Relapsed and Refractory Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to evaluate the safety, tolerability and overall response rate of carfilzomib in combination with dexamethasone for the treatment of multiple myeloma in China.
Interventions
DRUGDexamethasone
20 mg intravenous (IV) or oral dexamethasone on days 1, 2, 8, 9, 15, 16, 22, and 23 in 28-day cycles.
DRUGCarfilzomib
Infusion of IV carfilzomib on days 1, 2, 8, 9, 15 and 16 in each 28-day cycle.
Sponsors
Onyx Therapeutics, Inc.
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
- Multiple myeloma - Subjects must have measurable disease, defined as one or more of the following: -- Serum M-protein ≥ 1 g/dL -- Urine M-protein ≥ 200 mg/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 κ/λ ratio - Subjects must have been responsive (ie, achieved a minimal response \[MR\] or better) to at least one of their prior treatment regimens - Refractory to the most recently received therapy. Refractory disease defined as ≤ 25% response to, or progressing during therapy or within 60 days after completion of therapy - Subjects must have received ≥ 2 prior regimens. Induction therapy and stem cell transplant (± maintenance) will be considered as 1 regimen - Subjects must have received prior treatment with bortezomib and an immunomodulatory drug - Subjects must have received an alkylating agent or anthracycline alone or in combination with other myeloma treatments (this may include high dose melphalan as part of the conditioning regimen prior to a stem cell transplant) - Males and females ≥ 18 years of age - Life expectancy of more than 3 months - Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 - Adequate hepatic function, with bilirubin \< 2.0 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3.0 times the ULN - Absolute neutrophil count (ANC) ≥ 1,000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50,000/mm³ • Subjects should not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count • Screening ANC should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) support for ≥ 1 week and pegylated G-CSF for ≥ 2 weeks • Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed; however, most recent RBC transfusion may not have been done within 7 days prior to obtaining screening hemoglobin - Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/min. Calculated CrCl should be performed by using a widely accepted equation (eg, the Cockcroft and Gault equation): (\[140 - Age\] × Mass \[kg\] / \[72 × Creatinine mg/dL\]). Multiply the result by 0.85 if the subject is female. - Left ventricular ejection fraction (LVEF) ≥ 40%; 2-dimensional transthoracic echocardiogram (ECHO) is the preferred method of evaluation; multiple gated acquisition scan (MUGA) is acceptable if ECHO is not available - Written informed consent in accordance with federal, local, and institutional guidelines - Female subjects of child-bearing potential (FCBP) must have a negative serum pregnancy test within 21 days prior to enrollment and agree to use an effective method of contraception during and for 30 days following last dose of carfilzomib. This protocol defines a FCBP as a sexually mature woman who: 1) has not undergone a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or 2) has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) - Male subjects must use an effective barrier method of contraception during the study and for 3 months following the last dose of carfilzomib if sexually active with a FCBP. Male subjects must not donate sperm during treatment and for an additional 90 days after last dose of carfilzomib. Male subjects with pregnant partners must practice sexual abstinence or use a condom during vaginal sex.
Exclusion criteria
- Waldenström's macroglobulinemia or immunoglobulin M (IgM) multiple myeloma - Subjects who failed to achieve at least a confirmed MR on any of their prior regimens - Subjects with non-secretory multiple myeloma, defined as \< 1 g/dL M-protein in serum and \< 200 mg/24 hour M-protein in urine and SFLC ≤ 100 mg/L (involved light chain) - Glucocorticoid therapy (prednisone \> 10 mg/day or equivalent) within 3 weeks prior to Cycle 1 Day 1 - POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) - Plasma cell leukemia (\> 2.0 × 10⁹/L circulating plasma cells by standard differential) - Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the 3 weeks prior to Cycle 1 Day 1 - Radiation therapy or immunotherapy in the 4 weeks prior to Cycle 1 Day 1; localized radiation therapy within 1 week prior to Cycle 1 Day 1 - Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (T½) prior to Cycle 1 Day 1, whichever time is greater - Prior treatment with carfilzomib - Major surgery within 3 weeks before Cycle 1 Day 1 - Congestive heart failure (CHF; New York Heart Association Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months - Uncontrolled hypertension (a sustained systolic blood pressure \> 140 mmHg and/or diastolic blood pressure \> 90 mmHg) - Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to Cycle 1 Day 1 - Known human immunodeficiency virus (HIV) seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed) - Non-hematologic malignancy within the past 3 years except: -- Adequately treated basal cell or squamous cell skin cancer, -- Carcinoma in situ of the cervix, or -- Prostate cancer \< Gleason Score 6 with stable prostate-specific antigen - Subjects with treatment-related myelodysplastic syndrome - Significant neuropathy (Grade 3, 4, or Grade 2 with pain) at the time of baseline evaluation - Subjects in whom the required program of fluid hydration is contraindicated, eg, due to pre-existing pulmonary, cardiac, or renal impairment - Subjects with known or suspected amyloidosis - Subjects with pleural effusions requiring thoracentesis - Subjects with ascites requiring paracentesis - Any clinically significant medical disease or condition, that in the investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent - Female subjects who are pregnant or lactating, or planning to become pregnant during treatment and for an additional 30 days after discontinuing carfilzomib. - Serious psychiatric or medical conditions that could interfere with treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) After at Least 6 Cycles of Treatment Assessed by the Independent Review Committee | Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 5 November 2018; median follow-up time for progression was 8.9 months. | ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate After at Least 12 Cycles of Treatment Assessed by the Independent Review Committee | Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 12.8 months. | ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. |
| Overall Response Rate After at Least 12 Cycles of Treatment Assessed by the Investigator | Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 13.1 months. | ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. |
| Clinical Benefit Rate After at Least 6 Cycles of Treatment Assessed by the Independent Review Committee | Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 05 November 2018; median follow-up time for progression was 8.9 months. | Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to International Myeloma Working Group Uniform Response Criteria (IMWG-URC) (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required |
| Area Under the Plasma Concentration Curve From Time 0 to the Last Measurable Concentration (AUClast) for Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | AUClast of carfilzomib is the total area under the concentration-time curve beginning from time 0 to the time of the last measurable concentration of carfilzomib. |
| Clinical Benefit Rate After at Least 6 Cycles of Treatment Assessed by the Investigator | Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 05 November 2018; median follow-up time for progression was 10.3 months. | Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to IMWG-URC criteria (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas was also required. |
| Clinical Benefit Rate After at Least 12 Cycles of Treatment Assessed by the Independent Review Committee | Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 12.8 months. | Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to IMWG-URC criteria (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas was also required. |
| Clinical Benefit Rate After at Least 12 Cycles of Treatment Assessed by the Investigator | Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 13.1 months. | Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to IMWG-URC criteria (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas was also required. |
| Duration of Overall Response (DOR) | Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively. | Duration of response (DOR) is defined as the time from first evidence of PR or better to disease progression (PD) or death due to any cause per the IMWG-URC criteria. PD: * Increase of 25% from lowest response value in any of the following: * Serum M-component (absolute increase ≥ 0.5 g/dL) and/or * Urine M-component (absolute increase ≥ 200 mg/24 hours) * In patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase \>10 mg/dL) * Definite development of new or increase in size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. DOR was analyzed using the Kaplan-Meier method; Participants with no documented progression or death were censored at the date of their last disease assessment. DOR was determined based on both investigator and independent review committee response assessments. |
| Duration of Clinical Benefit (DCB) | Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively. | Duration of clinical benefit (DCB) is defined as the time from first evidence of MR or better to disease progression or death due to any cause based on the (IMWG-URC criteria. DCB was estimated using the Kaplan-Meier method; participants with no disease progression or death at the analysis cut-off date were censored at their last disease assessment date. Duration of clinical benefit was determined based on both investigator and independent review committee response assessments. |
| Progression-free Survival (PFS) | Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively. | Progression-free survival (PFS) is defined as the time from first dose of any study treatment to the earlier of disease progression or death due to any cause according to the IMWG-URC criteria. PFS was analyzed using the Kaplan-Meier method; participants with no disease progression or death at the time of the data cut-off date were censored at the date of their last disease assessment; participants who started new anti-cancer therapy before disease progression or death were censored at their last disease assessment prior to starting new anti-cancer therapy. Progression-free survival was determined based on both investigator and independent review committee response assessments. |
| Overall Response Rate (ORR) After at Least 6 Cycles of Treatment Assessed by the Investigator | Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 05 November 2018; median follow-up time for progression was 10.3 months. | ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline. |
| Time to Response (TTR) | Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively. | Time to response (TTR) is the time from the first dose of any study treatment to the first confirmed response (PR or better) based on both investigator and independent review committee response assessments. |
| Maximum Observed Plasma Concentration (Cmax) of Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | Cmax is the maximum observed plasma concentration over the concentration-time profile of carfilzomib. |
| Time to Maximum Plasma Concentration (Tmax) of Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | Tmax of carfilzomib is the time at which maximum observed plasma concentrations of carfilzomib were observed. |
| Area Under the Plasma Concentration Curve From Time 0 Extrapolated to Infinity (AUC0-inf) for Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | AUC0-inf of carfilzomib is the total area under the concentration-time curve beginning from time 0 extrapolated to infinity following carfilzomib dosing. |
| Terminal Elimination Half-Life (T½) for Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | The terminal elimination half-life is the time required for plasma concentrations to fall by 50% in the terminal phase of the concentration-time profile. |
| Systemic Clearance (CL) of Carfilzomib After Intravenous Infusion | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | Systemic clearance is a measure of the ability of the body to eliminate drug, expressed in units of volume per time. |
| Volume of Distribution (Varea) of Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | Volume of distribution is a pharmacokinetic parameter relating the amount of drug in the body to the concentration of drug in plasma. |
| Volume of Distribution at Steady State (Vss) for Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | Volume of distribution at steady-state is a pharmacokinetic parameter that relates the amount of drug in the body at steady-state to the concentration of drug in the plasma. |
| Mean Residence Time Observed From Time Zero to the Last Quantifiable Concentration (MRTlast) for Carfilzomib | Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion. | MRTlast is the mean residence time observed from time 0 until the time of the last quantifiable concentration. |
| Overall Survival (OS) | From first dose until the data cut-off date of 15 March 2019; median time on follow-up for survival was 15.3 months. | Overall survival (OS) is defined as the time from the first dose of any study treatment to the date of death due to any cause. Overall survival was analyzed using the Kaplan-Meier method; participants who were alive or lost to follow-up as of the data analysis cut-off date were censored at their date of last contact (last known to be alive). |
Countries
China
Participant flow
Recruitment details
This study was conducted at 18 centers in China. The primary efficacy analysis was prespecified to occur when all enrolled participants had received 6 cycles of therapy or discontinued treatment. This occurred on November 5, 2018. A final analysis for efficacy was prespecified when all enrolled participants had the opportunity to be treated with at least 12 cycles. This occurred on March 15, 2019. The final analysis for safety occurred once all participants completed the study, 4 June 2021.
Participants by arm
| Arm | Count |
|---|---|
| Carfilzomib With 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 20 mg dexamethasone IV or orally on days 1, 2, 8, 9, 15, 16, 22, and 23.
Participants received treatment until disease progression, unacceptable toxicity, initiation of new antimyeloma therapy, withdrawal of consent, subject noncompliance, or intercurrent illness or worsening of a chronic condition, whichever occurred first. | 123 |
| Total | 123 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 91 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Sponsor Decision | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Carfilzomib With Dexamethasone |
|---|---|
| Age, Continuous | 59.8 years STANDARD_DEVIATION 9.4 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 68 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restricted but ambulatory) | 45 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 10 Participants |
| Race/Ethnicity, Customized Asian | 123 Participants |
| Sex: Female, Male Female | 56 Participants |
| Sex: Female, Male Male | 67 Participants |
| Time From Initial Diagnosis to First Dose | 38.70 months |
| Total Number of Prior Regimens | 4.0 regimens |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 91 / 126 |
| other Total, other adverse events | 123 / 123 |
| serious Total, serious adverse events | 68 / 123 |
Outcome results
Primary
Overall Response Rate (ORR) After at Least 6 Cycles of Treatment Assessed by the Independent Review Committee
ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline.
Time frame: Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 5 November 2018; median follow-up time for progression was 8.9 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Overall Response Rate (ORR) After at Least 6 Cycles of Treatment Assessed by the Independent Review Committee | 35.8 percentage of participants |
95% CI: [27.3, 44.9]
Secondary
Area Under the Plasma Concentration Curve From Time 0 Extrapolated to Infinity (AUC0-inf) for Carfilzomib
AUC0-inf of carfilzomib is the total area under the concentration-time curve beginning from time 0 extrapolated to infinity following carfilzomib dosing.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic analyses were conducted on a subset of participants at selected sites. Results are reported for participants in the PK analysis population with available data at each time point. PK profiles with a coefficient of determination (R²; goodness of fit) \< 0.8 or percent extrapolated AUC \> 20% were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Area Under the Plasma Concentration Curve From Time 0 Extrapolated to Infinity (AUC0-inf) for Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 256 hr*ng/mL | Standard Deviation 104 |
| Carfilzomib With Dexamethasone | Area Under the Plasma Concentration Curve From Time 0 Extrapolated to Infinity (AUC0-inf) for Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 401 hr*ng/mL | Standard Deviation 173 |
Secondary
Area Under the Plasma Concentration Curve From Time 0 to the Last Measurable Concentration (AUClast) for Carfilzomib
AUClast of carfilzomib is the total area under the concentration-time curve beginning from time 0 to the time of the last measurable concentration of carfilzomib.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic (PK) analyses were conducted on a subset of participants at selected sites. The PK analysis population included participants who received at least 1 dose of carfilzomib and had adequate data for the noncompartmental estimation of PK parameters. Results are reported for participants with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Area Under the Plasma Concentration Curve From Time 0 to the Last Measurable Concentration (AUClast) for Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 254 hr*ng/mL | Standard Deviation 102 |
| Carfilzomib With Dexamethasone | Area Under the Plasma Concentration Curve From Time 0 to the Last Measurable Concentration (AUClast) for Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 401 hr*ng/mL | Standard Deviation 173 |
Secondary
Clinical Benefit Rate After at Least 12 Cycles of Treatment Assessed by the Independent Review Committee
Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to IMWG-URC criteria (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas was also required.
Time frame: Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 12.8 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Clinical Benefit Rate After at Least 12 Cycles of Treatment Assessed by the Independent Review Committee | 48.0 percentage of participants |
Secondary
Clinical Benefit Rate After at Least 12 Cycles of Treatment Assessed by the Investigator
Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to IMWG-URC criteria (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas was also required.
Time frame: Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 13.1 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Clinical Benefit Rate After at Least 12 Cycles of Treatment Assessed by the Investigator | 46.3 percentage of participants |
Secondary
Clinical Benefit Rate After at Least 6 Cycles of Treatment Assessed by the Independent Review Committee
Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to International Myeloma Working Group Uniform Response Criteria (IMWG-URC) (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas is also required
Time frame: Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 05 November 2018; median follow-up time for progression was 8.9 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Clinical Benefit Rate After at Least 6 Cycles of Treatment Assessed by the Independent Review Committee | 48.0 percentage of participants |
Secondary
Clinical Benefit Rate After at Least 6 Cycles of Treatment Assessed by the Investigator
Clinical benefit rate (CBR) is defined as the percentage of participants with the best overall response of minimal response (MR) or better according to IMWG-URC criteria (i.e., a minimal response, partial response, very good partial response, complete response, or stringent complete response). MR: 25% to 49% reduction in the level of serum M-protein and a 50% to 89% reduction in 24-hour urinary M-protein, which still exceeds 200 mg /24 hour; If present at baseline, a \>50% reduction in the size of soft tissue plasmacytomas was also required.
Time frame: Response was assessed every 28 days until disease progression; CBR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 05 November 2018; median follow-up time for progression was 10.3 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Clinical Benefit Rate After at Least 6 Cycles of Treatment Assessed by the Investigator | 46.3 percentage of participants |
Secondary
Duration of Clinical Benefit (DCB)
Duration of clinical benefit (DCB) is defined as the time from first evidence of MR or better to disease progression or death due to any cause based on the (IMWG-URC criteria. DCB was estimated using the Kaplan-Meier method; participants with no disease progression or death at the analysis cut-off date were censored at their last disease assessment date. Duration of clinical benefit was determined based on both investigator and independent review committee response assessments.
Time frame: Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively.
Population: Safety population participants who achieved a best overall response of minimal response or better.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib With Dexamethasone | Duration of Clinical Benefit (DCB) | Independent Review Committee Assessment | 8.3 months |
| Carfilzomib With Dexamethasone | Duration of Clinical Benefit (DCB) | Investigator Assessment | 8.6 months |
Secondary
Duration of Overall Response (DOR)
Duration of response (DOR) is defined as the time from first evidence of PR or better to disease progression (PD) or death due to any cause per the IMWG-URC criteria. PD: * Increase of 25% from lowest response value in any of the following: * Serum M-component (absolute increase ≥ 0.5 g/dL) and/or * Urine M-component (absolute increase ≥ 200 mg/24 hours) * In patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels (absolute increase \>10 mg/dL) * Definite development of new or increase in size of existing bone lesions or soft tissue plasmacytomas * Development of hypercalcemia attributed solely to the plasma cell proliferative disorder. DOR was analyzed using the Kaplan-Meier method; Participants with no documented progression or death were censored at the date of their last disease assessment. DOR was determined based on both investigator and independent review committee response assessments.
Time frame: Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively.
Population: Safety population participants who achieved an overall response (best response of PR or better)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib With Dexamethasone | Duration of Overall Response (DOR) | Independent Review Committee Assessment | 12.2 months |
| Carfilzomib With Dexamethasone | Duration of Overall Response (DOR) | Investigator Assessment | 9.7 months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Carfilzomib
Cmax is the maximum observed plasma concentration over the concentration-time profile of carfilzomib.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic (PK) analyses were conducted on a subset of participants at selected sites. The PK analysis population included participants who received at least 1 dose of carfilzomib and had adequate data for the noncompartmental estimation of PK parameters. Results are reported for participants with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Maximum Observed Plasma Concentration (Cmax) of Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 744 ng/mL | Standard Deviation 326 |
| Carfilzomib With Dexamethasone | Maximum Observed Plasma Concentration (Cmax) of Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 1210 ng/mL | Standard Deviation 678 |
Secondary
Mean Residence Time Observed From Time Zero to the Last Quantifiable Concentration (MRTlast) for Carfilzomib
MRTlast is the mean residence time observed from time 0 until the time of the last quantifiable concentration.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: PK analyses were conducted on a subset of participants at selected sites. Results are reported for the participants in PK analysis population with available data at each time point. PK profiles with a coefficient of determination \< 0.8, percent extrapolated AUC \> 20%, or negative values for MRT were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Mean Residence Time Observed From Time Zero to the Last Quantifiable Concentration (MRTlast) for Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 0.225 hours | Standard Deviation 0.0856 |
| Carfilzomib With Dexamethasone | Mean Residence Time Observed From Time Zero to the Last Quantifiable Concentration (MRTlast) for Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 0.196 hours | Standard Deviation 0.0975 |
Secondary
Overall Response Rate After at Least 12 Cycles of Treatment Assessed by the Independent Review Committee
ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline.
Time frame: Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 12.8 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Overall Response Rate After at Least 12 Cycles of Treatment Assessed by the Independent Review Committee | 35.8 percentage of participants |
Secondary
Overall Response Rate After at Least 12 Cycles of Treatment Assessed by the Investigator
ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline.
Time frame: Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 12 cycles or discontinued treatment; the data cut-off date was 15 March 2019; median follow-up time for progression was 13.1 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Overall Response Rate After at Least 12 Cycles of Treatment Assessed by the Investigator | 35.0 percentage of participants |
Secondary
Overall Response Rate (ORR) After at Least 6 Cycles of Treatment Assessed by the Investigator
ORR is defined as the percentage of participants with a best overall response of partial response (PR), very good PR (VGPR), complete response (CR), or stringent CR (sCR) based on the International Myeloma Working Group Uniform Response Criteria. sCR: As for CR, and absence of clonal plasma cells in bone marrow (BM). CR: No immunofixation on serum and urine, disappearance of soft tissue plasmacytomas and \< 5% plasma cells in BM. Normal serum free light chain (SFLC) ratio if disease measurable only by SFLC. VGPR: Serum and urine M-protein detectable by immunofixation but not electrophoresis or ≥ 90% decrease in serum M-protein with urine M-protein \<100 mg/24 hrs. If disease measurable only by SFLC, ≥ 90% decrease in the difference between involved and uninvolved FLC levels (dFLC). PR: ≥ 50% reduction of serum M-protein and ≥ 90% reduction in urine M-protein or to \< 200 mg/24 hrs, or a ≥ 50% decrease in dFLC. A ≥ 50% decrease in the size of soft tissue plasmacytomas present at baseline.
Time frame: Response was assessed every 28 days until disease progression; ORR was analyzed after all participants received at least 6 cycles or discontinued treatment; the data cut-off date was 05 November 2018; median follow-up time for progression was 10.3 months.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Carfilzomib With Dexamethasone | Overall Response Rate (ORR) After at Least 6 Cycles of Treatment Assessed by the Investigator | 35.0 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival (OS) is defined as the time from the first dose of any study treatment to the date of death due to any cause. Overall survival was analyzed using the Kaplan-Meier method; participants who were alive or lost to follow-up as of the data analysis cut-off date were censored at their date of last contact (last known to be alive).
Time frame: From first dose until the data cut-off date of 15 March 2019; median time on follow-up for survival was 15.3 months.
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Carfilzomib With Dexamethasone | Overall Survival (OS) | 15.2 months |
Secondary
Progression-free Survival (PFS)
Progression-free survival (PFS) is defined as the time from first dose of any study treatment to the earlier of disease progression or death due to any cause according to the IMWG-URC criteria. PFS was analyzed using the Kaplan-Meier method; participants with no disease progression or death at the time of the data cut-off date were censored at the date of their last disease assessment; participants who started new anti-cancer therapy before disease progression or death were censored at their last disease assessment prior to starting new anti-cancer therapy. Progression-free survival was determined based on both investigator and independent review committee response assessments.
Time frame: Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively.
Population: Safety population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib With Dexamethasone | Progression-free Survival (PFS) | Independent Review Committee Assessment | 5.6 months |
| Carfilzomib With Dexamethasone | Progression-free Survival (PFS) | Investigator Assessment | 5.5 months |
Secondary
Systemic Clearance (CL) of Carfilzomib After Intravenous Infusion
Systemic clearance is a measure of the ability of the body to eliminate drug, expressed in units of volume per time.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic analyses were conducted on a subset of participants at selected sites. Results are reported for participants in the PK analysis population with available data at each time point. PK profiles with a coefficient of determination (R²; goodness of fit) \< 0.8 or percent extrapolated AUC \> 20% were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Systemic Clearance (CL) of Carfilzomib After Intravenous Infusion | Cycle 1 Day 1 (20 mg/m²) | 157 L/hr | Standard Deviation 61.4 |
| Carfilzomib With Dexamethasone | Systemic Clearance (CL) of Carfilzomib After Intravenous Infusion | Cycle 2 Day 1 (27 mg/m²) | 153 L/hr | Standard Deviation 112 |
Secondary
Terminal Elimination Half-Life (T½) for Carfilzomib
The terminal elimination half-life is the time required for plasma concentrations to fall by 50% in the terminal phase of the concentration-time profile.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic analyses were conducted on a subset of participants at selected sites. Results are reported for participants in the PK analysis population with available data at each time point. PK profiles with a coefficient of determination (R²; goodness of fit) \< 0.8 or percent extrapolated AUC \> 20% were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Terminal Elimination Half-Life (T½) for Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 0.651 hours | Standard Deviation 0.259 |
| Carfilzomib With Dexamethasone | Terminal Elimination Half-Life (T½) for Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 0.792 hours | Standard Deviation 0.281 |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Carfilzomib
Tmax of carfilzomib is the time at which maximum observed plasma concentrations of carfilzomib were observed.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic (PK) analyses were conducted on a subset of participants at selected sites. The PK analysis population included participants who received at least 1 dose of carfilzomib and had adequate data for the noncompartmental estimation of PK parameters. Results are reported for participants with available data at each time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib With Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 0.50 hours |
| Carfilzomib With Dexamethasone | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 0.50 hours |
Secondary
Time to Response (TTR)
Time to response (TTR) is the time from the first dose of any study treatment to the first confirmed response (PR or better) based on both investigator and independent review committee response assessments.
Time frame: Response was assessed every 28 days until disease progression; the data cut-off date was 15 March 2019; median follow-up time for progression assessed by independent review committee and by investigators were 12.8 months and 13.1 months, respectively.
Population: Safety population participants who achieved an overall response (best response of PR or better)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Carfilzomib With Dexamethasone | Time to Response (TTR) | Independent Review Committee Assessment | 1.0 months |
| Carfilzomib With Dexamethasone | Time to Response (TTR) | Investigator Assessment | 1.0 months |
Secondary
Volume of Distribution at Steady State (Vss) for Carfilzomib
Volume of distribution at steady-state is a pharmacokinetic parameter that relates the amount of drug in the body at steady-state to the concentration of drug in the plasma.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: PK analyses were conducted on a subset of participants at selected sites. Results are reported for participants in the PK analysis population with available data at each time point. PK profiles with a coefficient of determination \< 0.8, percent extrapolated AUC \> 20%, or negative values for Vss were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Volume of Distribution at Steady State (Vss) for Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 35.0 liters | Standard Deviation 20.2 |
| Carfilzomib With Dexamethasone | Volume of Distribution at Steady State (Vss) for Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 27.2 liters | Standard Deviation 17.4 |
Secondary
Volume of Distribution (Varea) of Carfilzomib
Volume of distribution is a pharmacokinetic parameter relating the amount of drug in the body to the concentration of drug in plasma.
Time frame: Cycles 1 and 2, day 1 at predose, 5 minutes after the start of carfilzomib infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of infusion.
Population: Pharmacokinetic analyses were conducted on a subset of participants at selected sites. Results are reported for participants in the PK analysis population with available data at each time point. PK profiles with a coefficient of determination (R²; goodness of fit) \< 0.8 or percent extrapolated AUC \> 20% were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Carfilzomib With Dexamethasone | Volume of Distribution (Varea) of Carfilzomib | Cycle 1 Day 1 (20 mg/m²) | 148 Liters | Standard Deviation 88.7 |
| Carfilzomib With Dexamethasone | Volume of Distribution (Varea) of Carfilzomib | Cycle 2 Day 1 (27 mg/m²) | 164 Liters | Standard Deviation 102 |