Relapsed or Refractory Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, RRMM, Open-label, First Relapse Multiple Myeloma, Second Relapse Multiple Myeloma, Refractory to Lenalidomide, Triplicate Treatment Regimen, Dexamethasone, Carfilzomib, Pomalidomide
Brief summary
A Study Evaluating Treatment of Multiple Myeloma with Carfilzomib in Combination with Pomalidomide and Dexamethasone
Detailed description
An Open-label, Phase 2 Study Treating Subjects with First or Second Relapse of Multiple Myeloma with Carfilzomib, Pomalidomide, and Dexamethasone (KPd) This trial is designed to estimate the efficacy of a carfilzomib-based triplet in first or second relapse of multiple myeloma for subjects refractory to lenalidomide. The study is an open-label, phase 2 trial. Subjects may receive treatment until progression. Myeloma disease status will be monitored locally for response and progression per International Myeloma Working Group (IMWG) criteria (Kumar et al, 2016) every 28 ± 7 days from cycle 1 day 1 until confirmed progressive disease (PD), death, lost to follow-up, or withdrawal of full consent (whichever occurs first), regardless of cycle duration, dose delays or treatment discontinuation. Subjects with a suspected complete response (CR) or better will have a bone marrow for minimal residual disease (MRD) assessment at 12 and 24 months (± 4 weeks) from start of treatment (unless a MRD assessment was performed within 4 months before planned assessment). Subjects who end study drug(s) without confirmed PD are required to complete disease response assessments and report new anti-myeloma treatment every 28 ± 7 days until first subsequent anti-myeloma treatment, death, lost to follow-up, withdrawal of full consent, confirmed PD, or end of study, whichever occurs first. Subjects who discontinue treatment and either start new anti-myeloma treatment or have PD will enter long-term follow-up every 12 weeks until death or end of study. Approximately one-third of subjects enrolled in the study will be in first relapse and two-thirds in second relapse. This study will enroll adults ≥ 18 years of age with first or second relapse multiple myeloma. Eligible subjects will have relapsed multiple myeloma after receiving 1 or 2 prior lines of therapy. Subjects must be refractory to lenalidomide. Subjects may not have received prior pomalidomide. Prior exposure to a proteasome inhibitor is allowed. Subjects previously exposed to carfilzomib must have responded with at least a partial response to carfilzomib, must not have discontinued carfilzomib due to toxicity, may not have relapsed while receiving or within 60 days of the last dose of carfilzomib, and must have at least a 6 month carfilzomib treatment-free interval since their last dose of carfilzomib. Subjects must have measurable disease per IMWG consensus criteria, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2, and at least partial response to 1 line of therapy.
Interventions
DRUGCarfilzomib
Carfilzomib will be administered intravenously over 30 ± 5 minutes, on days 1, 8, and 15 (± 2 days) of each 28-day cycle for up to 12 cycles or progression. A dose of 20 mg/m\^2 will be administered on day 1 of cycle 1. All subsequent doses will be 56 mg/m\^2. The frequency of carfilzomib administration will be reduced to day 1 and 15 per cycle starting with cycle 13 and continued until progression or end of study.
DRUGDexamethasone
Dexamethasone will be administered at least 30 minutes, but no more than 4 hours prior to carfilzomib on days of carfilzomib administration. Dexamethasone will be administered at a dose of 40 mg on days 1, 8, 15, and 22 of each 28-day cycle up to progression during cycles 1 to 12. Dexamethasone will be administered at a dose of 20 mg on days 1 and 15 of each 28-day cycle up to progression during cycles 13 onward. For subjects more than or equal to 75 years of age, the dose will be 20 mg during cycles 1 through 12 and 10 mg from cycles 13 onward.
DRUGPomalidomide
Pomalidomide dose will be 4 mg per day orally on days 1 to 21 of each cycle until progression.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent prior to initiation of any study specific activities or procedures. * Male or female subjects age ≥ 18 years * First or second relapse of multiple myeloma by IMWG criteria (subjects refractory to the most recent line of therapy, excluding carfilzomib, are eligible) * Refractory to lenalidamide * Measurable disease with at least 1 of the following assessed within 28 days prior to enrollment: * IgG multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL * IgA, IgD, IgE multiple myeloma: serum M-protein level ≥ 0.5 g/dL * urine M-protein ≥ 200 mg per 24 hours * in subjects without measurable serum or urine M-protein, serum-free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio * Must have at least a PR to at least 1 line of prior therapy * Prior therapy with proteasome inhibitors is allowed. Subjects receiving prior carfilzomib therapy must have achieved at least a PR, was not removed due to toxicity, did not relapse within 60 days from discontinuation of carfilzomib, and must have at least a 6 month carfilzomib treatment-free interval from their last dose of carfilzomib * ECOG PS of 0 to 2
Exclusion criteria
* Primary refractory multiple myeloma * Waldenström macroglobulinemia * Multiple myeloma of IgM subtype * POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Plasma cell leukemia ( greater than 2.0 × 109/L circulating plasma cells by differential). If automated differential shows ≥ 20% of other cells, obtain manual differential to identify other cells. * Primary amyloidosis (patients with multiple myeloma with asymptomatic deposition of amyloid plaques found on biopsy would be eligible if all other criteria are met) * Previous diagnosis of amyloidosis associated with myeloma * Myelodysplastic syndrome * Toxicity requiring discontinuation of lenalidomide therapy * Prior treatment with pomalidomide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) As Assessed by the Independent Review Committee (IRC) | From day 1 cycle 1 until the primary analysis (PA) data cutoff (DCO); the mean duration of KPd treatment as of the DCO was 42.0 weeks | Overall response was defined as the best overall confirmed response of: Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to \< 200 mg/24-h. Assessment was by IRC per International Myeloma Working Group Uniform Response Criteria (IMWG-URC). The 90% confidence intervals were estimated using the Clopper-Pearson method (1994). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From the first dose of any study treatment until the end of study or 30 days after the last dose of any study treatment, whichever occured earlier; Median (min, max) was 8.5 (1.0, 46.6) months | TEAEs were defined as events with onset on or after the administration of the first dose of any study treatment and within the end of study, or 30 days after the last dose of any study treatment, whichever one was earlier, excluding events reported after end of study date. |
| Number of Participants Achieving MRD[-] Response | From day 1 cycle 1 until the end of study (EOS); the mean duration of KPd treatment as of the EOS was 55.3 weeks | MRD\[-\] response was defined as achievement of MRD\[-\] status using next generation sequencing (NGS) based method in the bone marrow at any time. |
| Number of Participants With Sustained MRD[-]CR for at Least 12 Months as Assessed by the IRC | Day 1 cycle 1 to month 12 (8 to 13 month window) | MRD\[-\]CR at the 12 months landmark was defined as achievement of CR (including sCR or better) per IMWG-URC by IRC and MRD\[-\] status at a sensitivity of 10\^-5 using NGS based method in the bone marrow at the 12 months landmark (from 8 months to 13 months window). Maintaining MRD\[-\]CR for at least 12 months (- 4 weeks) was considered as sustained. |
| Number of Participants With Sustained MRD[-]CR at Month 24 as Assessed by the IRC | Day 1 cycle 1 to month 26 (19 to 26 month window) | Sustained MRD\[-\]CR at 24 months included participants that maintained MRD\[-\]CR for 12 months or more after achieving MRD\[-\]CR status at 12 months. |
| Percentage of Participants With a Minimal Residual Disease Negative Complete Response (MRD[-]CR) as Assessed by the IRC | Day 1 cycle 1 to month 12 (8 to 13 month window) | The MRD\[-\]CR rate was defined as the percentage of participants who reached MRD\[-\]CR at the 12 month landmark (8- to 13-month window). MRD\[-\]CR was defined as the achievement of CR (including sCR or better) per IMWG-URC by IRC assessment and MRD\[-\] status at a sensitivity of 10\^-5 using next-generation sequencing based method in the bone marrow. The 90% CIs were estimated using the Clopper-Pearson method (1994). |
| Time to Response as Assessed by the IRC | From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks | Durations were calculated for responders. Time to response was defined as the time from start of any study treatment date to the earliest date when confirmed sCR, CR, very good partial response (VGPR), or partial response (PR) was first achieved. |
| Kaplan-Meier Estimate of Progression Free Survival (PFS) as Assessed by the IRC | From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks | PFS was defined as time from start of treatment until progression or death from any cause. Medians and percentiles were estimated using the Kaplan-Meier method by Klein and Moeschberger (1997). 90% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. |
| Kaplan-Meier Estimate of Overall Survival (OS) | From day 1 cycle 1 until the EOS; the mean duration of KPd treatment was 55.3 weeks. | OS was defined as the time from the start of treatment until death from any cause. Medians and percentiles were estimated using the Kaplan-Meier method. 90% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. |
| Number of Participants With Best Overall Confirmed Response of CR or Better as Assessed by the IRC | From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks | The number of safety analysis set participants whose best overall response was sCR or CR per IMWG-URC over the duration of the study. |
| Kaplan-Meier Estimate of Duration of Response as Assessed by the IRC | From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks | Disease response and progression were determined using IMWG-URC. Durations were calculated for responders. Medians and percentiles were estimated using the Kaplan-Meier method. 90% CIs for medians and percentiles were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. |
Countries
Denmark, Estonia, France, Germany, Greece, Italy, Spain, United States
Participant flow
Recruitment details
Participants were enrolled at 25 study centers in Denmark, France, Germany, Greece, Italy, Spain, and the United States from 06 August 2020 to 01 October 2024.
Pre-assignment details
Participants with relapsed multiple myeloma whose disease was refractory to lenalidomide were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) Carfilzomib was administered intravenously on days 1, 8, and 15 (± 2 days) of each 28-day cycle for up to 12 cycles or progression or end of study. A dose of 20 mg/m\^2 was administered on day 1 of cycle 1; all subsequent doses were 56 mg/m\^2. From cycle 13, the frequency of carfilzomib administration was reduced to days 1 and 15 (± 2 days) per cycle until progression or end of study.
Dexamethasone was administered orally or intravenously at a dose of 40 mg on days 1, 8, 15, and 22 of each cycle during cycles 1 to 12, and at a dose of 20 mg on days 1 and 15 from cycle 13 until progression or end of study.
Pomalidomide 4 mg was administered orally on days 1 to 21 of each cycle until progression or end of study. | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Pre-assignment Period | Did not receive study treatment | 2 |
| Treatment Period | Death | 37 |
| Treatment Period | Sponsor decision | 11 |
| Treatment Period | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Carfilzomib With Pomalidomide and Dexamethasone (KPd) |
|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Race/Ethnicity, Customized White | 47 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 37 / 54 |
| other Total, other adverse events | 48 / 52 |
| serious Total, serious adverse events | 22 / 52 |
Outcome results
Primary
Overall Response Rate (ORR) As Assessed by the Independent Review Committee (IRC)
Overall response was defined as the best overall confirmed response of: Complete response (CR): Negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). Stringent CR (sCR): CR and normal serum free light chain ratio and no clonal cells in BM. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-h). PR: ≥ 50% reduction of serum M-protein and 24-h urinary M-protein by ≥ 90% or to \< 200 mg/24-h. Assessment was by IRC per International Myeloma Working Group Uniform Response Criteria (IMWG-URC). The 90% confidence intervals were estimated using the Clopper-Pearson method (1994).
Time frame: From day 1 cycle 1 until the primary analysis (PA) data cutoff (DCO); the mean duration of KPd treatment as of the DCO was 42.0 weeks
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Overall Response Rate (ORR) As Assessed by the Independent Review Committee (IRC) | 57.7 percentage of participants |
Secondary
Kaplan-Meier Estimate of Duration of Response as Assessed by the IRC
Disease response and progression were determined using IMWG-URC. Durations were calculated for responders. Medians and percentiles were estimated using the Kaplan-Meier method. 90% CIs for medians and percentiles were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
Time frame: From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib. Only participants who achieved a partial response or better were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Kaplan-Meier Estimate of Duration of Response as Assessed by the IRC | 20.3 months |
Secondary
Kaplan-Meier Estimate of Overall Survival (OS)
OS was defined as the time from the start of treatment until death from any cause. Medians and percentiles were estimated using the Kaplan-Meier method. 90% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
Time frame: From day 1 cycle 1 until the EOS; the mean duration of KPd treatment was 55.3 weeks.
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Kaplan-Meier Estimate of Overall Survival (OS) | 17.6 months |
Secondary
Kaplan-Meier Estimate of Progression Free Survival (PFS) as Assessed by the IRC
PFS was defined as time from start of treatment until progression or death from any cause. Medians and percentiles were estimated using the Kaplan-Meier method by Klein and Moeschberger (1997). 90% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation.
Time frame: From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Kaplan-Meier Estimate of Progression Free Survival (PFS) as Assessed by the IRC | 11.1 months |
Secondary
Number of Participants Achieving MRD[-] Response
MRD\[-\] response was defined as achievement of MRD\[-\] status using next generation sequencing (NGS) based method in the bone marrow at any time.
Time frame: From day 1 cycle 1 until the end of study (EOS); the mean duration of KPd treatment as of the EOS was 55.3 weeks
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Number of Participants Achieving MRD[-] Response | 5 Participants |
Secondary
Number of Participants With Best Overall Confirmed Response of CR or Better as Assessed by the IRC
The number of safety analysis set participants whose best overall response was sCR or CR per IMWG-URC over the duration of the study.
Time frame: From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Number of Participants With Best Overall Confirmed Response of CR or Better as Assessed by the IRC | 3 Participants |
Secondary
Number of Participants With Sustained MRD[-]CR at Month 24 as Assessed by the IRC
Sustained MRD\[-\]CR at 24 months included participants that maintained MRD\[-\]CR for 12 months or more after achieving MRD\[-\]CR status at 12 months.
Time frame: Day 1 cycle 1 to month 26 (19 to 26 month window)
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Number of Participants With Sustained MRD[-]CR at Month 24 as Assessed by the IRC | 0 Participants |
Secondary
Number of Participants With Sustained MRD[-]CR for at Least 12 Months as Assessed by the IRC
MRD\[-\]CR at the 12 months landmark was defined as achievement of CR (including sCR or better) per IMWG-URC by IRC and MRD\[-\] status at a sensitivity of 10\^-5 using NGS based method in the bone marrow at the 12 months landmark (from 8 months to 13 months window). Maintaining MRD\[-\]CR for at least 12 months (- 4 weeks) was considered as sustained.
Time frame: Day 1 cycle 1 to month 12 (8 to 13 month window)
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Number of Participants With Sustained MRD[-]CR for at Least 12 Months as Assessed by the IRC | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as events with onset on or after the administration of the first dose of any study treatment and within the end of study, or 30 days after the last dose of any study treatment, whichever one was earlier, excluding events reported after end of study date.
Time frame: From the first dose of any study treatment until the end of study or 30 days after the last dose of any study treatment, whichever occured earlier; Median (min, max) was 8.5 (1.0, 46.6) months
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 50 Participants |
Secondary
Percentage of Participants With a Minimal Residual Disease Negative Complete Response (MRD[-]CR) as Assessed by the IRC
The MRD\[-\]CR rate was defined as the percentage of participants who reached MRD\[-\]CR at the 12 month landmark (8- to 13-month window). MRD\[-\]CR was defined as the achievement of CR (including sCR or better) per IMWG-URC by IRC assessment and MRD\[-\] status at a sensitivity of 10\^-5 using next-generation sequencing based method in the bone marrow. The 90% CIs were estimated using the Clopper-Pearson method (1994).
Time frame: Day 1 cycle 1 to month 12 (8 to 13 month window)
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib. The analysis was pre-specified until PA DCO only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Percentage of Participants With a Minimal Residual Disease Negative Complete Response (MRD[-]CR) as Assessed by the IRC | 3.8 percentage of participants |
Secondary
Time to Response as Assessed by the IRC
Durations were calculated for responders. Time to response was defined as the time from start of any study treatment date to the earliest date when confirmed sCR, CR, very good partial response (VGPR), or partial response (PR) was first achieved.
Time frame: From day 1 cycle 1 until the PA DCO; the mean duration of KPd treatment as of the DCO was 42.0 weeks
Population: The safety analysis set included all participants who received at least 1 dose of carfilzomib. Only participants who achieved a partial response or better were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib With Pomalidomide and Dexamethasone (KPd) | Time to Response as Assessed by the IRC | 1.0 months |