Isatuximab Single Agent Study in Japanese Relapsed AND Refractory Multiple Myeloma Patients

Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as 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. TEAEs were defined as AEs that develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).

Time frame: From first dose of study drug up to 30 days after the last dose of study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)

Phase 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

An AE was defined as any untoward medical occurrence in a participant or clinical investigation patient administered with a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. TESAEs was defined as 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. TEAEs are defined as AEs that develop, worsened or became serious during the on-treatment period (time from first dose of study drug up to 30 days after the last dose of study drug administration).

Time frame: From first dose of study drug up to 30 days after the last dose of study drug administration (maximum duration of exposure: up to 248 weeks)

Phase 1: Percentage of Participants With Overall Response (OR)

Percentage of participants with sCR, CR, VGPR, and PR assessed by IMWG uniform response criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells in bone marrow. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5 percentage (%) plasma cells in bone marrow; normal FLC ratio of 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 hour (h); \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required, in place of M-protein.

Time frame: From the date of the first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)

Phase 1: Duration of Response (DOR)

DOR: time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): increase (inc.) of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc. \>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute % \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.

Time frame: From the date of the first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 112 weeks for Cohort 1 and 137 weeks for Cohort 2)

Phase 2: Percentage of Participants With Clinical Benefit (CB)

CB defined as percentage of participants with sCR, CR, VGPR, PR or Minor/minimal response (MR) assessed by IMWG criteria. sCR: CR as defined plus normal FLC ratio \& absence of clonal cells. CR: negative immunofixation on serum \& urine; disappearance of any soft tissue plasmacytomas; \<5% plasma cells in bone marrow; normal FLC ratio: 0.26-1.65. VGPR: serum \& urine M-protein detectable by immunofixation; \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24h; \>90% decrease in difference between involved \& uninvolved FLC levels required. PR: \>=50% reduction of serum M-protein \& reduction in 24h urinary M protein by \>=90%/\<200 mg/24 h; if serum \& urine M-protein unmeasurable:\>=50% decrease in difference between involved \& uninvolved FLC; if serum \& urine M-protein not measurable:\>=50% reduction in plasma cells required. MR: \>=25% but \<=49% reduction of serum M protein and reduction in 24h urine M protein by 50-89%; 25-49% reduction in size of soft tissue plasmacytomas.

Time frame: From date of first study treatment administration until first documented response, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)

Phase 2: Overall Survival (OS)

Overall survival was defined as the time interval (in months) from the date of first study treatment administration to death due to any cause. In the absence of the confirmation of death before the cut-off date, OS was censored at the last date the participant was known to be alive or at the study cut-off date, whichever was earlier. Analysis was performed by Kaplan-Meier method.

Time frame: From date of first study treatment administration to the date of death due to any cause (maximum duration of exposure: up to 248 weeks)

Phase 2: Progression Free Survival (PFS)

PFS was defined as the time interval (in months) from date of first study treatment administration until disease progression or death due to any cause, whichever comes first. In absence of PD or death, PFS was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of \>=25% in any one of following: serum M-component absolute (abs.) inc. \>=0.5 g/dL) and/or; urine M-component (abs. inc. \>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein, difference between involved \& uninvolved FLC levels (abs. inc. \>10 mg/dL); in participants without measurable serum \& urine M-protein \& without measurable disease by FLC levels: bone marrow plasma cell % (abs. % \>=10%); definite development of new bone lesions or soft tissue plasmacytomas or definite inc. in size of existing bone lesions or soft tissue plasmacytomas; development of hypercalcemia.

Time frame: From date of first study treatment administration until disease progression or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)

Phase 2: Duration of Response (DOR)

DOR was defined as time (in weeks) from date of first response to date of subsequent progressive disease (PD) or death, whichever happens earlier. In absence of confirmation of subsequent PD or death before cut-off date, DOR was censored at date of last valid assessment performed or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria):inc. of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc.\>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.

Time frame: From the date of first response until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)

Phase 2: Time to Progression (TTP)

TTP: time interval (in months) from date of first study treatment administration to date of first assessed disease progression. In absence of disease progression, TTP was censored at date of last valid assessment performed before cut-off date or date of initiation of new anticancer treatment, whichever was earlier. PD (IMWG criteria): inc. of \>=25% from lowest response value in any one of following: serum M-component (absolute inc.\>=0.5 g/dL) and/or; urine M-component (absolute inc.\>=200 mg/24h) and/or, in participants without measurable serum \& urine M-protein: difference between involved \& uninvolved FLC levels (absolute inc.\>10 mg/dL); in participants without measurable serum \& urine M-protein and without measurable disease by FLC levels, bone marrow plasma cell % (absolute% \>=10%); development of new bone lesions or soft tissue plasmacytomas/definite inc. in size of existing bone lesions/soft tissue plasmacytomas; development of hypercalcemia.

Time frame: From date of first study treatment administration until disease progression, or death due to any cause, whichever comes first (maximum duration of exposure: up to 248 weeks)

Phase 1: Plasma Concentration Observed at the End of Intravenous Infusion (Ceoi) of Isatuximab

Ceoi is the plasma concentration observed at the end of intravenous infusion.

Time frame: End of infusion on Day 1 of Cycle 1

Phase 1: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab

Cmax was defined as the maximum concentration observed after the first infusion calculated using the non-compartmental analysis.

Time frame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), end of infusion (EOI) and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)

Phase 1: Time to Reach the Maximum Concentration (Tmax) After First Infusion of Isatuximab

Tmax was defined as the time to reach Cmax, calculated using the non-compartmental analysis after the intravenous infusion.

Time frame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), EOI and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)

Phase 1: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-week) After First Infusion of Isatuximab

AUC was defined as area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval.

Time frame: Cycle 1 Day 1 at 0 hour (pre-dose), mid-infusion (2 hours post-infusion), EOI and EOI+4-hour, Day 2 (24 hour), Day 3 (48 hour), Day 4 (72 hour) and pre-dose on Day 8 (0 hour)

Phase 1: Trough Plasma Concentrations (Ctrough) of Isatuximab

Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.

Time frame: Pre-infusion on Cycle 1 Day 8 (C1 D8), C1 D15, C1 D22, C2 D1, C2 D15, C3 D1, C3 D15, C4 D1, C4 D15, C5 D1, C5 D15, C6 D1, C6 D15, C7 D1, C7 D15, C8 D1, C8 D15, C9 D1, C9 D15, C10 D1, C10 D15, C11 D1

Phase 2: Maximum Observed Concentration (Cmax) After First Infusion of Isatuximab

Cmax was predicted using population pharmacokinetic model.

Time frame: Multiple timepoints from Cycle 1 to Cycle 10

Phase 2: Area Under the Plasma Concentration Versus Curve Over the Dosing Interval (AUC1-Week) After First Infusion of Isatuximab

AUC was predicted using population pharmacokinetic model.

Time frame: Multiple timepoints from Cycle 1 to Cycle 10

Phase 2: Trough Plasma Concentrations (Ctrough) of Isatuximab

Ctrough was the plasma concentration observed just before treatment administration during repeated dosing.

Time frame: Pre-infusion on C1 D8, C1 D15, C1 D22, C2 D1, C2 D15, C3 D1, C3 D15, C4 D1, C4 D15, C5 D1, C5 D15, C6 D1, C6 D15, C7 D1, C7 D15, C8 D1, C8 D15, C9 D1, C9 D15, C10 D1, C10 D15

Phase 1 and 2: CD38 Receptor Density at Baseline

CD38 receptor density assessed from bone marrow aspirates for responder and non-responders' participants was reported.

Time frame: At Baseline (Day 1)

Phase 1: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab

ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment \& posttreatment samples of at least two titer steps, during the ADA on-study observation period.

Time frame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 112 weeks for Cohort 1, and 137 weeks for Cohort 2)

Phase 2: Number of Participants With Anti-drug Antibodies (ADA) Response Against Isatuximab

ADA were categorized as: treatment induced, and treatment boosted response. Treatment-induced ADA: ADA that developed at any time during the ADA on-study observation period in participants without preexisting ADA (ADA that was present in samples drawn during the ADA pretreatment period). Treatment boosted ADA: Preexisting ADA with an increase in titer value between pretreatment \& posttreatment samples of at least two titer steps, during the ADA on-study observation period.

Time frame: From first dose of study drug up to 30 days after last study drug administration (maximum duration of exposure: up to 248 weeks)