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

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.

Time frame: 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.

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.

Time frame: 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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 12 months

Population: The ITT analysis set 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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: 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.

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.

Time frame: Day 28 of Cycle 4

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.

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

Population: The ITT population included all randomized participants.

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.

Time frame: 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.