Trial Outcomes & Findings for Phase 3 Study With Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone for Relapsed Multiple Myeloma Patients (NCT NCT01568866)

Last Updated: 2022-11-14

Results Overview

Progression-free survival (PFS) was defined as the time from randomization to the earlier of disease progression or death due to any cause. Participants were evaluated for disease response and progression according to the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) as assessed by an Independent Review Committee (IRC). Median PFS was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

929 participants

Primary outcome timeframe

From randomization until the data cut-off date of 10 November 2014; median follow-up time for PFS was 11.1.and 11.9 months in the bortezomib and carfilzomib arms respectively

Results posted on

2022-11-14

Participant Flow

Adults with relapsed multiple myeloma were enrolled between 20 June 2012 and 30 June 2014 at 198 centers in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Results are reported as of the data cut-off date of 03 January 2017, the pre-specified 2nd interim analysis of the secondary endpoint of overall survival.

Randomization was stratified by previous proteasome inhibitor therapy (yes vs no), previous lines of treatment (1 vs 2 or 3), International Staging System stage (I vs II-III), and planned route of bortezomib administration (intravenous vs subcutaneous) if randomly assigned to the bortezomib group.

Participant milestones

Participant milestones
Measure	Bortezomib + DEX Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Study STARTED	465	464
Overall Study Received Treatment	456	463
Overall Study COMPLETED	27	48
Overall Study NOT COMPLETED	438	416

Reasons for withdrawal

Reasons for withdrawal
Measure	Bortezomib + DEX Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Study Disease Progression	208	183
Overall Study Adverse Event	94	96
Overall Study Patient Request	55	71
Overall Study Physician Decision	40	32
Overall Study Withdrawal by Subject	19	11
Overall Study Death	10	18
Overall Study Protocol Non-compliance	2	4
Overall Study Lost to Follow-up	1	0
Overall Study Randomized but Not Dosed	9	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bortezomib + DEX n=465 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=464 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.	Total n=929 Participants Total of all reporting groups
Age, Continuous	65.0 years n=5 Participants	65.0 years n=7 Participants	65.0 years n=5 Participants
Age, Customized < 65 years	210 Participants n=5 Participants	223 Participants n=7 Participants	433 Participants n=5 Participants
Age, Customized 65 -74 years	189 Participants n=5 Participants	164 Participants n=7 Participants	353 Participants n=5 Participants
Age, Customized ≥ 75 years	66 Participants n=5 Participants	77 Participants n=7 Participants	143 Participants n=5 Participants
Sex: Female, Male Female	236 Participants n=5 Participants	224 Participants n=7 Participants	460 Participants n=5 Participants
Sex: Female, Male Male	229 Participants n=5 Participants	240 Participants n=7 Participants	469 Participants n=5 Participants
Race/Ethnicity, Customized White	353 Participants n=5 Participants	348 Participants n=7 Participants	701 Participants n=5 Participants
Race/Ethnicity, Customized Black	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Race/Ethnicity, Customized Asian	57 Participants n=5 Participants	56 Participants n=7 Participants	113 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian/Other Pacific Islander	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Not Reported	45 Participants n=5 Participants	50 Participants n=7 Participants	95 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active)	232 Participants n=5 Participants	221 Participants n=7 Participants	453 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory)	203 Participants n=5 Participants	211 Participants n=7 Participants	414 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work)	30 Participants n=5 Participants	32 Participants n=7 Participants	62 Participants n=5 Participants
Stratification Factor: Prior Proteasome Inhibitor Treatment Carfilzomib or bortezomib	253 Participants n=5 Participants	252 Participants n=7 Participants	505 Participants n=5 Participants
Stratification Factor: Prior Proteasome Inhibitor Treatment No prior carfilzomib or bortezomib	212 Participants n=5 Participants	212 Participants n=7 Participants	424 Participants n=5 Participants
Stratification Factor: Lines of Prior Treatment 1 line	229 Participants n=5 Participants	231 Participants n=7 Participants	460 Participants n=5 Participants
Stratification Factor: Lines of Prior Treatment 2 or 3 lines	236 Participants n=5 Participants	233 Participants n=7 Participants	469 Participants n=5 Participants
Stratification Factor: International Staging System (ISS) Stage Stage I	204 Participants n=5 Participants	205 Participants n=7 Participants	409 Participants n=5 Participants
Stratification Factor: International Staging System (ISS) Stage Stage II or III	261 Participants n=5 Participants	259 Participants n=7 Participants	520 Participants n=5 Participants
Stratification Factor: Route of Bortezomib Administration Intravenous	108 Participants n=5 Participants	108 Participants n=7 Participants	216 Participants n=5 Participants
Stratification Factor: Route of Bortezomib Administration Subcutaneous	357 Participants n=5 Participants	356 Participants n=7 Participants	713 Participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization until the data cut-off date of 10 November 2014; median follow-up time for PFS was 11.1.and 11.9 months in the bortezomib and carfilzomib arms respectively

Population: Intent-to-treat population

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=465 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=464 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Progression-free Survival	9.4 months Interval 8.4 to 10.4	18.7 months Interval 15.6 to Could not be estimated due to the low number of events.

SECONDARY outcome

Timeframe: From randomization until the data cut-off date of 03 January 2017; median follow-up time for OS was 36.9 and 37.5 months for each treatment group respectively.

Population: Intent-to-treat population

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

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=465 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=464 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Survival	40.0 months Interval 32.6 to 42.3	47.6 months Interval 42.5 to Could not be estimated due to the low number of events

SECONDARY outcome

Timeframe: Disease response was assessed every 28 days until end of treatment or the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.

Population: Intent-to-treat population

Disease response was evaluated according to the IMWG-URC by the IRC. Overall response was defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR) or stringent CR (sCR). sCR: As for CR, normal serum free light chain (SFLC) ratio and no clonal cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \< 5% plasma cells in BM biopsy; VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% reduction in serum M-protein with urine M-protein \<100 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline. PR: ≥ 50% reduction of serum M-protein and reduction in urine M-protein by ≥ 90% or to \< 200 mg/24 hours. A ≥ 50% reduction in the size of soft tissue plasmacytomas if present at baseline.

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=465 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=464 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Overall Response	62.6 percentage of participants Interval 58.0 to 67.0	76.9 percentage of participants Interval 72.8 to 80.7

SECONDARY outcome

Timeframe: From randomization until the data cut-off date of 10 November 2014; median follow-up time for DOR was 9.4 and 10.4 months for each treatment group respectively.

Population: Intent-to-treat population with an overall response

Duration of response (DOR) was calculated for participants who achieved an sCR, CR, VGPR, or PR. Duration of response is defined as the time from first evidence of PR or better to confirmation of disease progression or death due to any cause. Median duration of response was estimated using the Kaplan-Meier method. Participants with no baseline disease assessments, starting a new anticancer therapy before documentation of disease progression or death, death or disease progression immediately after more than 1 consecutively missed disease assessment visit, or alive without documentation of disease progression before the data cut-off date were censored.

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=291 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=357 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Duration of Response	10.4 months Interval 9.3 to 13.8	21.3 months Interval 21.3 to Could not be estimated due to the low number of events

SECONDARY outcome

Timeframe: From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 10 November 2014; median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group.

Population: Safety population (all participants who received at least 1 dose of study treatment)

Neuropathy events were defined as Grade 2 or higher peripheral neuropathy as specified by peripheral neuropathy Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query, narrow (scope) (SMQN) terms. Peripheral neuropathy was assessed by neurologic exam and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03: Grade 1: Asymptomatic; Grade 2: Moderate symptoms, limiting instrumental activities of daily living (ADL) Grade 3: Severe symptoms; limiting self-care ADL; Grade 4: Life-threatening consequences, urgent intervention indicated; Grade 5: Death.

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=456 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=463 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Percentage of Participants With ≥ Grade 2 Peripheral Neuropathy	32.0 percentage of participants Interval 27.7 to 36.3	6.0 percentage of participants Interval 3.9 to 8.2

SECONDARY outcome

Timeframe: Baseline and 24 weeks

Population: Cardiopulmonary Safety Evaluable subgroup (all randomized participants who enrolled in the cardiopulmonary substudy with evaluable baseline echocardiogram scans per the central laboratory) and with both baseline and at least one post-baseline LVEF measurement within 24 weeks.

A significant reduction in LVEF was defined as a ≥ 10% decrease (absolute change) from baseline in participants whose baseline LVEF is ≤ 55%. For participants with LVEF \> 55% at baseline, a significant change was defined as a decrease in LVEF to \< 45%.

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=40 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=48 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Percentage of Participants With a Significant Reduction in Left Ventricular Ejection Fraction (LVEF)	2.6 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group).

Population: Cardiopulmonary Safety Evaluable subgroup with available FAC data at baseline; "n" indicates participants whose results were available at both the baseline and the specified post-baseline visit.

Right ventricular function was assessed by measuring fractional area change (FAC) on echocardiogram.

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=52 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=55 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Change From Baseline in Right Ventricular Fractional Area Change (FAC) Week 12 (n=40, 40)	-0.7 percent fractional area change Standard Deviation 5.00	-1.1 percent fractional area change Standard Deviation 5.36
Change From Baseline in Right Ventricular Fractional Area Change (FAC) Week 24 (n=26, 31)	0.7 percent fractional area change Standard Deviation 6.10	-1.0 percent fractional area change Standard Deviation 5.03
Change From Baseline in Right Ventricular Fractional Area Change (FAC) Week 36 (n=15, 18)	-0.5 percent fractional area change Standard Deviation 7.27	-0.5 percent fractional area change Standard Deviation 6.38
Change From Baseline in Right Ventricular Fractional Area Change (FAC) End of Treatment (n=23, 18)	0.4 percent fractional area change Standard Deviation 4.73	-1.9 percent fractional area change Standard Deviation 5.47

SECONDARY outcome

Timeframe: Baseline and Weeks 12, 24 and 36 and at end of treatment (median duration of treatment was 27 weeks in the bortezomib group and 40 weeks in the carfilzomib treatment group).

Population: Cardiopulmonary Safety Evaluable subgroup with available PASP data at baseline; "n" indicates participants whose results were available at both the baseline and the specified post-baseline visit.

Pulmonary artery pressure was measured using transthoracic echocardiogram.

Outcome measures

Outcome measures
Measure	Bortezomib + DEX n=52 Participants Participants received bortezomib 1.3 mg/m² administered intravenously (IV) or subcutaneously (SC) on Days 1, 4, 8, and 11 of a 21-day cycle plus dexamethasone (DEX) 20 mg administered on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle.	Carfilzomib + DEX n=45 Participants Participants received 20 mg/m² carfilzomib administered by IV infusion on Days 1 and 2 of Cycle 1, followed by 56 mg/m² on Days 8, 9, 15, and 16 of Cycle 1 and for each 28-day cycle thereafter. Additionally, participants received 20 mg dexamethasone on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28 day cycle.
Change From Baseline in Pulmonary Artery Systolic Pressure (PASP) Week 12 (n=34, 30)	0.3 mmHg Standard Deviation 11.72	2.8 mmHg Standard Deviation 11.44
Change From Baseline in Pulmonary Artery Systolic Pressure (PASP) Week 24 (n=22, 20)	1.7 mmHg Standard Deviation 8.47	3.4 mmHg Standard Deviation 13.63
Change From Baseline in Pulmonary Artery Systolic Pressure (PASP) Week 36 (n=12, 14)	4.0 mmHg Standard Deviation 7.24	2.6 mmHg Standard Deviation 13.55
Change From Baseline in Pulmonary Artery Systolic Pressure (PASP) End of Treatment (n=21, 14)	3.4 mmHg Standard Deviation 8.14	0.9 mmHg Standard Deviation 11.40

Adverse Events

Bortezomib

Serious events: 182 serious events

Other events: 435 other events

Deaths: 0 deaths

Carfilzomib

Serious events: 272 serious events

Other events: 446 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER