Trial Outcomes & Findings for Once-weekly Versus Twice-weekly Carfilzomib in Combination With Dexamethasone in Adults With Relapsed and Refractory Multiple Myeloma (NCT NCT02412878)

Last Updated: 2022-09-23

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. 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

478 participants

Primary outcome timeframe

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.

Results posted on

2022-09-23

Participant Flow

Participants were enrolled from September 2015 to August 2016 at 118 sites in Australia, New Zealand, Japan, North America, and Europe.

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).

Participant milestones

Participant milestones
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone 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.
Overall Study STARTED	238	240
Overall Study Received Carfilzomib	235	238
Overall Study COMPLETED	217	227
Overall Study NOT COMPLETED	21	13

Reasons for withdrawal

Reasons for withdrawal
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone 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.
Overall Study Withdrawal by Subject	19	10
Overall Study Lost to Follow-up	2	3

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone n=238 Participants 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone n=240 Participants 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 n=478 Participants Total of all reporting groups
Age, Continuous	66.0 years n=5 Participants	66.0 years n=7 Participants	66.0 years n=5 Participants
Age, Customized 18 - 64 years	104 Participants n=5 Participants	104 Participants n=7 Participants	208 Participants n=5 Participants
Age, Customized 65 - 74 years	102 Participants n=5 Participants	90 Participants n=7 Participants	192 Participants n=5 Participants
Age, Customized 75 - 84 years	32 Participants n=5 Participants	45 Participants n=7 Participants	77 Participants n=5 Participants
Age, Customized ≥ 85 years	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Sex: Female, Male Female	110 Participants n=5 Participants	108 Participants n=7 Participants	218 Participants n=5 Participants
Sex: Female, Male Male	128 Participants n=5 Participants	132 Participants n=7 Participants	260 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	226 Participants n=5 Participants	235 Participants n=7 Participants	461 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	7 Participants n=5 Participants	3 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized Asian	15 Participants n=5 Participants	30 Participants n=7 Participants	45 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized White	202 Participants n=5 Participants	200 Participants n=7 Participants	402 Participants n=5 Participants
Race/Ethnicity, Customized Other	9 Participants n=5 Participants	4 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized Missing	10 Participants n=5 Participants	3 Participants n=7 Participants	13 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active)	118 Participants n=5 Participants	118 Participants n=7 Participants	236 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory)	120 Participants n=5 Participants	121 Participants n=7 Participants	241 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work)	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Stratification Factor: International Staging System (ISS) stage Stage 1	100 Participants n=5 Participants	100 Participants n=7 Participants	200 Participants n=5 Participants
Stratification Factor: International Staging System (ISS) stage Stage 2 or 3	138 Participants n=5 Participants	140 Participants n=7 Participants	278 Participants n=5 Participants
Stratification Factor: Refractory to Bortezomib Treatment Yes	88 Participants n=5 Participants	88 Participants n=7 Participants	176 Participants n=5 Participants
Stratification Factor: Refractory to Bortezomib Treatment No	150 Participants n=5 Participants	152 Participants n=7 Participants	302 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Population: Intent-to-treat population

Outcome measures

Outcome measures
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone n=238 Participants 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone n=240 Participants 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.
Progression Free Survival	7.6 months Interval 5.8 to 9.2	11.2 months Interval 8.6 to 13.0

SECONDARY outcome

Timeframe: 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.

Population: Intent-to-treat population

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.

Outcome measures

Outcome measures
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone n=238 Participants 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone n=240 Participants 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.
Overall Response Rate	40.8 percentage of participants Interval 34.5 to 47.3	62.9 percentage of participants Interval 56.5 to 69.0

SECONDARY outcome

Timeframe: 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.

Population: Intent-to-treat population

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.

Outcome measures

Outcome measures
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone n=238 Participants 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone n=240 Participants 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.
Overall Survival	NA months Interval 18.1 to Could not be estimated due to the low number of events	NA months Could not be estimated due to the low number of events

SECONDARY outcome

Timeframe: 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.

Population: All participants who received at least 1 dose of study drug

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.

Outcome measures

Outcome measures
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone n=235 Participants 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone n=238 Participants 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.
Number of Participants With Adverse Events (AEs) Adverse events (AEs)	230 Participants	233 Participants
Number of Participants With Adverse Events (AEs) Adverse events Grade ≥ 3	152 Participants	181 Participants
Number of Participants With Adverse Events (AEs) Serious adverse events	102 Participants	118 Participants
Number of Participants With Adverse Events (AEs) AEs leading to discontinuation of carfilzomib	29 Participants	35 Participants
Number of Participants With Adverse Events (AEs) AEs leading to discontinuation of dexamethasone	31 Participants	40 Participants
Number of Participants With Adverse Events (AEs) Fatal adverse events	20 Participants	21 Participants
Number of Participants With Adverse Events (AEs) Treatment-related adverse events (TRAEs)	176 Participants	180 Participants
Number of Participants With Adverse Events (AEs) Treatment-related adverse events Grade ≥ 3	82 Participants	108 Participants
Number of Participants With Adverse Events (AEs) Serious treatment-related adverse events	31 Participants	57 Participants
Number of Participants With Adverse Events (AEs) TRAE leading to discontinuation of carfilzomib	11 Participants	23 Participants
Number of Participants With Adverse Events (AEs) TRAEs leading to discontinuation of dexamethasone	13 Participants	29 Participants
Number of Participants With Adverse Events (AEs) Fatal treatment-related adverse events	3 Participants	5 Participants

SECONDARY outcome

Timeframe: 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

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

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

Outcome measures

Outcome measures
Measure	Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone n=36 Participants 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.	Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone n=55 Participants 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.
Plasma Carfilzomib Concentration During Cycle 2 15 minutes after start of infusion	—	1370 ng/mL Standard Deviation 1410
Plasma Carfilzomib Concentration During Cycle 2 Predose	36.2 ng/mL Standard Deviation 162	203 ng/mL Standard Deviation 1380
Plasma Carfilzomib Concentration During Cycle 2 End of infusion	1640 ng/mL Standard Deviation 1900	1130 ng/mL Standard Deviation 928
Plasma Carfilzomib Concentration During Cycle 2 30 minutes after end of infusion	104 ng/mL Standard Deviation 293	480 ng/mL Standard Deviation 2300

Adverse Events

Twice-weekly Carfilzomib 20/27 mg/m² + Dexamethasone

Serious events: 102 serious events

Other events: 204 other events

Deaths: 127 deaths

Once-weekly Carfilzomib 20/70 mg/m² + Dexamethasone

Serious events: 118 serious events

Other events: 217 other events

Deaths: 119 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: [email protected]

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