Trial Outcomes & Findings for A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma (NCT NCT03859427)

Last Updated: 2024-08-13

Results Overview

ORR 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) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-hours). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hours urinary M-protein by ≥ 90% or to \< 200 mg/24-hours. The ORR 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

454 participants

Primary outcome timeframe

Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Results posted on

2024-08-13

Participant Flow

Participants were enrolled at 80 study centers in Europe, Japan, and the United States, and participated from 08 May 2019 to 31 March 2023.

Participants with relapsed or refractory multiple myeloma were randomized in a 1:1 ratio to receive once-weekly or twice-weekly carfilzomib. Randomization was stratified by original International Staging System (ISS) stage at the time of study entry (stage 1 or 2 versus stage 3), prior lenalidomide treatment (yes versus no), prior proteasome inhibitor treatment (yes versus no), and prior anti-CD38 exposure (yes versus no).

Participant milestones

Participant milestones
Measure	Twice-weekly Kyprolis (Carfilzomib) + Lenalidomide + Dexamethsone (KRd) 20/27 mg/m^2 Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Overall Study STARTED	226	228
Overall Study Received Carfilzomib	226	228
Overall Study Completed 12 Cycles Carfilzomib	152	150
Overall Study Received Lenalidomide	226	228
Overall Study Received Dexamethasone	226	228
Overall Study Safety Population	231	223
Overall Study COMPLETED	197	191
Overall Study NOT COMPLETED	29	37

Reasons for withdrawal

Reasons for withdrawal
Measure	Twice-weekly Kyprolis (Carfilzomib) + Lenalidomide + Dexamethsone (KRd) 20/27 mg/m^2 Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Overall Study Withdrawal by Subject	4	7
Overall Study Decision by sponsor	0	3
Overall Study Lost to Follow-up	3	2
Overall Study Death	22	25

Baseline Characteristics

A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Total n=454 Participants Total of all reporting groups
Age, Continuous	64.0 years STANDARD_DEVIATION 8.2 • n=5 Participants	63.7 years STANDARD_DEVIATION 8.4 • n=7 Participants	63.8 years STANDARD_DEVIATION 8.3 • n=5 Participants
Sex: Female, Male Female	100 Participants n=5 Participants	118 Participants n=7 Participants	218 Participants n=5 Participants
Sex: Female, Male Male	126 Participants n=5 Participants	110 Participants n=7 Participants	236 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	8 Participants n=7 Participants	16 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	213 Participants n=5 Participants	215 Participants n=7 Participants	428 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	209 Participants n=5 Participants	209 Participants n=7 Participants	418 Participants n=5 Participants
Race/Ethnicity, Customized Other	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Original ISS Stage at Study Entry Stage 1 or 2	201 Participants n=5 Participants	201 Participants n=7 Participants	402 Participants n=5 Participants
Original ISS Stage at Study Entry Stage 3	25 Participants n=5 Participants	27 Participants n=7 Participants	52 Participants n=5 Participants
Prior Lenalidomide Treatment Yes	79 Participants n=5 Participants	85 Participants n=7 Participants	164 Participants n=5 Participants
Prior Lenalidomide Treatment No	147 Participants n=5 Participants	143 Participants n=7 Participants	290 Participants n=5 Participants
Prior Proteasome Inhibitor Treatment Yes	218 Participants n=5 Participants	214 Participants n=7 Participants	432 Participants n=5 Participants
Prior Proteasome Inhibitor Treatment No	8 Participants n=5 Participants	14 Participants n=7 Participants	22 Participants n=5 Participants
Prior Anti-CD38 Treatment Yes	17 Participants n=5 Participants	21 Participants n=7 Participants	38 Participants n=5 Participants
Prior Anti-CD38 Treatment No	209 Participants n=5 Participants	207 Participants n=7 Participants	416 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Population: The intent-to-treat (ITT) population included all randomized participants.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Overall Response Rate (ORR) Per International Myeloma Working Group Uniform Response Criteria (IMWG-URC)	86.3 percentage of participants Interval 81.1 to 90.5	82.5 percentage of participants Interval 76.9 to 87.2

SECONDARY outcome

Timeframe: 12 months

Population: The ITT analysis set included all randomized participants.

PFS rate was defined as the percentage of participants without disease progression or death due to any cause at 12 months. The PFS rate at 12 months was estimated using the Kaplan-Meier method by Klein and Moeschberger (1997). 95% CIs were estimated using the method by Kalbfleisch and Prentice (1980). PFS data was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of progressive disease (PD) or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after \> 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months	79.7 percentage of participants Interval 73.6 to 84.6	80.7 percentage of participants Interval 74.7 to 85.4

SECONDARY outcome

Timeframe: Day 28 of Cycle 4

Population: The ITT population included all randomized participants.

Patient-reported convenience was measured by the Patient-reported Convenience with Carfilzomib-dosing Schedule Question. The items in the questionnaire were categorized as 'Convenient', which included responses of 'Very Convenient' and 'Convenient', and 'Inconvenient' which included responses of 'Inconvenient' and 'Very Inconvenient'. The 95% CIs were estimated using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Percentage of Participants Who Reported Convenience as Measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question	80.5 percentage of participants Interval 74.8 to 85.5	81.6 percentage of participants Interval 75.9 to 86.4

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to end of Cycle 12 + 30 days, where each cycle was 28 days; median treatment duration (any study treatment) was 47.00 weeks in the twice-weekly KRd group and 47.14 weeks in the once-weekly KRd group

Population: The safety population included all randomized participants who received at least 1 dose of any study treatment (carfilzomib, lenalidomide, or dexamethasone). Participants were analyzed according to the treatment arm corresponding to the actual treatment received.

An adverse event (AE) was any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs were AEs starting on or after the first dose of any study drug, and up to 30 days of the last dose of any study drug, excluding AEs reported after End of Study date.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=231 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=223 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	219 Participants	209 Participants

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Population: The ITT population included all randomized participants. Data is presented for participants in the ITT population who achieved a confirmed response of PR or better.

TTR was defined as the time from randomization to the earliest date when confirmed sCR, CR, VGPR, or PR per IMWG-URC was first achieved.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=195 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=188 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Time to Response (TTR)	1.0 months Interval 1.0 to 12.0	1.0 months Interval 1.0 to 10.0

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Population: The ITT population included all randomized participants. Data is presented for participants in the ITT population who achieved a confirmed response of PR or better.

For participants who achieved a PR or better, i.e., sCR, CR, VGPR, or PR per IMWG-URC, the DOR was defined as the time from the earliest date when a PR or better was first achieved, and subsequently confirmed, to the earliest date of confirmed PD or death due to any cause. Median DOR was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. For those alive and who had not experienced PD by analysis time, DOR was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of PD or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after \> 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=195 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=188 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Kaplan-Meier Estimate of Duration of Response (DOR)	NA months The median and 95% CIs could not be estimated due to too few events.	NA months The median and 95% CIs could not be estimated due to too few events.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Population: The ITT population included all randomized participants.

TTP was defined as the duration from randomization for the first documented disease progression per IMWG-UCR. Median TTP was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. TTP was censored for participants who had no confirmed PD at the last non non-evaluable (non-NE), post-baseline disease assessment or the earlier of the following, where applicable: 1. the last non-NE, post-baseline disease assessment prior to start of a new anti-myeloma treatment, or 2. the last non-NE, post-baseline assessment followed \> 63 days later by disease progression; otherwise, at randomization.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Kaplan-Meier Estimate of Time to Progression (TTP)	NA months The median and 95% CIs could not be estimated due to too few events.	NA months The median and 95% CIs could not be estimated due to too few events.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Population: The ITT population included all randomized participants.

OS was defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. Participants still alive or lost to follow-up or withdrawn consent from study by the analysis time were censored at the date on which the participant was last known to be alive.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Kaplan-Meier Estimate of Overall Survival (OS)	NA months The median and 95% CIs could not be estimated due to too few events.	NA months The median and 95% CIs could not be estimated due to too few events.

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks.

Population: The ITT population included all randomized participants.

MRD\[-\]CR was defined as achievement of CR or better by IRC per IMWG-URC and achievement of MRD negativity as assessed by next generation sequencing method at a 10\^-5 threshold over the duration of the study. The 95% CIs for percentages were estimated using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Percentage of Participants Who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) Per IMWG-URC	18.1 percentage of participants Interval 13.3 to 23.8	21.5 percentage of participants Interval 16.3 to 27.4

SECONDARY outcome

Timeframe: Cycle 1 Day 1 up to 12 months (cycle = 28 days)

Population: The ITT population included all randomized participants.

The percentage of participants with achievement of MRD\[-\] at 12 months (± 4 weeks) from randomization, as assessed by next generation sequencing method at a 10\^-5 threshold. MRD negativity results from BM samples obtained at 8 to 13 months from randomization and prior to new anti-myeloma therapy or disease progression were considered in the calculation. The 95% CIs for percentages were estimated using the Clopper-Pearson method.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Percentage of Participants With Minimal Residual Disease Negativity (MRD[-]) by IRC Per IMWG-URC at 12 Months	18.1 percentage of participants Interval 13.3 to 23.8	18.9 percentage of participants Interval 14.0 to 24.6

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)

Population: The ITT population included all randomized participants. Participants with data available at each time point are presented. All participants in the overall number of participants analyzed contributed to the data in the endpoint.

The QLQ-C30 physical function is one of the functional domains of the EORTC QLQ-C30 self-reported instrument and the physical functioning score score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Cycle 3 Day 1	-2.76 Score on a scale Standard Deviation 16.84	-0.77 Score on a scale Standard Deviation 14.95
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Cycle 5 Day 1	-2.65 Score on a scale Standard Deviation 15.76	0.26 Score on a scale Standard Deviation 15.59
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Cycle 7 Day 1	-0.82 Score on a scale Standard Deviation 16.59	0.17 Score on a scale Standard Deviation 14.62
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Cycle 9 Day 1	-1.05 Score on a scale Standard Deviation 15.59	2.03 Score on a scale Standard Deviation 14.75
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Cycle 12 Day 1	-1.89 Score on a scale Standard Deviation 15.15	1.06 Score on a scale Standard Deviation 15.63
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Safety Follow-up	-1.55 Score on a scale Standard Deviation 16.31	2.11 Score on a scale Standard Deviation 18.27

SECONDARY outcome

Timeframe: Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)

The QLQ-C30 role function is one of the functional domains of the EORTC QLQ-C30 self-reported instrument and the role functioning score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=226 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=228 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Cycle 3 Day 1	-4.30 Score on a scale Standard Deviation 26.16	-2.47 Score on a scale Standard Deviation 24.81
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Cycle 5 Day 1	-2.67 Score on a scale Standard Deviation 25.77	-3.11 Score on a scale Standard Deviation 24.32
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Cycle 7 Day 1	-3.29 Score on a scale Standard Deviation 26.19	1.76 Score on a scale Standard Deviation 24.34
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Cycle 9 Day 1	-0.88 Score on a scale Standard Deviation 23.24	2.70 Score on a scale Standard Deviation 24.90
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Cycle 12 Day 1	-0.25 Score on a scale Standard Deviation 23.21	1.64 Score on a scale Standard Deviation 28.97
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Safety Follow-up	-2.28 Score on a scale Standard Deviation 24.73	3.68 Score on a scale Standard Deviation 26.24

SECONDARY outcome

Timeframe: Cycle 5 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose)

Population: The ITT population included all randomized participants. Participants with data available at each time point are presented.

The CTSQ measures treatment satisfaction in individuals with cancer and includes a domain for satisfaction with therapy. The satisfaction with therapy scores ranges from 0 to 100 points, with 100 points indicating greatest satisfaction. Analysis was based on ANCOVA model. The dependent variable of the models were the scale scores measured at each visit. The model included effects of intercept, scale score measured at cycle 2 day 1 visit, treatment arm, and randomization stratification factors.

Outcome measures

Outcome measures
Measure	Twice-weekly KRd 20/27 mg/m^2 n=169 Participants Carfilzomib was administered twice-weekly intravenously as a 10 ± 5 minute infusion using an infusion pump on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. The dose was 20 mg/m\^2 on Days 1 and 2 of Cycle 1 and 27 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.	Once-weekly KRd 20/56 mg/m^2 n=165 Participants Carfilzomib was administered once-weekly intravenously as a 30 ± 5 minute infusion using an infusion pump on Days 1, 8, and 15 of each 28-day cycle. The dose was 20 mg/m\^2 on Day 1 of Cycle 1 and 56 mg/m\^2 beginning on Day 8 of Cycle 1 and thereafter. Participants also received lenalidomide 25 mg daily orally on Days 1 to 21 of each cycle and dexamethasone 40 mg weekly orally or intravenously. Participants were treated for up to 12 28-day cycles.
Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ) Cycle 5 Day 1	75.73 Score on a scale Standard Error 1.78	75.47 Score on a scale Standard Error 1.76
Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ) Cycle 12 Day 1	78.39 Score on a scale Standard Error 2.40	77.91 Score on a scale Standard Error 2.40
Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ) Safety follow-up	74.55 Score on a scale Standard Error 2.58	75.99 Score on a scale Standard Error 2.49

Adverse Events

Twice-weekly KRd 20/27 mg/m^2

Serious events: 75 serious events

Other events: 190 other events

Deaths: 22 deaths

Once-weekly KRd 20/56 mg/m^2

Serious events: 84 serious events

Other events: 182 other events

Deaths: 26 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