FOCUS: A Study of Carfilzomib vs Best Supportive Care in Subjects With Relapsed and Refractory Multiple Myeloma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01302392
• Collaborator: (none)
• Enrollment: 315
• Locations: 68
• Arms: 2
• Duration (Months): 60
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for subjects with multiple myeloma who have received all available approved treatment options and may therefore be considered candidates for palliative care.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Carfilzomib; Drug: Best Supportive Care	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 315 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 vs Best Supportive Care in Subjects With Relapsed and Refractory Multiple Myeloma
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Sep 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Best Supportive Care	Drug: Best Supportive Care; Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).
Experimental: Carfilzomib	Drug: Carfilzomib; 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).; Other Names: PR-171

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization through the final analysis data cutoff with longest follow-up time of approximately 45 months. Median follow up times were 27.8 months and 29.8 months for Carfilzomib and Best Supportive Care groups, respectively.]

   Time elapsed between the randomization date and the date of death. Participants who were still alive were censored at date when the subject is last known alive or the data cutoff date, whichever occurs earlier.

Secondary Outcome Measures

1. Progression-free Survival [From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.]

   Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). 1 or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).

2. Overall Response [From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.]

   Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).

3. Duration of Response [From the time achieving response through the final analysis data cutoff with longest follow-up time of approximately 29 months.]

   Duration of response (DOR) was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.

4. Clinical Benefit Response [From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.]

   Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). (MR was determined using European Group for Blood and Marrow Transplantation criteria)

5. Duration of Clinical Benefit [From time of achieving clinical benefit through the final analysis data cutoff with longest follow-up time of approximately 30 months.]

   Duration of Clinical Benefit was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR) or minimal response (MR). Duration of Clinical Benefit was defined as the time in months from the initial start of response (MR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.

6. Disease Control [From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.]

   Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). (MR was determined using European Group for Blood and Marrow Transplantation criteria)

7. Duration of Disease Control [From time of achieving disease control through the final analysis data cutoff with longest follow-up time of approximately 31 months.]

   Duration of Disease Control was calculated for subjects who achieved disease control. Duration of Disease Control was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Multiple myeloma

2. Measurable disease based on central laboratory values, as defined by one or both of the following criteria (assessed within 21 days prior to randomization):

• Serum M-protein

• Serum protein electrophoresis (SPEP): ≥ 0.5 g/dL

• For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA): > 750 mg/dL (0.75 g/dL)

• Urine Bence Jones protein: ≥ 200 mg/24 h

1. Responsive (defined as a 25% or greater decrease in M-protein or total protein) to at least one line of prior therapy

2. Relapsed multiple myeloma, defined as disease progression while on or after at least 1 prior treatment regimen

3. Refractory multiple myeloma, defined as meeting one or more of the following:

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

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

1. Received 3 or more prior therapeutic regimens for multiple myeloma

2. Adequate prior treatment with bortezomib (if less than 4 complete cycles, the reason for discontinuation must be reviewed by the Medical Monitor and the reason documented)

3. Prior treatment with an immunomodulatory agent (lenalidomide, if available, and/or thalidomide)

4. Prior treatment with an alkylating agent (standard or high-dose)

5. Prior treatment with a corticosteroid

6. Criterion no longer applicable (with Amendment 2, Criterion 11, the requirement of "prior treatment with an anthracycline unless not clinically indicated" is removed.)

7. Age ≥ 18 years

8. Life expectancy of at least 1 month

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

10. Adequate hepatic function, with serum alanine aminotransferase (ALT) < 4 times the upper limit of normal and serum bilirubin < 2.5 mg/dL (42.5 µmol/L). Patients with total bilirubin ≥ 2.5 mg/dL may enrol if their serum direct bilirubin is < 2.5 mg/dL.

11. Total white blood cell (WBC) count ≥ 1.5 × 10^{9/L and absolute neutrophil count (ANC) ≥ 1.0 × 10}9/L (use of colony-stimulating factors to achieve these counts is allowed)

12. Hemoglobin ≥ 7.5 g/dL (75 g/L)

-Use of erythropoietic stimulating factors is allowed:

• For all patients who receive a red blood cell (RBC) transfusion within 28 days of obtaining the Screening hemoglobin value. The following information must be provided for the Medical Monitor's review for assessment for eligibility:

• Pre-transfusion hemoglobin (Hb)

• Number of RBC units administered

• Use of erythropoietic stimulating factors

1. Platelet count ≥ 30 × 10^9/L

-There is no restriction on platelet transfusions or thrombopoietic growth factor before or during the screening period

• For all patients who receive a platelet transfusion within 7 days of obtaining the Screening platelet value, the following information must be provided for the Medical Monitor's review for assessment of eligibility

• Pre-transfusion platelet count

• Number of platelet units administered

• Use of thrombopoietic growth factors

1. Creatinine clearance (CrCl) ≥ 15 mL/minute (either measured or calculated using a standard formula such as Cockcroft and Gault) and dialysis-independent

2. Written informed consent in accordance with regulatory guidelines

3. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of the first dose of study treatment and agree to use an effective method of contraception during the study and for 3 months following the last dose of study treatment. Post-menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from these requirements. Male patients must use an effective barrier method of contraception during the study and for 3 months following the last dose if sexually active with a female of childbearing potential.

Exclusion Criteria:

1. Waldenström's macroglobulinemia or IgM myeloma

2. Refractory to all prior therapies

3. Disease measurable only by serum free light chain assay (SFLC)

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

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

6. Prior carfilzomib treatment

7. Chemotherapy (approved or investigational) within 14 days prior to randomization

8. Immunotherapy or antibody therapy within 28 days prior to randomization

9. Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 14 days prior to randomization

10. Radiotherapy within 7 days prior to randomization

11. Major surgery within 21 days prior to randomization

12. Congestive heart failure (NYHA Class III or IV) or symptomatic cardiac ischemia, conduction system abnormalities uncontrolled by conventional intervention (conduction abnormalities not clinically warranting intervention are allowed)

13. Myocardial infarction in the previous 3 months

14. Acute active infection requiring systemic treatment (antibiotics, antivirals, or antifungals) within 14 days prior to randomization

15. Known human immunodeficiency virus seropositivity

16. Active hepatitis A, B, or C infection

17. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix, vulva, or breast; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder, carcinoma in situ of the breast, or benign tumors of the adrenal or pancreas

18. Significant neuropathy (Grades 3-4, or Grade 2 with pain) at the time of randomization

19. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent

20. Pregnant or lactating females

21. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity or known history of allergy to carfilzomib, Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) all anticoagulation and antiplatelet options, antiviral drugs; or intolerance to hydration due to preexisting pulmonary or cardiac impairment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nedlands		Australia
2		Perth		Australia
3		Linz		Austria
4		Salzburg		Austria
5		Vienna		Austria
6		Arlon		Belgium
7		Brugge		Belgium
8		Brussels		Belgium
9		Roeselare		Belgium
10		Brno		Czechia
11		Hradec Kralov		Czechia
12		Olomouc		Czechia
13		Prague		Czechia
14		Lyon		France
15		Nantes		France
16		Nimes		France
17		Dresden		Germany
18		Giessen		Germany
19		Koblenz		Germany
20		Mainz		Germany
21		Muenchen		Germany
22		Ulm		Germany
23		Athens		Greece
24		Rio Patras		Greece
25		Budapest		Hungary
26		Debrecen		Hungary
27		Gyor		Hungary
28		Gyula		Hungary
29		Kaposvar		Hungary
30		Pecs		Hungary
31		Szeged		Hungary
32		Haifa		Israel
33		Jerusalem		Israel
34		Kfar Saba		Israel
35		Nahariva		Israel
36		Petah-Tikva		Israel
37		Sheba		Israel
38		Ancona		Italy
39		Novara		Italy
40		Roma		Italy
41		Torino		Italy
42		Incheon		Korea, Republic of
43		Seoul		Korea, Republic of
44		North Shore City		New Zealand
45		Gdansk		Poland
46		Lodz		Poland
47		Pila		Poland
48		Torum		Poland
49		Warsaw		Poland
50		Wroclaw		Poland
51		Zamosc		Poland
52		Moscow		Russian Federation
53		St. Petersburg		Russian Federation
54		Beograd		Serbia
55		Nis		Serbia
56		Bratislava		Slovakia
57		Barcelona		Spain
58		Guipuzcoa		Spain
59		Murcia		Spain
60		Salamanca		Spain
61		Sevilla		Spain
62		Valencia		Spain
63		Zaragoza		Spain
64		Uppsala		Sweden
65		Hampshire		United Kingdom
66		London		United Kingdom
67		Manchester		United Kingdom
68		Oxford		United Kingdom

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT01302392
• Other Study ID Numbers: PX-171-011
• First Posted: Feb 24, 2011
• Last Update Posted: May 2, 2017
• Last Verified: Apr 1, 2017

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

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled from 06 Sep 2010 to 21OCT2012. Results are reported as of the data cut-off date of 10 Jul 2014.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Period Title: Overall Study
STARTED	158	157
Treated	153	157
COMPLETED	151	156
NOT COMPLETED	7	1

Baseline Characteristics

Arm/Group Title	Best Supportive Care	Carfilzomib	Total
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).	Total of all reporting groups
Overall Participants	158	157	315
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.5 (8.02)	63.3 (10.71)	64.4 (9.50)
Sex: Female, Male (Count of Participants)
Female	62 39.2%	75 47.8%	137 43.5%
Male	96 60.8%	82 52.2%	178 56.5%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	4 2.5%	1 0.6%	5 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 0.6%	1 0.6%	2 0.6%
White	148 93.7%	151 96.2%	299 94.9%
Other	5 3.2%	4 2.5%	9 2.9%
Region (participants) [Number]
Europe	138 87.3%	140 89.2%	278 88.3%
Non-Europe	20 12.7%	17 10.8%	37 11.7%
Number of Prior Regimens to Treat Multiple Myeloma (participants) [Number]
3	19 12%	17 10.8%	36 11.4%
4	35 22.2%	34 21.7%	69 21.9%
≥5	104 65.8%	106 67.5%	210 66.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Time elapsed between the randomization date and the date of death. Participants who were still alive were censored at date when the subject is last known alive or the data cutoff date, whichever occurs earlier.
Time Frame	From randomization through the final analysis data cutoff with longest follow-up time of approximately 45 months. Median follow up times were 27.8 months and 29.8 months for Carfilzomib and Best Supportive Care groups, respectively.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) analysis set comprised all randomized participants.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	158	157
Median (95% Confidence Interval) [months]	10.0	10.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Best Supportive Care, Carfilzomib
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4172
	Comments	Based on 1-sided test.
	Method	Log Rank
	Comments	Analysis was stratified by the number of previous therapies (3 vs 4 vs ≥ 5) and geographical region (Europe vs. non-Europe)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.975
	Confidence Interval	(2-Sided) 95%; 0.760 to 1.249
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival
Description	Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). 1 or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).
Time Frame	From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) analysis set comprised all randomized participants.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	158	157
Median (95% Confidence Interval) [months]	3.3	3.7

3. Secondary Outcome

Title	Overall Response
Description	Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
Time Frame	From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) analysis set comprised all randomized participants.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	158	157
Number [participants]	18 11.4%	30 19.1%

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response (DOR) was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.
Time Frame	From the time achieving response through the final analysis data cutoff with longest follow-up time of approximately 29 months.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population comprised randomized participants who achieved a best overall response of PR or better only.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	18	30
Median (95% Confidence Interval) [months]	9.5	7.2

5. Secondary Outcome

Title	Clinical Benefit Response
Description	Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). (MR was determined using European Group for Blood and Marrow Transplantation criteria)
Time Frame	From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) analysis set comprised all randomized participants.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	158	157
Number [participants]	33 20.9%	49 31.2%

6. Secondary Outcome

Title	Duration of Clinical Benefit
Description	Duration of Clinical Benefit was calculated for subjects who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR) or minimal response (MR). Duration of Clinical Benefit was defined as the time in months from the initial start of response (MR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.
Time Frame	From time of achieving clinical benefit through the final analysis data cutoff with longest follow-up time of approximately 30 months.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population comprised randomized participants who achieved a best overall response of MR or better only.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	33	49
Median (95% Confidence Interval) [months]	8.3	6.4

7. Secondary Outcome

Title	Disease Control
Description	Number of participants who achieved confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks as their best response. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). (MR was determined using European Group for Blood and Marrow Transplantation criteria)
Time Frame	From randomization through the final analysis data cutoff with longest follow-up time of approximately 31 months. Median follow up times were 26.6 months and 23.1 months for Carfilzomib and Best Supportive Care groups, respectively.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) analysis set comprised all randomized participants.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	158	157
Number [participants]	107 67.7%	119 75.8%

8. Secondary Outcome

Title	Duration of Disease Control
Description	Duration of Disease Control was calculated for subjects who achieved disease control. Duration of Disease Control was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for progression-free survival.
Time Frame	From time of achieving disease control through the final analysis data cutoff with longest follow-up time of approximately 31 months.

Outcome Measure Data

Analysis Population Description

The intent to treat (ITT) population comprised randomized participants who achieved disease control.

Arm/Group Title	Best Supportive Care	Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).	Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
Measure Participants	107	119
Median (95% Confidence Interval) [months]	6.6	5.5

Adverse Events

Time Frame	From randomization through the final analysis data cutoff with range of follow-up time of 0.4 - 138.3 weeks with median of 10.7 weeks in Best Supportive Care arm, and 0.3 - 138.4 weeks with median of 16.3 weeks in carfilzomib arm
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Best Supportive Care		Carfilzomib
Arm/Group Description	Best Supportive Care: Corticosteroid (either prednisolone 30 mg orally (PO) every other day, dexamethasone 6 mg PO every other day, or other equivalent corticosteroid). Optional cyclophosphamide 50 mg PO once daily may be given at the Investigator's discretion (maximum of 1400 mg per 28-day cycle).		Carfilzomib: 20mg/m² IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m² IV on Days 8,9,15,and 16 of Cycle 1 and continuing on Days 1,2,8,9,15,and 16 of Cycles 2 through Cycle 9. Cycles 10 and beyond will receive 27 mg/m² IV on Days 1,2,15, and 16 (alternatively, the investigator could choose to continue the dosing frequency on the original dosing days [Days 1, 2, 8, 9, 15, 16] for individual subjects).
All Cause Mortality
	Best Supportive Care		Carfilzomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Best Supportive Care		Carfilzomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	78/153 (51%)		92/157 (58.6%)
Blood and lymphatic system disorders
Anaemia	8/153 (5.2%)		4/157 (2.5%)
Febrile neutropenia	1/153 (0.7%)		3/157 (1.9%)
Hyperviscosity syndrome	1/153 (0.7%)		0/157 (0%)
Leukocytosis	1/153 (0.7%)		0/157 (0%)
Leukopenia	0/153 (0%)		1/157 (0.6%)
Neutropenia	3/153 (2%)		1/157 (0.6%)
Thrombocytopenia	5/153 (3.3%)		3/157 (1.9%)
Cardiac disorders
Acute left ventricular failure	0/153 (0%)		1/157 (0.6%)
Atrial fibrillation	0/153 (0%)		1/157 (0.6%)
Atrial flutter	0/153 (0%)		1/157 (0.6%)
Atrioventricular block complete	0/153 (0%)		1/157 (0.6%)
Cardiac arrest	1/153 (0.7%)		2/157 (1.3%)
Cardiac failure	1/153 (0.7%)		4/157 (2.5%)
Cardiac failure acute	0/153 (0%)		1/157 (0.6%)
Cardiac failure congestive	3/153 (2%)		2/157 (1.3%)
Cardio-respiratory arrest	0/153 (0%)		1/157 (0.6%)
Eye disorders
Ulcerative keratitis	1/153 (0.7%)		0/157 (0%)
Gastrointestinal disorders
Diarrhoea	1/153 (0.7%)		1/157 (0.6%)
Diverticulum intestinal	0/153 (0%)		1/157 (0.6%)
Gastric haemorrhage	0/153 (0%)		1/157 (0.6%)
Gastrointestinal haemorrhage	1/153 (0.7%)		0/157 (0%)
Haematemesis	0/153 (0%)		1/157 (0.6%)
Intestinal obstruction	0/153 (0%)		1/157 (0.6%)
Nausea	2/153 (1.3%)		1/157 (0.6%)
Upper gastrointestinal haemorrhage	0/153 (0%)		1/157 (0.6%)
Vomiting	2/153 (1.3%)		0/157 (0%)
General disorders
Asthenia	2/153 (1.3%)		0/157 (0%)
Chest pain	1/153 (0.7%)		0/157 (0%)
Death	1/153 (0.7%)		0/157 (0%)
Disease progression	19/153 (12.4%)		16/157 (10.2%)
General physical health deterioration	1/153 (0.7%)		0/157 (0%)
Malaise	1/153 (0.7%)		0/157 (0%)
Multi-organ failure	0/153 (0%)		2/157 (1.3%)
Pain	1/153 (0.7%)		1/157 (0.6%)
Pyrexia	2/153 (1.3%)		6/157 (3.8%)
Hepatobiliary disorders
Biliary colic	0/153 (0%)		1/157 (0.6%)
Cholelithiasis	0/153 (0%)		1/157 (0.6%)
Immune system disorders
Anaphylactic reaction	0/153 (0%)		1/157 (0.6%)
Hypersensitivity	1/153 (0.7%)		0/157 (0%)
Infections and infestations
Bacteraemia	1/153 (0.7%)		0/157 (0%)
Bronchitis	1/153 (0.7%)		3/157 (1.9%)
Bronchopneumonia	5/153 (3.3%)		6/157 (3.8%)
Clostridium difficile colitis	0/153 (0%)		1/157 (0.6%)
Herpes zoster	1/153 (0.7%)		0/157 (0%)
Infection	1/153 (0.7%)		1/157 (0.6%)
Influenza	0/153 (0%)		1/157 (0.6%)
Kidney infection	0/153 (0%)		1/157 (0.6%)
Lobar pneumonia	1/153 (0.7%)		1/157 (0.6%)
Lower respiratory tract infection	0/153 (0%)		1/157 (0.6%)
Meningitis	0/153 (0%)		1/157 (0.6%)
Metapneumovirus infection	0/153 (0%)		1/157 (0.6%)
Nasopharyngitis	0/153 (0%)		1/157 (0.6%)
Neutropenic sepsis	1/153 (0.7%)		0/157 (0%)
Periorbital cellulitis	1/153 (0.7%)		0/157 (0%)
Pneumonia	18/153 (11.8%)		10/157 (6.4%)
Pneumonia pneumococcal	0/153 (0%)		1/157 (0.6%)
Pneumonia streptococcal	0/153 (0%)		1/157 (0.6%)
Respiratory tract infection	4/153 (2.6%)		1/157 (0.6%)
Sepsis	1/153 (0.7%)		3/157 (1.9%)
Sepsis syndrome	1/153 (0.7%)		0/157 (0%)
Septic shock	3/153 (2%)		0/157 (0%)
Staphylococcal sepsis	0/153 (0%)		1/157 (0.6%)
Tracheobronchitis	0/153 (0%)		1/157 (0.6%)
Urinary tract infection	1/153 (0.7%)		3/157 (1.9%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/153 (0.7%)		0/157 (0%)
Femur fracture	0/153 (0%)		1/157 (0.6%)
Hip fracture	0/153 (0%)		1/157 (0.6%)
Lumbar vertebral fracture	1/153 (0.7%)		0/157 (0%)
Periprosthetic fracture	1/153 (0.7%)		0/157 (0%)
Sternal fracture	1/153 (0.7%)		0/157 (0%)
Thoracic vertebral fracture	0/153 (0%)		1/157 (0.6%)
Investigations
Hepatic enzyme increased	0/153 (0%)		1/157 (0.6%)
Metabolism and nutrition disorders
Dehydration	1/153 (0.7%)		0/157 (0%)
Hypercalcaemia	4/153 (2.6%)		7/157 (4.5%)
Hyperglycaemia	2/153 (1.3%)		1/157 (0.6%)
Hyperkalaemia	0/153 (0%)		1/157 (0.6%)
Hyperuricaemia	1/153 (0.7%)		0/157 (0%)
Tumour lysis syndrome	0/153 (0%)		3/157 (1.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/153 (0.7%)		0/157 (0%)
Back pain	3/153 (2%)		6/157 (3.8%)
Bone pain	2/153 (1.3%)		1/157 (0.6%)
Joint effusion	0/153 (0%)		1/157 (0.6%)
Musculoskeletal chest pain	0/153 (0%)		2/157 (1.3%)
Musculoskeletal pain	1/153 (0.7%)		0/157 (0%)
Osteoarthritis	0/153 (0%)		1/157 (0.6%)
Osteolysis	0/153 (0%)		1/157 (0.6%)
Osteonecrosis of jaw	0/153 (0%)		1/157 (0.6%)
Osteoporosis	0/153 (0%)		1/157 (0.6%)
Pathological fracture	1/153 (0.7%)		2/157 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/153 (0.7%)		0/157 (0%)
Hepatic neoplasm malignant	0/153 (0%)		1/157 (0.6%)
Leukaemia plasmacytic	1/153 (0.7%)		0/157 (0%)
Malignant pleural effusion	0/153 (0%)		1/157 (0.6%)
Nervous system disorders
Cerebrovascular accident	1/153 (0.7%)		1/157 (0.6%)
Coma	0/153 (0%)		1/157 (0.6%)
Convulsion	1/153 (0.7%)		0/157 (0%)
Dizziness	0/153 (0%)		1/157 (0.6%)
Epilepsy	1/153 (0.7%)		0/157 (0%)
Haemorrhage intracranial	1/153 (0.7%)		0/157 (0%)
Paraparesis	0/153 (0%)		1/157 (0.6%)
Spinal cord compression	1/153 (0.7%)		2/157 (1.3%)
Psychiatric disorders
Confusional state	1/153 (0.7%)		0/157 (0%)
Renal and urinary disorders
Hydronephrosis	0/153 (0%)		1/157 (0.6%)
Oliguria	0/153 (0%)		1/157 (0.6%)
Renal failure	0/153 (0%)		3/157 (1.9%)
Renal failure acute	6/153 (3.9%)		15/157 (9.6%)
Renal impairment	0/153 (0%)		2/157 (1.3%)
Reproductive system and breast disorders
Vaginal haemorrhage	1/153 (0.7%)		0/157 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	1/153 (0.7%)		1/157 (0.6%)
Dyspnoea	1/153 (0.7%)		2/157 (1.3%)
Dyspnoea exertional	0/153 (0%)		1/157 (0.6%)
Epistaxis	0/153 (0%)		2/157 (1.3%)
Pulmonary congestion	0/153 (0%)		1/157 (0.6%)
Pulmonary embolism	0/153 (0%)		1/157 (0.6%)
Pulmonary haemorrhage	1/153 (0.7%)		0/157 (0%)
Pulmonary oedema	0/153 (0%)		2/157 (1.3%)
Respiratory failure	1/153 (0.7%)		1/157 (0.6%)
Vascular disorders
Deep vein thrombosis	1/153 (0.7%)		0/157 (0%)
Hypotension	0/153 (0%)		2/157 (1.3%)
Venous thrombosis	0/153 (0%)		1/157 (0.6%)
Other (Not Including Serious) Adverse Events
	Best Supportive Care		Carfilzomib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	135/153 (88.2%)		141/157 (89.8%)
Blood and lymphatic system disorders
Anaemia	72/153 (47.1%)		88/157 (56.1%)
Leukopenia	15/153 (9.8%)		9/157 (5.7%)
Neutropenia	23/153 (15%)		22/157 (14%)
Thrombocytopenia	43/153 (28.1%)		58/157 (36.9%)
Gastrointestinal disorders
Constipation	20/153 (13.1%)		10/157 (6.4%)
Diarrhoea	18/153 (11.8%)		23/157 (14.6%)
Dyspepsia	4/153 (2.6%)		10/157 (6.4%)
Nausea	14/153 (9.2%)		31/157 (19.7%)
Vomiting	5/153 (3.3%)		15/157 (9.6%)
General disorders
Asthenia	20/153 (13.1%)		26/157 (16.6%)
Chest pain	8/153 (5.2%)		5/157 (3.2%)
Chills	1/153 (0.7%)		8/157 (5.1%)
Fatigue	28/153 (18.3%)		29/157 (18.5%)
Oedema peripheral	12/153 (7.8%)		17/157 (10.8%)
Pain	1/153 (0.7%)		8/157 (5.1%)
Pyrexia	28/153 (18.3%)		41/157 (26.1%)
Infections and infestations
Bronchitis	13/153 (8.5%)		13/157 (8.3%)
Nasopharyngitis	10/153 (6.5%)		13/157 (8.3%)
Respiratory tract infection	6/153 (3.9%)		10/157 (6.4%)
Upper respiratory tract infection	3/153 (2%)		16/157 (10.2%)
Investigations
Blood creatinine increased	10/153 (6.5%)		13/157 (8.3%)
Creatinine renal clearance decreased	4/153 (2.6%)		9/157 (5.7%)
Neutrophil count decreased	10/153 (6.5%)		13/157 (8.3%)
Platelet count decreased	12/153 (7.8%)		12/157 (7.6%)
Metabolism and nutrition disorders
Decreased appetite	7/153 (4.6%)		9/157 (5.7%)
Hypercalcaemia	9/153 (5.9%)		13/157 (8.3%)
Hyperglycaemia	8/153 (5.2%)		6/157 (3.8%)
Hyperkalaemia	2/153 (1.3%)		8/157 (5.1%)
Hyperuricaemia	10/153 (6.5%)		19/157 (12.1%)
Hypocalcaemia	10/153 (6.5%)		11/157 (7%)
Hypokalaemia	13/153 (8.5%)		14/157 (8.9%)
Hypomagnesaemia	11/153 (7.2%)		11/157 (7%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/153 (3.9%)		11/157 (7%)
Back pain	16/153 (10.5%)		13/157 (8.3%)
Bone pain	16/153 (10.5%)		18/157 (11.5%)
Musculoskeletal pain	10/153 (6.5%)		5/157 (3.2%)
Pain in extremity	7/153 (4.6%)		13/157 (8.3%)
Nervous system disorders
Dizziness	3/153 (2%)		10/157 (6.4%)
Headache	6/153 (3.9%)		17/157 (10.8%)
Psychiatric disorders
Insomnia	18/153 (11.8%)		4/157 (2.5%)
Renal and urinary disorders
Renal failure	3/153 (2%)		8/157 (5.1%)
Renal impairment	5/153 (3.3%)		11/157 (7%)
Respiratory, thoracic and mediastinal disorders
Cough	10/153 (6.5%)		19/157 (12.1%)
Dyspnoea	12/153 (7.8%)		21/157 (13.4%)
Epistaxis	10/153 (6.5%)		12/157 (7.6%)
Vascular disorders
Hypertension	9/153 (5.9%)		23/157 (14.6%)

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.