A Phase 3 Trial Evaluating the Safety and Efficacy of SARCLISA® + Kd vs. Kd
A prospective, multicentre, randomized, open-label, two-arm, phase 3 study in patients with relapsed and/or refractory multiple myeloma who had received one to three prior therapies1
Patients with primary refractory disease or who were refractory to previous anti-CD38 monoclonal antibody treatment were excluded.
SARCLISA® 10 mg/kg was administered as an IV infusion weekly in the first cycle and every 2 weeks thereafter
Treatment was administered in both groups in 28-day cycles until disease progression or unacceptable toxicity
Carfilzomib 20 mg/m² was given by IV on days 1 and 2; 56 mg/m² on days 8, 9, 15 and 16 of cycle 1; and 56 mg/m² on days 1, 2, 8, 9, 15 and 16 for subsequent cycles of each 28-day cycle
Dexamethasone 20 mg was given by IV on the days of SARCLISA® and/or carfilzomib infusions and PO on the other days; dexamethasone was given on days 1, 2, 8, 9, 15, 16, 22 and 23 for each 28-day cycle
Please refer to the SARCLISA®, carfilzomib and dexamethasone Product Monographs for full dosing and administration guidelines
*PFS results were assessed by an IRC based on central laboratory data for M-protein and a central radiologic imaging review using the IMWG criteria.
†sCR, CR, VGPR and PR were evaluated by an IRC using the IMWG response criteria (2016).
CD38 = cluster of differentiation 38; CR = complete response; IMWG = International Myeloma Working Group; IRC = Independent Response Committee; IV = intravenous; Kd = carfilzomib and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PO = by mouth; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
Patient Population1,3
Baseline demographics and patient characteristics of the intention-to-treat population
Adapted from Moreau et al. 2021.
Data are median (IQR) or n (%).
*Incidence calculated in patients with race reported in case report form – 165 patients in SARCLISA® + Kd group and 111 patients in Kd group.
†Percentages were calculated out of 176 evaluable patients in the SARCLISA® + Kd group and 122 in the Kd group.
‡High-risk cytogenetic status is defined as the presence of del(17p) or translocation t(4;14) or translocation t(14;16); chromosomal abnormality was considered positive if present in at least 30% of analyzed plasma cells, except for del(17p) where the threshold is at least 50%.
§For two patients, the number of previous lines was overestimated by the algorithm because of complex specific cases; the number of previous lines was reviewed by a clinician and confirmed to be three.
ECOG = Eastern Cooperative Oncology Group; eGFR = estimated glomerular filtration rate; IgA = immunoglobulin A; IgD = immunoglobulin D; IgG = immunoglobulin G; IQR = interquartile range; ISS = International Staging System; IU = international units; Kd = carfilzomib and dexamethasone; MDRD = modification of diet in renal disease; ORR = overall response rate; PFS = progression-free survival; R-ISS = Revised International Staging System.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
PFS Results1,3
Significant Reduction in the Instantaneous Risk of Disease Progression or Death in SARCLISA® + Kd Group vs. Kd Group
Adapted from Moreau et al. 2021.
PFS results were assessed by an IRC based on central laboratory data for M-protein and a central radiologic imaging review using the IMWG criteria.
46.9% reduction in the instantaneous risk of disease progression or death in patients treated with SARCLISA® + Kd vs. Kd (HR†=0.531; 99% CI: 0.318–0.889; P=0.0013)1
Subgroup analyses based on PFS HR were consistent across the pre-specified subgroups including patients with high-risk cytogenetics, ≥65 years of age, with baseline eGFR (MDRD) <60 mL/min/1.73 m², with >1 prior line of therapy, or with ISS stage III at study entry.‡,1,3
Adapted from Moreau et al. 2021.
Subgroup analyses based on PFS HR that did not show significant results were as follows:
Adapted from Moreau et al. 2021.
*Based on a prespecified interim analysis with a cut-off date of 7 February 2020.
†Stratified on number of previous lines of therapy (1 vs. >1) and R-ISS (I or II vs. III vs. not classified) according to log-rank test.
‡High-risk cytogenetic status is defined as the presence of del(17p) or translocation t(4;14) or translocation t(14;16); chromosomal abnormality was considered positive if present in at least 30% of analyzed plasma cells, except for del(17p) where the threshold is at least 50%.
§Determined using an isatuximab-specific IFE assay to remove isatuximab interference. In the Isa-Kd group, 4 patients who achieved VGPR at the interim analysis were reclassified to CR using the isatuximab-specific IFE.
CI = confidence interval; eGFR = estimated glomerular filtration rate; HR = hazard ratio; IMWG = International Myeloma Working Group; IRC = Independent Response Committee; ISS = International Staging System; Kd = carfilzomib and dexamethasone; MDRD = modification of diet in renal disease; NC = not calculable; NR = not reached; ORR = overall response rate; PFS = progression-free survival; R-ISS = Revised International Staging System.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
ORR1,3
ORR Data in SARCLISA® + Kd Group vs. Kd Group*
Adapted from SARCLISA® Product Monograph.
72.6% (95% CI: 0.65–0.79) of patients in the SARCLISA® + Kd group demonstrated VGPR or better vs. 56.1% (95% CI: 0.47–0.65) of patients in the Kd group; P=0.0011†,‡,§
VGPR or better includes patients who achieved sCR, CR and VGPR
39.7% (95% CI: 0.32–0.47) of patients in the SARCLISA® + Kd group had CR vs. 27.6% (95% CI: 0.20–0.36) in the Kd group†
*sCR, CR, VGPR and PR were evaluated by an IRC using IMWG response criteria (2016).
†95% CI estimated using Clopper-Pearson method.
‡Stratified on randomization factors according to interactive response technology; one-sided significance level is 0.025.
§For descriptive purposes only.
CI = confidence interval; CR = complete response; IMWG = International Myeloma Working Group; IRC = Independent Response Committee; Kd = carfilzomib and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
*PFS results were assessed by an IRC based on central laboratory data for M-protein and a central radiologic imaging review using the IMWG criteria.
†sCR, CR, VGPR and PR were evaluated by an IRC using the IMWG response criteria (2016).
CD38 = cluster of differentiation 38; CR = complete response; IMWG = International Myeloma Working Group; IRC = Independent Response Committee; IV = intravenous; Kd = carfilzomib and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PO = by mouth; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
ECOG = Eastern Cooperative Oncology Group; eGFR = estimated glomerular filtration rate; IgA = immunoglobulin A; IgD = immunoglobulin D; IgG = immunoglobulin G; IQR = interquartile range; ISS = International Staging System; IU = international units; Kd = carfilzomib and dexamethasone; MDRD = modification of diet in renal disease; ORR = overall response rate; PFS = progression-free survival; R-ISS = Revised International Staging System.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
*Based on a prespecified interim analysis with a cut-off date of 7 February 2020.
†Stratified on number of previous lines of therapy (1 vs. >1) and R-ISS (I or II vs. III vs. not classified) according to log-rank test.
‡High-risk cytogenetic status is defined as the presence of del(17p) or translocation t(4;14) or translocation t(14;16); chromosomal abnormality was considered positive if present in at least 30% of analyzed plasma cells, except for del(17p) where the threshold is at least 50%.
§Determined using an isatuximab-specific IFE assay to remove isatuximab interference. In the Isa-Kd group, 4 patients who achieved VGPR at the interim analysis were reclassified to CR using the isatuximab-specific IFE.
CI = confidence interval; eGFR = estimated glomerular filtration rate; HR = hazard ratio; IMWG = International Myeloma Working Group; IRC = Independent Response Committee; ISS = International Staging System; Kd = carfilzomib and dexamethasone; MDRD = modification of diet in renal disease; NC = not calculable; NR = not reached; ORR = overall response rate; PFS = progression-free survival; R-ISS = Revised International Staging System.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
*sCR, CR, VGPR and PR were evaluated by an IRC using IMWG response criteria (2016).
†95% CI estimated using Clopper-Pearson method.
‡Stratified on randomization factors according to interactive response technology; one-sided significance level is 0.025.
§For descriptive purposes only.
CI = confidence interval; CR = complete response; IMWG = International Myeloma Working Group; IRC = Independent Response Committee; Kd = carfilzomib and dexamethasone; ORR = overall response rate; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.
References
PrSARCLISA® Product Monograph. Sanofi Canada. January 12, 2024.
Moreau P, Dimopoulos M-A, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397(10292):2361–2371.
SARCLISA® (isatuximab for injection) is indicated:
in combination with pomalidomide and dexamethasone, for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
Important Safety Information
Clinical use:
SARCLISA® is not indicated in pediatric patients (<18 years of age). No overall differences in safety and efficacy were observed between older (≥65 years of age) and younger patients.
Contraindications:
Hypersensitivity to SARCLISA® or any ingredient in the formulation or any of its components.
Most serious warnings and precautions:
Neutropenia: Neutropenia occurred as a laboratory abnormality in 54.8% of patients treated with SARCLISA® in combination with carfilzomib and dexamethasone, with Grade 3–4 neutropenia reported as a laboratory abnormality in 19.2% of patients (Grade 3 in 17.5%, Grade 4 in 1.7%). Neutropenic complications occurred in 2.8% of patients, including febrile neutropenia (1.1%) and neutropenic infections (1.7%). Grade 3 and 4 neutropenia occurred as laboratory abnormalities in 24.3% and 60.5% of patients treated with SARCLISA® in combination with pomalidomide and dexamethasone. Neutropenic complications included febrile neutropenia (11.8% of patients) and neutropenic infections (25% of patients). Monitor complete blood cell counts at baseline and periodically during treatment. Monitor patients with neutropenia for signs of infection.
Infusion-related reactions (IRRs): IRRs, mostly Grade 1 or 2, were reported in 81 patients (45.8%) treated with SARCLISA® in combination with carfilzomib and dexamethasone (Grade 1 in 13.6%, Grade 2 in 31.6%, Grade 3 in 0.6%); IRRs occurred on the infusion day in 99.2% of episodes. 94.4% of those experiencing an IRR experienced it during the first cycle of treatment. All IRRs resolved, with 73.8% of IRRs resolving on the same day they were experienced, 23.8% resolving the day after, and 2.5% resolving after more than 2 days. IRRs, mostly Grade 1 or 2, were observed in 38.2% of patients treated with SARCLISA® in combination with pomalidomide and dexamethasone. All IRRs started during the first SARCLISA® infusion and resolved on the same day in most patients. To decrease the risk and severity of IRRs, patients should be premedicated prior to the SARCLISA® infusion. Vital signs should be frequently monitored during the entire SARCLISA® infusion. In the event of an IRR in which infusion interruption or intervention (Grade 2) is indicated, interrupt the SARCLISA® infusion and provide appropriate medical and supportive measures. If symptoms improve to Grade ≤1, restart SARCLISA® infusion at half the initial infusion rate, with supportive care as needed, and closely monitor patients. If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate and then increased incrementally per the Infusion Rates of SARCLISA® Administration, consistent with the Product Monograph. If symptoms do not improve to Grade ≤1 after interruption of SARCLISA® infusion, persist or worsen despite appropriate medications, require hospitalization or are life-threatening (Grade 3 or 4), permanently discontinue SARCLISA® and institute appropriate management. SARCLISA® may cause serious infusion reactions, including anaphylactic reactions. Signs and symptoms of anaphylactic reactions include bronchospasm, dyspnea, angioedema and swelling.
Other relevant warnings and precautions:
Interference with serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) assays
Interference with indirect antiglobulin test
Driving and operating machinery
Fertility
Pregnancy and breastfeeding
Second primary malignancies
Tumour lysis syndrome
For more information:
Please consult the Product Monograph at http://products.sanofi.ca/en/sarclisa-en.pdf for important information relating to the adverse events, drug interactions and dosing information that have not been discussed in this piece.
The Product Monograph is also available by calling Sanofi Canada Medical Information at 1-800-589-6215.
The content of the website you are visiting is not controlled by the sarclisa.ca team. The link is being offered for your convenience and should not be viewed as an endorsement of the content, product or services offered here.
SARCLISA® (isatuximab for injection) is indicated:
in combination with pomalidomide and dexamethasone, for the treatment of patients with relapsed and refractory multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
in combination with carfilzomib and dexamethasone, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received 1 to 3 prior lines of therapy.
Important Safety Information
Clinical use:
SARCLISA® is not indicated in pediatric patients (<18 years of age). No overall differences in safety and efficacy were observed between older (≥65 years of age) and younger patients.
Contraindications:
Hypersensitivity to SARCLISA® or any ingredient in the formulation or any of its components.
Most serious warnings and precautions:
Neutropenia: Neutropenia occurred as a laboratory abnormality in 54.8% of patients treated with SARCLISA® in combination with carfilzomib and dexamethasone, with Grade 3–4 neutropenia reported as a laboratory abnormality in 19.2% of patients (Grade 3 in 17.5%, Grade 4 in 1.7%). Neutropenic complications occurred in 2.8% of patients, including febrile neutropenia (1.1%) and neutropenic infections (1.7%). Grade 3 and 4 neutropenia occurred as laboratory abnormalities in 24.3% and 60.5% of patients treated with SARCLISA® in combination with pomalidomide and dexamethasone. Neutropenic complications included febrile neutropenia (11.8% of patients) and neutropenic infections (25% of patients). Monitor complete blood cell counts at baseline and periodically during treatment. Monitor patients with neutropenia for signs of infection.
Infusion-related reactions (IRRs): IRRs, mostly Grade 1 or 2, were reported in 81 patients (45.8%) treated with SARCLISA® in combination with carfilzomib and dexamethasone (Grade 1 in 13.6%, Grade 2 in 31.6%, Grade 3 in 0.6%); IRRs occurred on the infusion day in 99.2% of episodes. 94.4% of those experiencing an IRR experienced it during the first cycle of treatment. All IRRs resolved, with 73.8% of IRRs resolving on the same day they were experienced, 23.8% resolving the day after, and 2.5% resolving after more than 2 days. IRRs, mostly Grade 1 or 2, were observed in 38.2% of patients treated with SARCLISA® in combination with pomalidomide and dexamethasone. All IRRs started during the first SARCLISA® infusion and resolved on the same day in most patients. To decrease the risk and severity of IRRs, patients should be premedicated prior to the SARCLISA® infusion. Vital signs should be frequently monitored during the entire SARCLISA® infusion. In the event of an IRR in which infusion interruption or intervention (Grade 2) is indicated, interrupt the SARCLISA® infusion and provide appropriate medical and supportive measures. If symptoms improve to Grade ≤1, restart SARCLISA® infusion at half the initial infusion rate, with supportive care as needed, and closely monitor patients. If symptoms do not recur after 30 minutes, the infusion rate may be increased to the initial rate and then increased incrementally per the Infusion Rates of SARCLISA® Administration, consistent with the Product Monograph. If symptoms do not improve to Grade ≤1 after interruption of SARCLISA® infusion, persist or worsen despite appropriate medications, require hospitalization or are life-threatening (Grade 3 or 4), permanently discontinue SARCLISA® and institute appropriate management. SARCLISA® may cause serious infusion reactions, including anaphylactic reactions. Signs and symptoms of anaphylactic reactions include bronchospasm, dyspnea, angioedema and swelling.
Other relevant warnings and precautions:
Interference with serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) assays
Interference with indirect antiglobulin test
Driving and operating machinery
Fertility
Pregnancy and breastfeeding
Second primary malignancies
Tumour lysis syndrome
For more information:
Please consult the Product Monograph at http://products.sanofi.ca/en/sarclisa-en.pdf for important information relating to the adverse events, drug interactions and dosing information that have not been discussed in this piece.
The Product Monograph is also available by calling Sanofi Canada Medical Information at 1-800-589-6215.
