Multinational Clinical Study Comparing Isatuximab, Pomalidomide, and Dexamethasone to Pomalidomide and Dexamethasone in Refractory or Relapsed and Refractory Multiple Myeloma Patients

PFS:time from date of randomization to date of first documentation of progressive disease (PD) determined by Independent Response Committee (IRC) or date of death from any cause, whichever comes first. If progression or death was not observed, participant was censored at date of last progression-free tumor assessment prior to study cut-off date. Analysis was performed by Kaplan-Meier method. PD as per International Myeloma Working Group (IMWG) criteria was defined as increase of \>=25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute increase must be \>=0.5gram(g)/dL), serum M-protein increase \>=1g/dL if lowest M component was \>=5g/dL; urine M-component (absolute increase must be \>=200mg/24hour), appearance of new lesion(s),\>=50% increase from nadir in sum of the products of the maximal perpendicular diameters of measured lesions (SPD) of \>1 lesion, or \>=50% increase in the longest diameter of a previous lesion \>1 centimeter in short axis.

Time frame: From the date of randomization to the date of first documentation of progression, or the date of death from any cause, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration: 76.7 weeks)

Population: Analysis was performed on Intent-to-treat (ITT) population which included all randomized participants.

EORTC-Quality of Life Questionnaire (QLQ)-C30 is a cancer-specific instrument with 30 questions for evaluation of new chemotherapy and provides an assessment of participant reported outcome dimensions. EORTC QLQ-C30 included 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 were a 4-point scale (1/Not at All to 4/Very Much), except Items 29-30, which comprise GHS scale and were a 7-point scale (1/Very Poor to 7/Excellent). Answers were converted into grading scale, with values between 0 and 100. A high score represented a favorable outcome with a best quality of life for participant.

Time frame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)

Population: Analysis was performed on safety population evaluable for global health status. Here, 'Number analyzed' = participants with available data for each specified category.

EORTC QLQ-MY20 is a validated questionnaire to assess the overall quality of life in participants with multiple myeloma. Disease symptoms domain is one of the four domain scores. Disease symptoms domain score used 4-point scale (1 'Not at All' to 4 'Very Much'). Scores are averaged, and transformed to 0 -100 scale, where higher scores = more symptoms and lower health-related quality of life (HRQL) and lower score = less symptoms and more HRQL

Time frame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)

Population: Analysis was performed on safety population evaluable for disease symptoms. Here, 'Number analyzed' = participants with available data for each specified category.

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 score used 4-point scale (1 'Not at All' to 4 'Very Much'). 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.

Time frame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)

Population: Analysis was performed on safety population evaluable for side effects of treatment. Here, 'Number analyzed' = participants with available data for each specified category.

The EQ-5D-5L is a standardized measure of health status that provides a general assessment of health and wellbeing. The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. 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 (for the 5L version). 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.

Time frame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)

Population: Analysis was performed on safety population evaluable for health state utility index. Here, 'Number analyzed' = participants with available data for each specified category.

EQ-5D-5L is a standardized, participant-rated questionnaire to assess health-related quality of life. The EQ-5D-5L includes 2 components: the EQ-5D-5L health state utility index (descriptive system) and the EQ-5D-5L Visual Analog Scale. The Visual Analogue Scale is designed to rate the participant's current health state on a scale from 0 to 100, where 0 represents the worst imaginable health state and 100 represents the best imaginable health state.

Time frame: Baseline, Day 1 of each cycle (Cycle 3, Cycle 6, Cycle 9, and Cycle 17)

Population: Analysis was performed on safety population evaluable for visual analogue scale. Here, 'Number analyzed' = participants with available data for each specified category.

CBR was defined as the percentage of participants achieving a MR or better as BOR. MR was defined as \>= 25% but \<= 49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%, which still exceed 200 mg/24h; if present at baseline, \>=50% reduction in size (SPD) of soft tissue plasmacytomas was also required. BOR was defined as the best sequential response, using the IRC's assessment of response, from the start of treatment until disease progression (provided that the progression is subsequently confirmed in case of progression requiring confirmation), death, initiation of further anti-myeloma treatment, or cut-off date, whichever occurs first.

Time frame: From the date of randomization to the date of first documentation of progression, death, initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.

DOR:time from date of first IRC determined response(PR or better) to date of first IRC-PD or death, whichever occurred first.DOR was determined only for participants who had achieved a response of PR or better based on disease assessment by IRC.If progression or death was not observed,participant was censored at date of participants last progression-free tumor assessment prior to initiation of further anti-myeloma treatment(if any)and study cut-off date. PD(IMWG criteria):increase of \>=25% from lowest confirmed value in any one of following criteria: serum M-protein (absolute increase must be \>=0.5 g/dL), serum M-protein increase \>=1g/dL if lowest M component was \>=5g/dL;urine M-component (absolute increase must be \>=200mg/24 hour),appearance of new lesion(s), \>=50% increase from nadir in SPD of \>1 lesion,or \>=50% increase in the longest diameter of a previous lesion \>1 cm in short axis. PR:\>=50% reduction of serum M-protein and reduction in 24h urinary M-protein by \>=90%/\<200mg/24h.

Time frame: From the date of the first IRC determined response to the date of first IRC progression or death, whichever occurred first (maximum duration 76.7 weeks)

Population: Analysis was performed on responders in ITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

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 preexisting ADA, including participants without pretreatment samples. Treatment boosted ADA was defined as pre-existing ADA that increased at least 2 titer steps between pre-treatment and post-treatment.

Time frame: From randomization up to 60 days after last dose of study drug (maximum duration 76.7 weeks)

Population: Analysis was performed on ADA evaluable population which included participants who received at least one dose of study drug from the IPd arm with at least one ADA assessment during the ADA on-study observation period with a reportable result. Data for this OM was not planned to be collected and analyzed for Pd arm.

MRD was assessed by next-generation sequencing in bone marrow samples from participants who achieved CR, to determine the depth of response at the molecular level. IMWG criteria for CR: Negative immunofixation on the serum and urine, disappearance of any soft tissue plasmacytomas, and \<5% plasma cells in bone marrow aspirates. MRD was classified as positive or negative at the minimum sensitivity of 1 in 10\^5 nucleated cells. MRD negativity was defined as the absence of the dominant clonotype sequence(s) identified in the bone marrow aspirate collected at screening. MRD positivity was defined as the presence of the dominant clonotype sequence(s) identified in the bone marrow aspirate collected at screening.

Time frame: Up to 76.7 weeks

Population: Analysis was performed on ITT population who were evaluable for MRD.

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 (according to the Investigator opinion), 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 is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a medically important event.

Time frame: From randomization up to 30 days after last dose of study drug (maximum duration up to 241.6 weeks for Pd arm and 245.6 weeks for IPd arm)

Population: Analysis was performed on safety population which included all participants from the ITT population who received at least one dose or a part of a dose of the study treatments.

ORR (IMWG criteria): percentage of participants with stringent complete response(sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as best overall response, assessed by IRC. 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.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. PR: \>=50% reduction of serum M-protein and reduction in 24h urinary M-protein by \>=90%/\<200mg/24h,if present at baseline,\>=50% reduction in the size (SPD) of soft tissue plasmacytomas.

Time frame: From the date of randomization to the date of first documentation of progression or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.

OS was defined as the time from the date of randomization to death from any cause. In the absence of confirmation of death, survival time was censored at the last date participant was known to be alive or at the cut-off date, whichever comes first. This pre-specified final analysis was performed when the 220 OS events were met.

Time frame: From the date of randomization to date of death from any cause or data cut-off date, whichever was earlier (maximum duration 245.6 weeks)

Population: Analysis was performed on ITT population.

BOR:best sequential response from start of treatment until disease progression, death, initiation of further anti-myeloma treatment/data cut-off, whichever comes first. Ordering of evaluations from best to worse was: sCR,CR,VGPR,PR, minimal response (MR), stable disease (SD), PD, and not evaluable.CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates. sCR:CR as defined previously plus normal FLC ratio (0.26 to 1.65), absence of clonal cells in bone marrow biopsy. VGPR: serum and urine M-protein detectable by immunofixation,\>=90% reduction in serum M-protein plus urine M-protein level \<100mg/24h,\>=90% decrease in SPD compared to baseline in soft tissue plasmacytoma. PR: \>=50% reduction of serum M-protein and reduction in 24h urinary M-protein by \>=90%/\<200mg/24h. MR:\>=25% but \<=49% reduction in serum M-protein and reduction in 24h urine M-protein by 50-89%. SD: Not meeting criteria for CR,VGPR,PR,MR/PD.

Time frame: From the date of randomization until disease progression, or death, initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.

VGPR rate was defined as the percentage of participants achieving a VGPR or better as BOR. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein plus urine M-protein level \<100 mg/24 h or \>=90% decrease in the sum of maximal perpendicular diameter compared to baseline in soft tissue plasmacytoma. BOR was defined as the best sequential response, using the IRC's assessment of response, from the start of treatment until disease progression (provided that the progression is subsequently confirmed in case of progression requiring confirmation), death, initiation of further anti-myeloma treatment, or cut-off date, whichever occurs first. CR: negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas,\<5% plasma cells in bone marrow aspirates.

Time frame: From the date of randomization to the date of first documentation of progression, death, initiation of further anti-myeloma treatment, or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.

Accumulation Ratio was defined as the ratio of CEOI of Cycle 2 Day 1 versus Cycle 1 Day 1 and Cycle 4 Day 1 versus Cycle 1 Day 1, where CEOI was the plasma concentration at the end of infusion.

Time frame: End of infusion on Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 4 Day 1

Population: Analysis was performed on PK population. Here, 'Number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Pd arm.

CEOI+1 hour was defined as the plasma concentration of isatuximab at 1 hour after end of infusion.

Time frame: Cycle 1:1 hour after End of Infusion on Day 1; Cycle 4:1 hour after End of Infusion on Day 1

Population: Analysis was performed on PK population. Here, 'Number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Pd arm.

CEOI was defined as the plasma concentration at end of infusion.

Time frame: End of infusion on Cycle(C)1 Day(D)1 and Cycle1 Day 15; Cycle 2 Day 1; and Cycle 4 Day 1

Population: Analysis was performed on PK population which included participants who received at least 1 dose of Isatuximab, with data for at least 1 PK parameter available. Here, 'Number analyzed' = participants with available data for each specified category. Data for this outcome measure (OM) was not planned to be collected and analyzed for Pd arm.

Accumulation Ratio was defined as the ratio of Ctrough of Cycle 2 Day 1 versus Cycle 1 Day 8 and Cycle 4 Day 1 versus Cycle 1 Day 8, where Ctrough is the concentration prior to study drug administration.

Time frame: Pre-infusion on Cycle 1 Day 8, Cycle 2 Day 1, and Cycle 4 Day 1

Population: Analysis was performed on PK population. Here, 'Number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Pd arm.

Trough Concentration (Ctrough) is the concentration prior to study drug administration.

Time frame: Pre-infusion on C1D1, C1D8, C1D15, C1D22, C2D1, C2D15, C3D1, C3D15, C4D1, C4D15, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1, C13D1, C14D1, C15D1, C16D1, C17D1, C18D1, C19D1, C20D1; End of treatment (EOT [30 days after last drug administration])

Population: Analysis was performed on PK population. Here, 'Number analyzed' = participants with available data for each specified category. Data for this OM was not planned to be collected and analyzed for Pd arm.

PFS in high risk cytogenetic population was defined as PFS in subgroup of participants carrying high risk cytogenetic changes including del(17p), translocation (t)(4;14) or translocation t(14;16) assessed by fluorescence in situ hybridization (FISH). PFS was defined as the time from date of randomization to date of first documentation of PD (determined by IRC) or date of death from any cause, whichever comes first. PD defined as per IMWG criteria as: increase of \>=25% from lowest confirmed value in any one 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 the longest diameter of previous lesion \>1 centimeter (cm) in short axis.

Time frame: From the date of randomization to the date of first documentation of progression, or the date of death from any cause, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed in high-risk cytogenetic population which included participants carrying del (17p), t(4;14) or t(14;16) in each arm.

TTBR was defined as the time from randomization to the date of first occurrence of IRC determined BOR (PR or better) that was subsequently confirmed. PR 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. BOR was defined as the best sequential response, using the IRC's assessment of response, from the start of treatment until disease progression (provided that the progression is subsequently confirmed in case of progression requiring confirmation), death, initiation of further anti-myeloma treatment, or cut-off date, whichever occurs first.

Time frame: From the date of randomization to date of first occurrence of IRC determined best overall response or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.

TT1R was defined as the time from randomization to the date of first IRC determined response (PR or better) that is subsequently confirmed. PR 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.

Time frame: From the date of randomization to the date of first IRC determined response, or death or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.

TTP was defined as time from randomization to the date of first documentation of PD, as determined by the IRC. As per IMWG criteria, PD was defined for participants with increase of \>= 25% from lowest confirmed value in any one of the following criteria: serum M-protein (the absolute increase must be \>= 0.5 g/dL), serum M-protein increase \>=1 g/dL if the lowest M component was \>=5 g/dL; urine M-component (the 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 the longest diameter of a previous lesion \>1 centimeter in short axis.

Time frame: From the date of randomization to the date of first documentation of progression, or initiation of further anti-myeloma treatment or data cut-off whichever comes first (maximum duration 76.7 weeks)

Population: Analysis was performed on ITT population.