Multinational Clinical Study Comparing Isatuximab, Carfilzomib And Dexamethasone To Carfilzomib And Dexamethasone In Relapse And/Or Refractory Multiple Myeloma Patients (IKEMA)

• ClinicalTrials.gov Identifier: NCT03275285
• Recruitment Status: Active, not recruiting
• First Posted: September 7, 2017
• Results First Posted: February 13, 2023
• Last Update Posted: February 20, 2024
• Sponsor: Sanofi
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

The purpose of this study it to compare the efficacity of isatuximab when combined to carfilzomib and dexamethasone versus carfilzomib and dexamethasone in patients with multiple myeloma already treated with 1 to 3 prior lines of therapy.

Condition or disease	Intervention/treatment	Phase
Plasma Cell Myeloma	Drug: isatuximab SAR650984; Drug: carfilzomib; Drug: dexamethasone	Phase 3

Detailed Description:

The duration of the study for a patient will include a period for screening of up to 3 weeks. Patients will be treated until disease progression, unacceptable AE, or patient decision to stop the study treatment. After study treatment discontinuation, patients will have follow-up visits until the analysis of overall survival.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 302 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Open Label, Multicenter Study Assessing The Clinical Benefit Of Isatuximab Combined With Carfilzomib (Kyprolis®) And Dexamethasone Versus Carfilzomib With Dexamethasone In Patients With Relapse And/Or Refractory Multiple Myeloma Previously Treated With 1 to 3 Prior Lines
• Actual Study Start Date: October 25, 2017
• Actual Primary Completion Date: January 14, 2022
• Estimated Study Completion Date: November 19, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Isatuximab + Carfilzomib + Dexamethasone (IKd); Isatuximab (intravenous) on day 1, 8, 15 and 22 of 1st cycle, then on day 1 and 15 of subsequent cycles in combination with carfilzomib (intravenous) on day 1, 2, 8, 9, 15 and 16 + dexamethasone (intravenous or by mouth [po]) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.	Drug: isatuximab SAR650984; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Sarclisa; Drug: carfilzomib; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Kyprolis; Drug: dexamethasone; Pharmaceutical form: tablets or solution for infusion Route of administration: oral or intravenous
Active Comparator: Carfilzomib + Dexamethasone (Kd); Carfilzomib (intravenous) on day 1, 2, 8, 9, 15, 16 + dexamethasone (intravenous or po) on day 1, 2, 8, 9, 15, 16, 22 and 23 of a 28 day cycle.	Drug: carfilzomib; Pharmaceutical form: solution for infusion Route of administration: intravenous; Other Name: Kyprolis; Drug: dexamethasone; Pharmaceutical form: tablets or solution for infusion Route of administration: oral or intravenous

Outcome Measures

Primary Outcome Measures :

1. Progression Free Survival (PFS) As Determined by Independent Response Committee (IRC): Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (median duration of follow-up was 20.73 months) ]
   Time (in months) from randomization to date of 1st documentation of progressive disease (PD)/date of death from any cause, whichever comes 1st. If PD & death are not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever comes 1st. PD(IMWG criteria):any 1 of following:Increase(inc) of >=25% in serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component >=5 g/dL; and/or inc of >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% increase in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. Estimated by Kaplan-Meier method.
2. Progression Free Survival as Determined by Independent Response Committee: [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
   Time (in months) from randomization to date of 1st PD documentation/death date, whichever is 1st. If PD & death not observed before cut-off date/date of further anti-myeloma treatment initiation, PFS censored at date of last valid disease assessment not showing PD performed prior to initiation of further anti-myeloma treatment/cut-off date, whichever was 1st. Progression/deaths occurring >8 weeks after last disease assessment censored at earliest date of last disease assessment without evidence of progression before initiation of new anti-myeloma treatment & cut-off date. PD (IMWG criteria): meeting any 1: Inc >=25% in Serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component >=5 g/dL; and/or inc >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion >1 cm short axis.
3. Progression Free Survival as Determined by Independent Response Committee: Final Analysis [ Time Frame: From randomization until the final analysis data cut-off date of 14 January 2022 (the median duration of follow-up was 43.96 months) ]
   PFS: time (in months) from randomization to date of first documentation of PD or date of death from any cause, whichever comes first. If PD and death are not observed before analysis cut-off date or date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment or analysis cut-off date, whichever comes first. PD as per IMWG criteria: any 1 of following: Inc of >=25% in Serum M-component from nadir; serum M component increase >=1 g/dL in 2 consecutive assessment, if starting M component was >=5 g/dL; and/or inc of >=25% in Urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion if >1 lesion/ >=50% inc in longest diameter of previous soft tissue extramedullary disease lesion >1 cm in short axis. PFS estimated by Kaplan-Meier method.
4. Progression Free Survival as Determined by Independent Response Committee [Event Censored if Occurred >8 Weeks From Last Disease Assessment]: Final Analysis [ Time Frame: From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months) ]
   Time (in months) from randomization to date of 1st documentation of PD/date of death from any cause, whichever comes 1st. If PD & death are not observed before cut-off date/date of initiation of further anti-myeloma treatment, PFS was censored at date of last valid disease assessment not showing PD/cut-off date, whichever comes 1st. Progressions/deaths occurring >8 weeks after last disease assessment were censored at earliest date of last valid disease assessment not showing PD before initiation of further anti-myeloma treatment & cut-off date. PD (per IMWG criteria): meeting any 1 criteria: Inc of >=25% in serum M-component from nadir; serum M component inc >=1 g/dL in 2 consecutive assessment, if starting M component was >=5 g/dL; and/or inc of >=25% in urine M-component from nadir and/or development of new bone lesion/soft tissue extramedullary disease/inc >=50% from nadir in sum of perpendicular diameters of existing soft tissue extramedullary disease lesion >1 cm in short axis.

Secondary Outcome Measures :

1. Percentage of Participants With Overall Response (OR) as Determined by Independent Response Committee: Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
   OR: participants with sCR, CR, VGPR & partial response (PR) as best overall response assessed by IRC using IMWG response criteria (from start of treatment until disease progression, death, initiation of further anti-myeloma treatment/cutoff date, whichever occurs 1st). sCR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in bone marrow aspirate (BMA) + normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum & urine, disappearance of soft tissue plasmacytoma, <5% plasma cells in BMA. VGPR: serum & urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein + urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. PR:>=50% reduction of serum M-protein & decrease in 24h urinary M-protein by >=90%/<200mg/24h, if present at baseline,>=50% decrease in SPD of soft tissue plasmacytoma.
2. Percentage of Participants With Very Good Partial Response (VGPR) or Better as Determined by Independent Response Committee: Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
   VGPR or better: defined as participants with sCR, CR and VGPR as the best overall response (defined as best response from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date whichever occurs first) as per IRC. As per IMWG response criteria: sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.
3. Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
   Percentage of participants with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in bone marrow aspiration samples from participants who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of participants with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in BMAs. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.
4. Percentage of Participants With VGPR or Better With Minimal Residual Disease (MRD) Negativity: Final Analysis [ Time Frame: From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months) ]
   Percentage of participants with sCR, CR and VGPR for whom MRD assessed by sequencing was negative at any time after first dose of study treatment. MRD was assessed centrally by next-generation sequencing in BM aspiration samples from participants who achieve VGPR or better, to determine depth of response at molecular level. VGPR or better: percentage of participants with sCR, CR and VGPR. sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio, absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. VGPR: serum and urine M-protein detectable by immunofixation, not on electrophoresis/,>=90% reduction in serum M-protein plus urine M-protein level <100mg/24h/,>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma.
5. Percentage of Participants With Complete Response (CR) as Per Independent Response Committee: Final Analysis [ Time Frame: From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months) ]
   Complete response was defined as the participants with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal free light chain (FLC) ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at the time of the final analysis was assessed with hydrashift isatuximab immunofixation electrophoresis (IFE) assay, which separated immunoglobulin G (IgG) isatuximab from IgG M protein.
6. Percentage of Participants With Complete Response With MRD Negativity: Final Analysis [ Time Frame: From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months) ]
   MRD negativity was defined as the percentage of participants for whom MRD was negative by next-generation sequencing at any timepoint after first dose of study treatment. Threshold for negativity is 10^-5. MRD status in a participant was negative if at least one result of the assessment was negative in the participant otherwise MRD was considered as positive (MRD status reported as positive, missing or unevaluable). CR: participants with sCR and CR. IMWG response criteria for sCR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates plus normal FLC ratio (0.26-1.65), absence of clonal cells in bone marrow biopsy. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas, <5% plasma cells in bone marrow aspirates. Complete response at the time of the final analysis was assessed with Hydrashift isatuximab IFE assay, which separated IgG isatuximab from IgG M protein.
7. Overall Survival (OS) [ Time Frame: From randomization until the final analysis data cut-off date of 7 Feb 2023 (the median duration of follow-up was 56.61 months) ]
   Overall survival, defined as the time from the date of randomization to death from any cause. The data reported is based on cut-off date of 7 Feb 2023.
8. Duration of Response (DOR): Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
   DOR: time (in months) from date of 1st IRC determined response for participants achieving PR/better to date of 1st documented PD determined by IRC/death, whichever happens 1st. If disease progression/death before analysis cut-off date was not observed, DOR was censored at date of last valid disease assessment performed prior to initiation of further anti-myeloma treatment/data cut-off date, whichever was 1st. PD (IMWG criteria): inc of >=25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute inc must be >=0.5 g/dL), serum M-protein inc >=1g/dL if lowest M component was >=5g/dL; urine M-component (absolute inc must be >=200mg/24 hour),appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in the longest diameter of previous lesion >1 cm in short axis. PR: >=50% reduction of serum M-protein & reduction in 24h urinary M-protein by >=90%/<200mg/24 h. Estimated by Kaplan Meier method.
9. Time to Progression (TTP): Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
   TTP was defined as time in months from randomization to the date of first documentation of PD (as determined by the IRC). If progression was not observed before the analysis cut-off date or the date of initiation of further anti-myeloma treatment, TTP was censored at the date of the last valid disease assessment not showing disease progression performed prior to initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. As per IMWG criteria, PD was defined for participants with inc of >= 25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute inc must be >= 0.5 g/dL), serum M-protein inc >=1 g/dL if the lowest M component was >=5 g/dL; urine M-component (the absolute inc must be >=200 mg/24hour), appearance of new lesion(s), >=50% inc from nadir in SPD of >1 lesion, or >=50% inc in the longest diameter of a previous lesion >1 centimeter in short axis.
10. Time to First Response: Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
    Time to first response was defined as the time (in months) from randomization to the date of first IRC determined response (PR or better) that is subsequently confirmed. In the absence of response, participants were censored at the earliest of the date of the last valid disease assessment before disease progression or death, the date of the last valid disease assessment before initiation of a further anti-myeloma treatment (if any) or the analysis cut-off date, whichever comes first. PR per IMWG criteria was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. In addition to the above listed criteria, if present at baseline, a >=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required.
11. Time to Best Response: Primary Analysis [ Time Frame: From randomization until the primary analysis data cut-off date of 7 Feb 2020 (the median duration of follow-up was 20.73 months) ]
    Time to best response was defined as time (in months) from randomization to the date of first occurrence of IRC determined as best overall response (PR or better) that is subsequently confirmed. In absence of response, participants were censored at earliest date of last valid disease assessment before disease progression/death, date of last valid disease assessment before initiation of further anti-myeloma treatment (if any)/ analysis cut-off date, whichever was 1st. PR (IMWG criteria) was defined as >=50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >=90% or to <200 mg/24 h. In addition to above listed criteria, if present at baseline, a >=50% reduction in the size (SPD) of soft tissue plasmacytomas was also required. Best Overall Response was defined as the best response, using the IRC's assessment of response, from start of treatment until disease progression, death, initiation of further anti-myeloma treatment or cut-off date, whichever occurs 1st.
12. Second Progression Free Survival (PFS2): Final Analysis - Data Cut-off Date of 14 Jan 2022 [ Time Frame: From randomization until the final analysis data cut-off date of 14 Jan 2022 (the median duration of follow-up was 43.96 months) ]
    PFS2 defined as time (in months) from date of randomization to date of 1st documentation of PD (as assessed by investigator) after initiation of further anti-myeloma treatment /death from any cause, whichever comes 1st. Participants alive without progression after initiation of further anti-myeloma treatment before analysis cut-off date, PFS2 censored at date of last follow-up visit not showing disease progression after initiation of further anti-myeloma treatment /analysis cut-off date, whichever comes 1st. As per IMWG criteria, PD: defined for participants with increase of >= 25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute increase must be >= 0.5 g/dL), serum M-protein increase >=1 g/dL if lowest M component was >=5 g/dL; urine M-component (absolute increase must be >=200 mg/24hour), appearance of new lesion(s), >=50% increase from nadir in SPD of >1 lesion, or >=50% increase in longest diameter of previous lesion >1 centimeter short axis.
13. Second Progression Free Survival (PFS2): Overal Survival Analysis - Data Cut-off Date of 07 Feb 2023 [ Time Frame: From randomization until the overal survival analysis data cut-off date of 07 Feb 2023 (the median duration of follow-up was 56.61 months) ]
    PFS2 defined as time (in months) from date of randomization to date of 1st documentation of PD (as assessed by investigator) after initiation of further anti-myeloma treatment /death from any cause, whichever comes 1st. Participants alive without progression after initiation of further anti-myeloma treatment before analysis cut-off date, PFS2 censored at date of last follow-up visit not showing disease progression after initiation of further anti-myeloma treatment /analysis cut-off date, whichever comes 1st. As per IMWG criteria, PD: defined for participants with increase of >= 25% from lowest confirmed value in any 1 of following criteria: serum M-protein (absolute increase must be >= 0.5 g/dL), serum M-protein increase >=1 g/dL if lowest M component was >=5 g/dL; urine M-component (absolute increase must be >=200 mg/24hour), appearance of new lesion(s), >=50% increase from nadir in SPD of >1 lesion, or >=50% increase in longest diameter of previous lesion >1 centimeter short axis.
14. Number of Participants With Renal Response (RR): Primary Analysis [ Time Frame: From the first dose of study treatment to 30 days following the last administration of study treatment (maximum duration: up to 114 weeks) ]
    RR comprises of complete RR (CR renal), partial RR (PR renal) & minor RR (MR renal). CR renal was defined as an improvement in estimated glomerular filtration rate (eGFR) from <50 mL/min/1.73m^2 at Baseline to >=60 mL/min/1.73m^2 in at least 1 assessment during the treatment period (time from first dose of study treatment up to 30 days after last dose of study treatment); PR renal was defined as improvement in eGFR from <15 mL/min/1.73m^2 at baseline to at least 1 assessment in the range of 30 to 60 mL/min/1.73m^2 during the on-treatment-period and MR renal was defined as an improvement in eGFR from <15 mL/min/1.73m^2 at Baseline to at least 1 assessment in the range of 15 to 30 mL/min/1.73m^2 during the on-treatment-period or from 15 to 30 mL/min/1.73m^2 at Baseline to at least 1 assessment in the range of 30 to 60 mL/min/1.73m^2 during the on-treatment-period.
15. Health Related Quality of Life (HRQL): Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 30 Items (EORTC QLQ-C30): Global Health Status Score at Specified Timepoints [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    EORTC QLQ-C30 is a cancer-specific instrument that contains 30 items & provides multidimensional assessment of HRQL. EORTC QLQ-C30 includes global health status/quality of life (GHS/QOL), functional scales (physical, role, cognitive, emotional, social), symptom scales (fatigue, pain, nausea/vomiting), and 6 single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, financial difficulties). Most questions from QLQ-C30 are 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale & are 7-point scale (1/Very Poor to 7/Excellent). GHS total score is calculated as ([{Q29+Q30}/2]-1)/6*100. Answers are converted into grading scale, with values between 0 (worse outcome) to100 (best outcome). High score represents a favorable outcome with best quality of life for participant. Results reported for primary analysis with data cut-off date 7-Feb-2020.
16. HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Disease Symptoms Domain Score at Specified Timepoints: Primary Analysis [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. Disease symptoms domain is one of the four domain scores. Disease symptoms domain consist of 6 questions and the score uses 4-point scale (1 'Not at All' to 4 'Very Much'). Disease Symptoms Domain Score is calculated as ([{Q31+Q32+Q33+Q34+Q35+Q36}/6]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more symptoms and lower HRQL.
17. HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Side Effects of Treatment at Specified Timepoints: Primary Analysis [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. Side effects of treatment domain is one of the four domain scores. Side effects of treatment domain consists of 10 questions and the score uses a 4-point scale (1 'Not at All' to 4 'Very Much'). Side Effects of Treatment Score (MYSE) is calculated as ([{Q37+Q38+Q39+Q40+Q41+Q42+Q43+Q44+Q45+Q46}/10]-1)/3*100. Scores are averaged, and transformed to 0-100 scale, where higher scores = more side effects and lower HRQL and lower scores = less side effects and better HRQL.
18. HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Body Image Score at Specified Timepoints: Primary Analysis [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of one question and scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much". Body image score is calculated as: (1 - [Q47-1]/3)*100. Scores are averaged, and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life.
19. HRQL: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Cancer Specific Questionnaire With 20 Items (EORTC QLQ-MY20): Future Perspective at Specified Timepoints: Primary Analysis [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. It is used in conjunction with the EORTC QLQ-C30 to assess symptoms and side effects due to treatment or the disease. It consists of three questions and the scores are based on the 4-point Likert scale ranging from "Not at all" to "Very much". Future Perspective score is calculated as (1 - ([{Q48+Q49+Q50}/3] -1)/3)*100. Scores are averaged and transformed to scale ranging from 0 to 100. A higher score represents a better quality of life.
20. HRQL: Change From Baseline in European Quality of Life Group Questionnaire With 5 Dimensions and 5 Levels Per Dimension (EQ-5D-5L): Health State Utility Index Value at Specified Timepoints: Primary Analysis [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist in 2 sections a descriptive system comprising 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and Visual Analog Scale (VAS). Each dimension has a 5-level response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Response options are measured with a 5-point Likert scale. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state and lower score indicate worse health state.
21. HRQL: Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Score: Visual Analogic Scale (VAS) at Specified Timepoints: Primary Analysis [ Time Frame: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 25), at the End of Treatment visit (any day up to 114 weeks) ]
    The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health utility and consist of 2 sections; descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a VAS. The VAS records the respondent's self-rated health on a 20 centimeter (cm) vertical VAS; the scale went from 0 (worst imaginable health state) to 100 (best imaginable health state). This information can be used as a quantitative measure of health as judged by the individual respondents.
22. Pharmacokinetics: Plasma Concentration at End of Infusion (Ceoi) of Isatuximab: Primary Analysis [ Time Frame: End of infusion on Cycle 1 Day 1 and Cycle 1 Day 15; Cycle 2 Day 1 ]
    Ceoi is the plasma concentration observed at the end of intravenous infusion.
23. Pharmacokinetics: Plasma Concentration of Isatuximab at Ctrough: Primary Analysis [ Time Frame: Pre-infusion on Cycle 1 Day 1, Day 8, Day 15 and Day 22, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 7 Day 1, Cycle 8 Day 1, Cycle 9 Day 1 and Cycle 10 Day 1 ]
    Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.
24. Pharmacokinetics: Maximum Observed Concentration (Cmax) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 minutes (min), 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
25. Pharmacokinetics: Clast of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    Clast was defined as the last concentration observed above the lower limit of quantification.
26. Pharmacokinetics: Tmax of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
27. Pharmacokinetics: Tlast of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    Tlast was defined as the time of last concentration observed above the lower limit of quantification, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
28. Pharmacokinetics: Area Under the Plasma Concentration Time Curve (AUC) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    AUC was defined as area under the plasma concentration-time curve extrapolated to infinity according to the equation: AUC= AUClast + Clast/λz. AUC was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
29. Pharmacokinetics: Area Under the Plasma Concentration Time Curve From Time 0 to Last Quantifiable Concentration (AUClast) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    AUClast was defined as area under the plasma concentration versus time curve calculated from time 0 to last quantifiable concentration. AUClast was calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
30. Pharmacokinetics: Percentage of Extrapolation of AUC (AUCext) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    AUCext was defined as the percentage of the extrapolation of AUC, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
31. Pharmacokinetics: Terminal Half-life (t1/2z) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    T1/2 was defined as the time required for the concentration of the drug to reach half of its original value, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
32. Pharmacokinetics: Clearance at Steady State (CLss) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    CLss was defined as a quantitative measure of the rate at which a drug substance is removed from the body at steady state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
33. Pharmacokinetics: Volume of Distribution at Steady State (Vss) of Carfilzomib: Primary Analysis [ Time Frame: Cycle 1: pre-dose (0 hour), 30 min, 35 min, 45 min, 60 min, 1 hour 30 min, 2 hours 30 min and 4 hours 30 min post-dose on Day 15 ]
    Volume of Distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state, calculated using the non-compartmental analysis after the intravenous infusion of carfilzomib with isatuximab.
34. Number of Participants With Anti-Drug Antibodies (ADA): Primary Analysis [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: 111 weeks) ]
    ADA were categorized as: pre-existing, treatment induced, and treatment boosted response. Pre-existing ADA was defined as ADA that were present in samples drawn during the pretreatment period (i.e., before the first isatuximab administration). Treatment-induced ADA was defined as ADA that developed at any time during the ADA on-study observation period in participants without pre-existing ADA, including participants without pretreatment samples. Treatment boosted ADA was defined as pre-existing ADA with an increase in titer during the ADA on-study observation period.
35. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs): Final Analysis [ Time Frame: From first dose of study treatment up to 30 days after last dose of study treatment (maximum duration: up to 265 weeks for Kd arm and 268 weeks for IKd arm) ]
    Adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment period (time from the first dose of study treatments up to 30 days after last dose of study treatments). An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability / incapacity, was a congenital anomaly/birth defect, was a medically important event.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Participants with MM previously treated with prior 1 to 3 lines and with measurable serum M-protein (>= 0.5 gram/deciliter) and/or urine M-protein (>= 200 milligram/24 hours).

Exclusion criteria:

• Participants previously pretreated with carfilzomib, who never achieved at least one minor response during previous therapies and/or last previous therapy completed within 14 last days.
• Participants with serum free light chain (FLC) measurable disease only.
• Participants less than 18 years old, participants with Eastern Cooperative Oncology Group performance status more than 2.
• Participants with inadequate biological tests.
• Participants with myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association class III or IV congestive heart failure, superior or equal to grade 3 arrhythmias, stroke or transient ischemic attack within last 6 months, and/or left ventricular ejection fraction lower than 40%.
• Participants with previous cancer unless disease free for more than 5 years or in situ cancer curatively treated.
• Participants with known acquired immunodeficiency syndrome related illness or human immunodeficiency virus requiring antiretroviral treatment, or hepatitis A, B, or C active infection.
• Women of childbearing potential or male participant with women of childbearing potential who do not agree to use highly effective method of birth control.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

United States, California

UCSF MS Center Site Number : 8400002

San Francisco, California, United States, 94117

United States, South Carolina

Spartanburg Medical Center Site Number : 8400003

Spartanburg, South Carolina, United States, 29303-3040

Australia, New South Wales

Investigational Site Number : 0360005

Blacktown, New South Wales, Australia, 2148

Investigational Site Number : 0360006

Tweed Heads, New South Wales, Australia, 2485

Investigational Site Number : 0360002

Wollongong, New South Wales, Australia, 2500

Australia, Victoria

Investigational Site Number : 0360001

Fitzroy, Victoria, Australia, 3065

Investigational Site Number : 0360004

Heidelberg West, Victoria, Australia, 3081

Australia, Western Australia

Investigational Site Number : 0360007

Nedlands, Western Australia, Australia, 6009

Investigational Site Number : 0360008

West Perth, Western Australia, Australia, 6005

Brazil

Hospital Sao Rafael Site Number : 0760005

Salvador, Bahia, Brazil, 41253-900

Hospital Mae de Deus Site Number : 0760003

Porto Alegre, Rio Grande Do Sul, Brazil, 90110-270

Hospital de Amor - Hospital do Cancer de Barretos - Fundacao Pio XII Site Number : 0760001

Barretos, São Paulo, Brazil, 14784-400

Hospital das Clinicas de Sao Paulo Site Number : 0760002

Sao Paulo, São Paulo, Brazil, 05403-000

Instituto COI de Educacao e Pesquisa Site Number : 0760004

Rio De Janeiro, Brazil, 22775-002

Canada, British Columbia

Investigational Site Number : 1240003

Surrey, British Columbia, Canada, V3V 1Z2

Canada, New Brunswick

Investigational Site Number : 1240001

Saint John, New Brunswick, Canada, E2L 4L2

Canada, Quebec

Investigational Site Number : 1240002

Montreal, Quebec, Canada, H1T 2M4

Czechia

Investigational Site Number : 2030002

Brno, Czechia, 62500

Investigational Site Number : 2030004

Olomouc, Czechia, 77900

Investigational Site Number : 2030003

Ostrava - Poruba, Czechia, 70852

Investigational Site Number : 2030001

Praha 2, Czechia, 12808

France

Investigational Site Number : 2500003

Lille, France, 59037

Investigational Site Number : 2500001

Nantes, France, 44093

Investigational Site Number : 2500006

Paris, France, 75012

Investigational Site Number : 2500002

Pessac, France, 33600

Investigational Site Number : 2500005

Pierre Benite, France, 69495

Investigational Site Number : 2500004

POITIERS Cedex, France, 86021

Greece

Investigational Site Number : 3000002

Athens, Greece, 10676

Investigational Site Number : 3000005

Athens, Greece, 11527

Investigational Site Number : 3000001

Athens, Greece, 11528

Investigational Site Number : 3000004

Patra, Greece, 26504

Investigational Site Number : 3000003

Thessaloniki, Greece, 57010

Hungary

Investigational Site Number : 3480003

Budapest, Hungary, 1083

Investigational Site Number : 3480001

Budapest, Hungary, 1097

Investigational Site Number : 3480004

Budapest, Hungary, 1125

Investigational Site Number : 3480005

Kaposvár, Hungary, 7400

Italy

Investigational Site Number : 3800003

Bologna, Italy, 40138

Investigational Site Number : 3800001

Pisa, Italy, 56126

Investigational Site Number : 3800004

Reggio Emilia, Italy, 42123

Investigational Site Number : 3800002

Torino, Italy, 10126

Japan

Investigational Site Number : 3920005

Shiwa-gun, Iwate, Japan, 028-3695

Investigational Site Number : 3920007

Kumamoto-shi, Kumamoto, Japan, 860-8556

Investigational Site Number : 3920001

Suwa-shi, Nagano, Japan, 392-8510

Investigational Site Number : 3920003

Sunto-gun, Shizuoka, Japan, 411-8777

Investigational Site Number : 3920004

Shibuya-ku, Tokyo, Japan, 150-8935

Investigational Site Number : 3920006

Shinjuku-ku, Tokyo, Japan, 162-8666

Investigational Site Number : 3920002

Yamagata-shi, Japan, 990-9585

Korea, Republic of

Investigational Site Number : 4100002

Gangnam-gu, Seoul-teukbyeolsi, Korea, Republic of, 06351

Investigational Site Number : 4100001

Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03080

Investigational Site Number : 4100004

Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03722

Investigational Site Number : 4100005

Seoul, Seoul-teukbyeolsi, Korea, Republic of, 06591

Investigational Site Number : 4100006

Busan, Korea, Republic of, 602-715

New Zealand

Investigational Site Number : 5540001

Auckland, New Zealand, 1640

Investigational Site Number : 5540002

Wellington, New Zealand, 6021

Russian Federation

Investigational Site Number : 6430002

Ekaterinburg, Russian Federation, 620102

Investigational Site Number : 6430003

Kirov, Russian Federation, 610027

Investigational Site Number : 6430004

Novosibirsk, Russian Federation, 630047

Spain

Investigational Site Number : 7240001

Badalona, Catalunya [Cataluña], Spain, 08916

Investigational Site Number : 7240005

Barcelona, Catalunya [Cataluña], Spain, 08036

Investigational Site Number : 7240002

Valencia, Valenciana, Comunidad, Spain, 46017

Investigational Site Number : 7240003

Madrid, Spain, 28041

Investigational Site Number : 7240004

Sevilla, Spain, 41013

Turkey

Investigational Site Number : 7920003

Adana, Turkey, 01250

Investigational Site Number : 7920001

Ankara, Turkey, 06500

Investigational Site Number : 7920005

Bursa, Turkey, 16059

Investigational Site Number : 7920002

Istanbul, Turkey, 34381

Investigational Site Number : 7920004

Samsun, Turkey, 55139

United Kingdom

Investigational Site Number : 8260004

Plymouth, Devon, United Kingdom, PL6 8DH

Investigational Site Number : 8260005

Leicester, Leicestershire, United Kingdom, LE1 5WW

Investigational Site Number : 8260001

Bristol, Somerset, United Kingdom, BS2 8ED

Sponsors and Collaborators

Sanofi

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] November 24, 2022

Statistical Analysis Plan  [PDF] February 16, 2023

More Information

Publications of Results:

Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Spicka I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Risse ML, Asset G, Mace S, Martin T; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021 Jun 19;397(10292):2361-2371. doi: 10.1016/S0140-6736(21)00592-4. Epub 2021 Jun 4.

Martin TG, Capra M, Mohty M, Suzuki K, Quach H, Cavo M, Moreau P, Dimopoulos M, Yong K, Tekle C, Foster MC, Barnes Y, Risse ML, Mikhael J. Isatuximab Plus Carfilzomib and Dexamethasone Versus Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: IKEMA Subgroup Analysis by Prior Transplantation. Transplant Cell Ther. 2023 Feb;29(2):134.e1-134.e7. doi: 10.1016/j.jtct.2022.11.005. Epub 2022 Nov 11.

Chami B, Okuda M, Moayeri M, Pirenne F, Hidaka Y, Nambiar A, Song Z, Bedel O, Zhang B, Hopke J, Deng G, Zhu C, Mace S, Chiron M, Adrian F, Fukao T, Basile FG, Martin T. Anti-CD38 monoclonal antibody interference with blood compatibility testing: Differentiating isatuximab and daratumumab via functional epitope mapping. Transfusion. 2022 Nov;62(11):2334-2348. doi: 10.1111/trf.17137. Epub 2022 Oct 14.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Moreau P, Dimopoulos MA, Yong K, Mikhael J, Risse ML, Asset G, Martin T. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design. Future Oncol. 2020 Jan;16(2):4347-4358. doi: 10.2217/fon-2019-0431. Epub 2019 Dec 13.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03275285
• Other Study ID Numbers: EFC15246; U1111-1195-5957 ( Registry Identifier: ICTRP ); 2017-001940-37 ( EudraCT Number )
• First Posted: September 7, 2017
• Results First Posted: February 13, 2023
• Last Update Posted: February 20, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sanofi:

Anti-CD38 monoclonal antibody

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents