A Randomized, Multicenter, Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma
Overview
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Amgen
- Enrollment
- 792
- Locations
- 126
- Primary Endpoint
- Progression-free Survival (PFS)
Overview
Brief Summary
The primary objective was to compare progression-free survival in adults with relapsed multiple myeloma who are receiving CRd vs participants receiving Rd in a randomized multicenter setting.
Detailed Description
This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for adults with relapsed multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive either the control Rd or CRd. Randomization will be stratified by β2 microglobulin levels (< vs ≥ 2.5 mg/L), prior bortezomib (no vs yes), and prior lenalidomide (no vs yes). Participants will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity (whichever occurs first).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Symptomatic multiple myeloma
- •Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):
- •Serum M-protein ≥ 0.5 g/dL
- •Urine Bence-Jones protein ≥ 200 mg/24 hours
- •For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)
- •Prior treatment with at least one, but no more than three, regimens for multiple myeloma
- •Documented relapse or progressive disease on or after any regimen
- •Achieved a response to at least one prior regimen
- •Age ≥ 18 years
- •Life expectancy ≥ 3 months
Exclusion Criteria
- •If previously treated with bortezomib (alone or in combination), progression during treatment
- •If previously treated with a lenalidomide and dexamethasone (len/dex) combination:
- •Progression during the first 3 months of initiating treatment
- •Any progression during treatment if the len/dex combination was the subject's most recent line of therapy
- •Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
- •Prior carfilzomib treatment
- •POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
- •Waldenström's macroglobulinemia or IgM myeloma
- •Plasma cell leukemia (\> 2.0 × 10\^9/L circulating plasma cells by standard differential)
- •Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization
Arms & Interventions
Lenalidomide and Dexamethasone (Rd)
Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22.
Intervention: Dexamethasone (Drug)
Lenalidomide and Dexamethasone (Rd)
Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22.
Intervention: Lenalidomide (Drug)
Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher.
Intervention: Dexamethasone (Drug)
Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher.
Intervention: Lenalidomide (Drug)
Carfilzomib, Lenalidomide, and Dexamethasone (CRd)
Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher.
Intervention: Carfilzomib (Drug)
Outcomes
Primary Outcomes
Progression-free Survival (PFS)
Time Frame: From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.
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). One 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).
Secondary Outcomes
- Overall Survival(From randomization through the data cutoff date of 28 April 2017 for the final analysis of overall survival; median follow up time was 67.1 months in each treatment group.)
- Overall Response Rate(From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.)
- Duration of Response(From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months.)
- Duration of Disease Control(From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months.)
- Disease Control Rate(From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.)
- Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores(Cycle 1 Day 1 (Baseline), Day 1 of Cycles 3, 6, 12, 18)