count (ANC) ≥ 1000/mm³ (screening ANC should be independent of growth factor support for ≥ 1 week)

• Hemoglobin ≥ 8.0 g/dL (Use of erythropoietic stimulating factors and red blood cell [RBC] transfusion per institutional guidelines is allowed, however the most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin.)

• Platelet count ≥ 50,000/mm³ (≥ 30,000/mm³ if myeloma involvement in the bone marrow is > 50%. Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count.)

• Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min

Key Exclusion Criteria:

1. Waldenström macroglobulinemia

2. Multiple myeloma of Immunoglobin M (IgM) subtype

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

4. Plasma cell leukemia (> 2.0 × 10⁹/L circulating plasma cells by standard differential)

5. Myelodysplastic syndrome

6. Second malignancy within the past 5 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

• Ductal breast carcinoma in situ with full surgical resection (i.e., negative margins)

• Treated medullary or papillary thyroid cancer

• Similar condition with an expectation of > 95% five-year disease-free survival

1. History of or current amyloidosis

2. Cytotoxic chemotherapy within the 28 days prior to randomization

3. Immunotherapy within the 21 days prior to randomization

4. Glucocorticoid therapy within the 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or 1000 mg prednisone

5. Radiation therapy:

• Focal therapy within the 7 days prior to randomization

• Extended field therapy within the 21 days prior to randomization

1. Prior treatment with either carfilzomib or oprozomib

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

3. Contraindication to dexamethasone or any of the required concomitant drugs or supportive treatments, including hypersensitivity to antiviral drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment

4. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, acute diffuse infiltrative pulmonary disease, pericardial disease, or myocardial infarction within 6 months prior to enrollment

5. Active infection within the 14 days prior to randomization requiring systemic antibiotics

6. Pleural effusions requiring thoracentesis within the 14 days prior to randomization

7. Ascites requiring paracentesis within the 14 days prior to randomization

8. Ongoing graft-versus-host disease

9. Uncontrolled hypertension or uncontrolled diabetes despite medication

10. Significant neuropathy (≥ Grade 3) within the 14 days prior to randomization

11. Known cirrhosis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Scottsdale	Arizona	United States	85259-5499
2	Mayo Clinic	Scottsdale	Arizona	United States
3	Research Site	Bethesda	Maryland	United States	20817
4	Center for Cancer and Blood Disorders	Bethesda	Maryland	United States
5	Research Site	Rockville	Maryland	United States	20850
6	Maryland Oncology Hematology, P.A	Rockville	Maryland	United States
7	Research Site	Hackensack	New Jersey	United States	07601
8	John Theurer Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey	United States
9	Research Site	New York	New York	United States	10021
10	Research Site	Pittsburgh	Pennsylvania	United States	15224
11	Research Site	Tyler	Texas	United States	75701
12	Blood and Cancer Center of East Texas	Tyler	Texas	United States
13	Research Site	Darlinghurst	New South Wales	Australia	2010
14	Research Site	Tweed Heads	New South Wales	Australia	2485
15	Research Site	Waratah	New South Wales	Australia	2298
16	Research Site	Box Hill	Victoria	Australia	3128
17	Research Site	Antwerpen		Belgium	2060
18	Research Site	Brugge		Belgium	8000
19	Research Site	Brussel		Belgium	1090
20	Research Site	Bruxelles		Belgium	1200
21	Research Site	Ghent		Belgium	9000
22	Research Site	Leuven		Belgium	3000
23	Research Site	Calgary	Alberta	Canada	T2N 2T9
24	Research Site	Kelowna	British Columbia	Canada	V1Y 5L3
25	Research Site	Vancouver	British Columbia	Canada	V5Z 1M9
26	Research Site	St. Johns	Newfoundland and Labrador	Canada	A1B 3V6
27	Research Site	Halifax	Nova Scotia	Canada	B3H 2Y9
28	Research Site	Ottawa	Ontario	Canada	K1H 8L6
29	Research Site	Toronto	Ontario	Canada	M5G 2M9
30	Research Site	Montreal	Quebec	Canada	H4J 1C5
31	Research Site	Quebec		Canada	G1J 1Z4
32	Research Site	Brno		Czechia	625 00
33	Research Site	Hradec Kralove		Czechia	500 05
34	Research Site	Olomouc		Czechia	775 20
35	Research Site	Ostrava-Poruba		Czechia	708 52
36	Research Site	Praha 10		Czechia	100 34
37	Research Site	Praha		Czechia	128 08
38	Research Site	Aalborg		Denmark	9000
39	Research Site	Copenhagen		Denmark	2100
40	Research Site	Odense C		Denmark	5000
41	Research Site	Vejle		Denmark	7100
42	Research Site	Helsinki		Finland	00290
43	Research Site	Tampere		Finland	33521
44	Research Site	Turku		Finland	20520
45	Research Site	Bayonne		France	64109
46	Research Site	Brest		France	29609
47	Research Site	Dijon		France	21000
48	Research Site	Nantes Cedex 1		France	44093
49	Research Site	Nimes cedex 09		France	30029
50	Research Site	Paris		France	75012
51	Research Site	Pierre-Benite cedex		France	69495
52	Research Site	Rennes		France	35033
53	Research Site	Tours Cedex 1		France	37044
54	Research Site	Köln		Germany	50937
55	Research Site	Leipzig		Germany	04103
56	Research Site	München		Germany	81241
57	Research Site	Rostock		Germany	18057
58	Research Site	Tubingen		Germany	72076
59	Research Site	Athens		Greece	10676
60	Research Site	Athens		Greece	11528
61	Research Site	Patra		Greece	26504
62	Research Site	Budapest		Hungary	1097
63	Research Site	Debrecen		Hungary	4032
64	Research Site	Gyula		Hungary	5700
65	Research Site	Kaposvar		Hungary	7400
66	Research Site	Ancona		Italy	60126
67	Research Site	Bologna		Italy	40138
68	Research Site	Brescia		Italy	25123
69	Research Site	Cagliari		Italy	09121
70	Research Site	Catania		Italy	95124
71	Research Site	Firenze		Italy	50134
72	Research Site	Genova		Italy	16132
73	Research Site	Napoli		Italy	80131
74	Research Site	Pavia		Italy	27100
75	Research Site	Piacenza		Italy	29100
76	Research Site	Pisa		Italy	56100
77	Research Site	Roma		Italy	00161
78	Research Site	Roma		Italy	00168
79	Research Site	Torino		Italy	10126
80	Research Site	Toyohashi-shi	Aichi	Japan	441-8570
81	Research Site	Fukuoka-shi	Fukuoka	Japan	812-8582
82	Research Site	Ogaki-shi	Gifu	Japan	503-8502
83	Research Site	Maebashi-shi	Gunma	Japan	371-8511
84	Research Site	Shibukawa-shi	Gunma	Japan	377-8511
85	Research Site	Sapporo-shi	Hokkaido	Japan	060-8543
86	Research Site	Isehara-shi	Kanagawa	Japan	259-1193
87	Research Site	Kyoto-shi	Kyoto	Japan	602-8566
88	Research Site	Sendai-shi	Miyagi	Japan	980-8574
89	Research Site	Okayama-shi	Okayama	Japan	701-1192
90	Research Site	Suita-shi	Osaka	Japan	565-0871
91	Research Site	Kawagoe-shi	Saitama	Japan	350-8550
92	Research Site	Utsunomiya-shi	Tochigi	Japan	320-0834
93	Research Site	Chuo-ku	Tokyo	Japan	104-0045
94	Research Site	Koto-ku	Tokyo	Japan	135-8550
95	Research Site	Shibuya-ku	Tokyo	Japan	150-8935
96	Research Site	Tachikawa-shi	Tokyo	Japan	190-0014
97	Research Site	Fukuoka-shi		Japan	811-1395
98	Research Site	Nagoya-shi		Japan	467-8602
99	Research Site	Niigata-shi		Japan	951-8566
100	Research Site	Tokushima-shi		Japan	770-8539
101	Research Site	Christchurch		New Zealand	8011
102	Research Site	Otahuhu, Auckland		New Zealand	1640
103	Research Site	Oslo		Norway	0372
104	Research Site	Trondheim		Norway	7006
105	Research Site	Brzozow		Poland	36-200
106	Research Site	Chorzow		Poland	41-500
107	Research Site	Katowice		Poland	40-032
108	Research Site	Krakow		Poland	31-501
109	Research Site	Lodz		Poland	93-510
110	Research Site	Olsztyn		Poland	10-228
111	Research Site	Poznan		Poland	60-569
112	Research Site	Torun		Poland	87-100
113	Research Site	Warszawa		Poland	02-106
114	Research Site	Wroclaw		Poland	50-367
115	Research Site	Brazov		Romania	500152
116	Research Site	Bucharest		Romania	022328
117	Research Site	Sevilla	Andalucía	Spain	41013
118	Research Site	Zaragoza	Aragón	Spain	50012
119	Research Site	Palma de Mallorca	Baleares	Spain	07010
120	Research Site	Salamanca	Castilla León	Spain	37007
121	Research Site	Badalona	Cataluña	Spain	08916
122	Research Site	Barcelona	Cataluña	Spain	08036
123	Research Site	Girona	Cataluña	Spain	17007
124	Research Site	Pamplona	Navarra	Spain	31008
125	Research Site	Madrid		Spain	28034
126	Research Site	Madrid		Spain	28040
127	Research Site	Madrid		Spain	28041
128	Research Site	Goteborg		Sweden	413 45
129	Research Site	Helsingborg		Sweden	251 87
130	Research Site	Lund		Sweden	221 85
131	Research Site	Stockholm		Sweden	141 86
132	Research Site	Stockholm		Sweden	171 76
133	Research Site	Uddevalla		Sweden	451 80
134	Research Site	Bournemouth		United Kingdom	BH7 7DW
135	Research Site	London		United Kingdom	EC1A 7BE
136	Research Site	London		United Kingdom	NW1 2PG
137	Research Site	Manchester		United Kingdom	M13 9WL
138	Research Site	Nottingham		United Kingdom	NG5 1PB
139	Research Site	Sheffield		United Kingdom	S10 2JF
140	Research Site	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Mar 7, 2017
• Statistical Analysis Plan - Jun 9, 2017

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. doi: 10.1016/S1470-2045(18)30354-1. Epub 2018 Jun 1. Erratum in: Lancet Oncol. 2018 Aug;19(8):e382.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02412878
• Other Study ID Numbers: CFZ014; 2014-005325-12; 20140355
• First Posted: Apr 9, 2015
• Last Update Posted: Dec 16, 2019
• Last Verified: Nov 1, 2019

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone

Study Results

Participant Flow

Recruitment Details	Participants were enrolled from September 2015 to August 2016 at 118 sites in Australia, New Zealand, Japan, North America, and Europe.
Pre-assignment Detail	Participants were randomized in a 1:1 ratio to receive a regimen consisting of either once-weekly or twice weekly carfilzomib in combination with dexamethasone. Randomization was stratified by International Staging System (ISS) stage (stage 1 vs stages 2 or 3), refractory to bortezomib treatment (yes vs no), and age (< 65 vs ≥ 65 years).

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
Period Title: Overall Study
STARTED	238	240
Received Carfilzomib	235	238
COMPLETED	217	227
NOT COMPLETED	21	13

Baseline Characteristics

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone	Total
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Total of all reporting groups
Overall Participants	238	240	478
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	66.0	66.0	66.0
Age, Customized (Count of Participants)
18 - 64 years	104 43.7%	104 43.3%	208 43.5%
65 - 74 years	102 42.9%	90 37.5%	192 40.2%
75 - 84 years	32 13.4%	45 18.8%	77 16.1%
≥ 85 years	0 0%	1 0.4%	1 0.2%
Sex: Female, Male (Count of Participants)
Female	110 46.2%	108 45%	218 45.6%
Male	128 53.8%	132 55%	260 54.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 2.1%	2 0.8%	7 1.5%
Not Hispanic or Latino	226 95%	235 97.9%	461 96.4%
Unknown or Not Reported	7 2.9%	3 1.3%	10 2.1%
Race/Ethnicity, Customized (Count of Participants)
Asian	15 6.3%	30 12.5%	45 9.4%
Black or African American	2 0.8%	3 1.3%	5 1%
White	202 84.9%	200 83.3%	402 84.1%
Other	9 3.8%	4 1.7%	13 2.7%
Missing	10 4.2%	3 1.3%	13 2.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 (Fully active)	118 49.6%	118 49.2%	236 49.4%
1 (Restrictive but ambulatory)	120 50.4%	121 50.4%	241 50.4%
2 (Ambulatory but unable to work)	0 0%	1 0.4%	1 0.2%
Stratification Factor: International Staging System (ISS) stage (Count of Participants)
Stage 1	100 42%	100 41.7%	200 41.8%
Stage 2 or 3	138 58%	140 58.3%	278 58.2%
Stratification Factor: Refractory to Bortezomib Treatment (Count of Participants)
Yes	88 37%	88 36.7%	176 36.8%
No	150 63%	152 63.3%	302 63.2%

Outcome Measures

1. Secondary Outcome

Title	Overall Response Rate
Description	Disease response was evaluated according to the IMWG-URC using a validated computer algorithm. Overall response rate 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 28 days until progressive disease, up to the data cut-off date of 15 June 2017; median time on follow-up was 12.0 and 12.6 months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
Measure Participants	238	240
Number (95% Confidence Interval) [percentage of participants]	40.8 17.1%	62.9 26.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
	Method	Cochran-Mantel-Haenszel
	Comments	One-sided p-value from CMH test stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.485
	Confidence Interval	(2-Sided) 95%; 1.716 to 3.598
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was calculated using the Mantel-Haenszel method stratified by the randomization stratification factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.466
	Confidence Interval	(2-Sided) 95%; 1.707 to 3.563
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was calculated using the Mantel-Haenszel method.

2. 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. Disease status was assessed at a central laboratory with serum and urine protein electrophoresis, immunofixation, serum-free light chain (SFLC) assay, bone marrow sample evaluation, serum calcium, plasmacytoma evaluation, and skeletal survey. Response and disease progression were determined using a validated computer algorithm based on the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). Median PFS was derived using the Kaplan-Meier method; participants still alive with no disease progression were censored at the time of their last disease assessment.
Time Frame	From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for PFS was 12.0 (0, 20) and 12.6 (0, 19) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
Measure Participants	238	240
Median (95% Confidence Interval) [months]	7.6	11.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Comments	To ensure proper control of type I error, analysis of PFS was performed under a group sequential design framework with the stopping boundaries constructed using the Lan-DeMets spending function with an O'Brien-Fleming approach. The inferential comparison between the 2 treatment groups for PFS used the 1-sided log-rank test stratified by the randomization stratification factors. A 1-sided p-value was compared against the prespecified adjusted alpha value of 0.011 to determine significance.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments	Progression-free survival, overall response rate, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
	Method	Log Rank
	Comments	One-sided stratified log-rank test, stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.693
	Confidence Interval	(2-Sided) 95%; 0.544 to 0.883
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using a Cox proportional hazards model stratified by the randomization stratification factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments
	Method	Log Rank
	Comments	One-sided unstratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.720
	Confidence Interval	(2-Sided) 95%; 0.567 to 0.913
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using an unstratified Cox proportional hazards model.

3. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the time from randomization to death due to any cause. Median overall survival was derived using the Kaplan-Meier method; participants still alive were censored at the date last known to be alive.
Time Frame	From randomization until the data cut-off date of 15 June 2017; median (minimum, maximum) follow-up time for OS was 12.6 (0, 20) and 13.2 (0, 19) months in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

Intent-to-treat population

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
Measure Participants	238	240
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1070
	Comments	Progression-free survival, overall response, and overall survival were tested using a fixed sequence hierarchical testing procedure to control the family-wise type I error rate below one-sided 0.025 level.
	Method	Log Rank
	Comments	One-sided stratified log-rank test, stratified by the randomization factors (ISS stage at study entry, refractory to bortezomib treatment, and age).
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.800
	Confidence Interval	(2-Sided) 95%; 0.563 to 1.138
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using a Cox proportional hazards model stratified by the randomization stratification factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone, Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1326
	Comments
	Method	Log Rank
	Comments	One-sided unstratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.820
	Confidence Interval	(2-Sided) 95%; 0.578 to 1.164
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio (once weekly carfilzomib 20/70 mg/m²/ twice weekly carfilzomib 20/27 mg/m²) was estimated using an unstratified Cox proportional hazards model.

4. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	The severity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, where where Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life-threatening; Grade 5 = Fatal. 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 first dose of study drug up to 30 days after last dose, up to the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
Measure Participants	235	238
Adverse events (AEs)	230 96.6%	233 97.1%
Adverse events Grade ≥ 3	152 63.9%	181 75.4%
Serious adverse events	102 42.9%	118 49.2%
AEs leading to discontinuation of carfilzomib	29 12.2%	35 14.6%
AEs leading to discontinuation of dexamethasone	31 13%	40 16.7%
Fatal adverse events	20 8.4%	21 8.8%
Treatment-related adverse events (TRAEs)	176 73.9%	180 75%
Treatment-related adverse events Grade ≥ 3	82 34.5%	108 45%
Serious treatment-related adverse events	31 13%	57 23.8%
TRAE leading to discontinuation of carfilzomib	11 4.6%	23 9.6%
TRAEs leading to discontinuation of dexamethasone	13 5.5%	29 12.1%
Fatal treatment-related adverse events	3 1.3%	5 2.1%

5. Secondary Outcome

Title	Plasma Carfilzomib Concentration During Cycle 2
Description	Concentrations of carfilzomib in plasma were measured using a validated assay method. The lower limit of quantification was 0.100 ng/mL.
Time Frame	Cycle 2 day 1 predose, 15 minutes after the start of infusion (once-weekly carfilzomib only), end of infusion, and 30 minutes after the end of infusion

Outcome Measure Data

Analysis Population Description

Participants at a subset of sites who participated in the sparse pharmacokinetic sampling, with available data at each time point.

Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.	Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
Measure Participants	36	55
Predose	36.2 (162)	203 (1380)
15 minutes after start of infusion	1370 (1410)
End of infusion	1640 (1900)	1130 (928)
30 minutes after end of infusion	104 (293)	480 (2300)

Adverse Events

Time Frame	All-cause mortality includes deaths that occurred from randomization until the end of study; median (minimum, maximum) follow-up time was 30.7 (0, 39) and 31.2 (0, 38) months in each treatment group respectively. Adverse events are reported from the first dose of study drug up to 30 days after last dose, as of the end of study; median (minimum, maximum) duration of treatment was 29.1 (0.1, 156.3) weeks and 38.0 (0.1, 158.3) weeks in each treatment group respectively.
Adverse Event Reporting Description	All-cause mortality is reported for all participants randomized in the study. Serious adverse events and other adverse events are reported for all participants who received at least one dose of study drug.
Arm/Group Title	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone		Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
Arm/Group Description	Participants received carfilzomib administered by intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m² on days 1 and 2 of cycle 1 and 27 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.		Participants received carfilzomib administered by IV infusion on days 1, 8, and 15 of each 28-day cycle (20 mg/m² on day 1 of cycle 1 and 70 mg/m² thereafter). Participants also received 40 mg dexamethasone IV or orally on days 1, 8, 15 and 22 for the first 8 cycles; starting with cycle 9, dexamethasone was administered only on days 1, 8, and 15.
All Cause Mortality
	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone		Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	127/238 (53.4%)		119/240 (49.6%)
Serious Adverse Events
	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone		Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/235 (43.4%)		118/238 (49.6%)
Blood and lymphatic system disorders
Anaemia	8/235 (3.4%)		4/238 (1.7%)
Anaemia folate deficiency	1/235 (0.4%)		0/238 (0%)
Anaemia vitamin B12 deficiency	1/235 (0.4%)		0/238 (0%)
Febrile neutropenia	0/235 (0%)		1/238 (0.4%)
Haemolytic uraemic syndrome	0/235 (0%)		1/238 (0.4%)
Hyperviscosity syndrome	0/235 (0%)		1/238 (0.4%)
Thrombocytopenia	3/235 (1.3%)		3/238 (1.3%)
Thrombotic microangiopathy	0/235 (0%)		2/238 (0.8%)
Cardiac disorders
Acute myocardial infarction	1/235 (0.4%)		2/238 (0.8%)
Atrial fibrillation	3/235 (1.3%)		2/238 (0.8%)
Atrial flutter	0/235 (0%)		1/238 (0.4%)
Cardiac arrest	1/235 (0.4%)		1/238 (0.4%)
Cardiac failure	3/235 (1.3%)		3/238 (1.3%)
Cardiac failure acute	2/235 (0.9%)		3/238 (1.3%)
Cardiac failure congestive	3/235 (1.3%)		1/238 (0.4%)
Cardiopulmonary failure	0/235 (0%)		1/238 (0.4%)
Left ventricular dysfunction	1/235 (0.4%)		0/238 (0%)
Myocardial ischaemia	0/235 (0%)		1/238 (0.4%)
Stress cardiomyopathy	1/235 (0.4%)		0/238 (0%)
Supraventricular tachycardia	1/235 (0.4%)		0/238 (0%)
Endocrine disorders
Adrenal insufficiency	1/235 (0.4%)		0/238 (0%)
Eye disorders
Cataract	2/235 (0.9%)		1/238 (0.4%)
Retinal detachment	1/235 (0.4%)		1/238 (0.4%)
Retinal vein occlusion	1/235 (0.4%)		0/238 (0%)
Gastrointestinal disorders
Diarrhoea	1/235 (0.4%)		1/238 (0.4%)
Gastric haemorrhage	0/235 (0%)		1/238 (0.4%)
Gastritis	0/235 (0%)		1/238 (0.4%)
Nausea	0/235 (0%)		1/238 (0.4%)
Pancreatitis	1/235 (0.4%)		0/238 (0%)
Peritoneal haematoma	0/235 (0%)		1/238 (0.4%)
Rectal haemorrhage	1/235 (0.4%)		0/238 (0%)
Retroperitoneal haematoma	0/235 (0%)		1/238 (0.4%)
Mallory-Weiss syndrome	0/235 (0%)		1/238 (0.4%)
General disorders
Asthenia	0/235 (0%)		2/238 (0.8%)
Catheter site vesicles	1/235 (0.4%)		0/238 (0%)
Chest pain	0/235 (0%)		1/238 (0.4%)
Critical illness	1/235 (0.4%)		0/238 (0%)
Death	1/235 (0.4%)		1/238 (0.4%)
Disease progression	3/235 (1.3%)		2/238 (0.8%)
Fatigue	0/235 (0%)		3/238 (1.3%)
Papillitis	1/235 (0.4%)		0/238 (0%)
Pyrexia	5/235 (2.1%)		4/238 (1.7%)
Drug intolerance	0/235 (0%)		1/238 (0.4%)
Non-cardiac chest pain	0/235 (0%)		2/238 (0.8%)
Hepatobiliary disorders
Cholecystitis acute	1/235 (0.4%)		0/238 (0%)
Hepatic failure	1/235 (0.4%)		0/238 (0%)
Cholecystitis	1/235 (0.4%)		0/238 (0%)
Infections and infestations
Bronchitis	4/235 (1.7%)		1/238 (0.4%)
Bronchitis bacterial	0/235 (0%)		1/238 (0.4%)
Bronchopulmonary aspergillosis	1/235 (0.4%)		0/238 (0%)
Diverticulitis	1/235 (0.4%)		0/238 (0%)
Erysipelas	1/235 (0.4%)		0/238 (0%)
Gastroenteritis	1/235 (0.4%)		1/238 (0.4%)
Infected skin ulcer	1/235 (0.4%)		0/238 (0%)
Infection	2/235 (0.9%)		4/238 (1.7%)
Influenza	2/235 (0.9%)		4/238 (1.7%)
Lower respiratory tract infection	1/235 (0.4%)		2/238 (0.8%)
Lower respiratory tract infection viral	1/235 (0.4%)		0/238 (0%)
Lung infection	0/235 (0%)		3/238 (1.3%)
Lung infection pseudomonal	0/235 (0%)		1/238 (0.4%)
Neutropenic infection	1/235 (0.4%)		0/238 (0%)
Osteomyelitis	1/235 (0.4%)		0/238 (0%)
Otitis media acute	0/235 (0%)		1/238 (0.4%)
Periodontitis	1/235 (0.4%)		0/238 (0%)
Pneumonia	22/235 (9.4%)		23/238 (9.7%)
Pneumonia bacterial	3/235 (1.3%)		3/238 (1.3%)
Pneumonia haemophilus	0/235 (0%)		1/238 (0.4%)
Pneumonia streptococcal	1/235 (0.4%)		0/238 (0%)
Pyelonephritis acute	1/235 (0.4%)		0/238 (0%)
Respiratory syncytial virus infection	2/235 (0.9%)		0/238 (0%)
Respiratory tract infection	1/235 (0.4%)		3/238 (1.3%)
Sepsis	3/235 (1.3%)		6/238 (2.5%)
Septic shock	2/235 (0.9%)		5/238 (2.1%)
Spinal cord infection	1/235 (0.4%)		0/238 (0%)
Upper respiratory tract infection	4/235 (1.7%)		1/238 (0.4%)
Urinary tract infection	1/235 (0.4%)		2/238 (0.8%)
Wound infection bacterial	1/235 (0.4%)		0/238 (0%)
Gastroenteritis viral	0/235 (0%)		1/238 (0.4%)
Perineal abscess	1/235 (0.4%)		0/238 (0%)
Post procedural sepsis	0/235 (0%)		1/238 (0.4%)
Respiratory tract infection viral	0/235 (0%)		1/238 (0.4%)
Staphylococcal sepsis	0/235 (0%)		1/238 (0.4%)
Injury, poisoning and procedural complications
Contusion	1/235 (0.4%)		0/238 (0%)
Fall	1/235 (0.4%)		0/238 (0%)
Femoral neck fracture	1/235 (0.4%)		1/238 (0.4%)
Femur fracture	1/235 (0.4%)		1/238 (0.4%)
Infusion related reaction	1/235 (0.4%)		1/238 (0.4%)
Limb traumatic amputation	1/235 (0.4%)		0/238 (0%)
Rib fracture	2/235 (0.9%)		0/238 (0%)
Upper limb fracture	0/235 (0%)		1/238 (0.4%)
Humerus fracture	1/235 (0.4%)		0/238 (0%)
Tibia fracture	0/235 (0%)		1/238 (0.4%)
Traumatic fracture	0/235 (0%)		1/238 (0.4%)
Investigations
Alanine aminotransferase increased	0/235 (0%)		1/238 (0.4%)
Aspartate aminotransferase increased	0/235 (0%)		1/238 (0.4%)
Blood creatinine increased	2/235 (0.9%)		1/238 (0.4%)
Blood lactate dehydrogenase increased	0/235 (0%)		1/238 (0.4%)
C-reactive protein increased	0/235 (0%)		1/238 (0.4%)
Ejection fraction decreased	1/235 (0.4%)		1/238 (0.4%)
Liver function test abnormal	1/235 (0.4%)		0/238 (0%)
Platelet count decreased	2/235 (0.9%)		2/238 (0.8%)
General physical condition abnormal	1/235 (0.4%)		0/238 (0%)
Monoclonal immunoglobulin present	0/235 (0%)		1/238 (0.4%)
Metabolism and nutrition disorders
Dehydration	0/235 (0%)		1/238 (0.4%)
Diabetes mellitus	1/235 (0.4%)		0/238 (0%)
Hypercalcaemia	4/235 (1.7%)		2/238 (0.8%)
Hyperglycaemia	1/235 (0.4%)		0/238 (0%)
Hyperuricaemia	0/235 (0%)		1/238 (0.4%)
Tumour lysis syndrome	1/235 (0.4%)		4/238 (1.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/235 (0.4%)		0/238 (0%)
Back pain	2/235 (0.9%)		0/238 (0%)
Bone pain	1/235 (0.4%)		2/238 (0.8%)
Osteolysis	1/235 (0.4%)		1/238 (0.4%)
Pain in extremity	1/235 (0.4%)		0/238 (0%)
Pathological fracture	1/235 (0.4%)		3/238 (1.3%)
Bone lesion	0/235 (0%)		1/238 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung adenocarcinoma	0/235 (0%)		1/238 (0.4%)
Myelodysplastic syndrome	0/235 (0%)		1/238 (0.4%)
Plasma cell leukaemia	1/235 (0.4%)		0/238 (0%)
Plasma cell myeloma	7/235 (3%)		4/238 (1.7%)
Plasmacytoma	1/235 (0.4%)		1/238 (0.4%)
Urethral neoplasm	1/235 (0.4%)		0/238 (0%)
Bladder transitional cell carcinoma	0/235 (0%)		1/238 (0.4%)
Nervous system disorders
Altered state of consciousness	0/235 (0%)		1/238 (0.4%)
Cerebral haemorrhage	0/235 (0%)		1/238 (0.4%)
Cerebrovascular accident	0/235 (0%)		1/238 (0.4%)
Intracranial mass	0/235 (0%)		1/238 (0.4%)
Spinal cord compression	0/235 (0%)		1/238 (0.4%)
Syncope	0/235 (0%)		1/238 (0.4%)
Haemorrhage intracranial	0/235 (0%)		1/238 (0.4%)
Psychiatric disorders
Bradyphrenia	0/235 (0%)		1/238 (0.4%)
Delirium	1/235 (0.4%)		0/238 (0%)
Renal and urinary disorders
Acute kidney injury	8/235 (3.4%)		12/238 (5%)
Renal failure	3/235 (1.3%)		1/238 (0.4%)
Renal impairment	1/235 (0.4%)		0/238 (0%)
Chronic kidney disease	0/235 (0%)		1/238 (0.4%)
Urinary bladder polyp	0/235 (0%)		1/238 (0.4%)
Reproductive system and breast disorders
Pelvic pain	1/235 (0.4%)		0/238 (0%)
Respiratory, thoracic and mediastinal disorders
Acute lung injury	0/235 (0%)		2/238 (0.8%)
Acute respiratory distress syndrome	0/235 (0%)		1/238 (0.4%)
Aspiration	1/235 (0.4%)		0/238 (0%)
Dyspnoea	1/235 (0.4%)		0/238 (0%)
Epistaxis	1/235 (0.4%)		1/238 (0.4%)
Hypoxia	1/235 (0.4%)		0/238 (0%)
Interstitial lung disease	0/235 (0%)		1/238 (0.4%)
Lung consolidation	1/235 (0.4%)		0/238 (0%)
Pleural effusion	2/235 (0.9%)		1/238 (0.4%)
Pulmonary alveolar haemorrhage	0/235 (0%)		1/238 (0.4%)
Pulmonary arterial hypertension	0/235 (0%)		1/238 (0.4%)
Pulmonary congestion	0/235 (0%)		1/238 (0.4%)
Pulmonary embolism	0/235 (0%)		6/238 (2.5%)
Pulmonary hypertension	0/235 (0%)		1/238 (0.4%)
Pulmonary oedema	1/235 (0.4%)		0/238 (0%)
Respiratory failure	2/235 (0.9%)		0/238 (0%)
Social circumstances
Homicide	0/235 (0%)		1/238 (0.4%)
Vascular disorders
Deep vein thrombosis	4/235 (1.7%)		0/238 (0%)
Hypertension	1/235 (0.4%)		0/238 (0%)
Hypotension	1/235 (0.4%)		0/238 (0%)
Pelvic venous thrombosis	0/235 (0%)		1/238 (0.4%)
Other (Not Including Serious) Adverse Events
	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone		Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	204/235 (86.8%)		217/238 (91.2%)
Blood and lymphatic system disorders
Anaemia	73/235 (31.1%)		69/238 (29%)
Neutropenia	23/235 (9.8%)		20/238 (8.4%)
Thrombocytopenia	19/235 (8.1%)		30/238 (12.6%)
Eye disorders
Cataract	13/235 (5.5%)		14/238 (5.9%)
Gastrointestinal disorders
Constipation	22/235 (9.4%)		21/238 (8.8%)
Diarrhoea	51/235 (21.7%)		53/238 (22.3%)
Nausea	30/235 (12.8%)		38/238 (16%)
Vomiting	17/235 (7.2%)		25/238 (10.5%)
General disorders
Asthenia	29/235 (12.3%)		29/238 (12.2%)
Fatigue	47/235 (20%)		50/238 (21%)
Oedema peripheral	26/235 (11.1%)		23/238 (9.7%)
Pyrexia	38/235 (16.2%)		55/238 (23.1%)
Chest pain	4/235 (1.7%)		12/238 (5%)
Infections and infestations
Bronchitis	25/235 (10.6%)		31/238 (13%)
Respiratory tract infection	23/235 (9.8%)		18/238 (7.6%)
Upper respiratory tract infection	28/235 (11.9%)		39/238 (16.4%)
Influenza	9/235 (3.8%)		13/238 (5.5%)
Nasopharyngitis	30/235 (12.8%)		35/238 (14.7%)
Pneumonia	5/235 (2.1%)		15/238 (6.3%)
Investigations
Blood creatinine increased	8/235 (3.4%)		14/238 (5.9%)
Neutrophil count decreased	5/235 (2.1%)		12/238 (5%)
Platelet count decreased	21/235 (8.9%)		27/238 (11.3%)
Metabolism and nutrition disorders
Decreased appetite	14/235 (6%)		14/238 (5.9%)
Hypokalaemia	10/235 (4.3%)		20/238 (8.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	15/235 (6.4%)		19/238 (8%)
Back pain	31/235 (13.2%)		35/238 (14.7%)
Bone pain	17/235 (7.2%)		20/238 (8.4%)
Muscle spasms	20/235 (8.5%)		22/238 (9.2%)
Musculoskeletal pain	12/235 (5.1%)		14/238 (5.9%)
Pain in extremity	19/235 (8.1%)		17/238 (7.1%)
Nervous system disorders
Headache	25/235 (10.6%)		28/238 (11.8%)
Psychiatric disorders
Insomnia	49/235 (20.9%)		39/238 (16.4%)
Respiratory, thoracic and mediastinal disorders
Cough	33/235 (14%)		44/238 (18.5%)
Dyspnoea	21/235 (8.9%)		27/238 (11.3%)
Skin and subcutaneous tissue disorders
Rash	13/235 (5.5%)		9/238 (3.8%)
Vascular disorders
Hypertension	49/235 (20.9%)		58/238 (24.4%)

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.