Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Isatuximab IV, Isatuximab SAR650984, isatuximab SAR650984 IV, Isatuximab intravenous (IV), Isatuximab SC-OBDS, Isatuximab-OBDS, Pomalidomide, Dexamethasone
Isatuximab · 36 trials · 24 indications
sMRD-negative CR rate is defined as the proportion of participants who sustain MRD negativity at a minimum 10\^-5 sensitivity assessed by next-generation sequencing (NGS) during the time of confirmed CR or better response per the International Myeloma Working Group Uniform Response Criteria (IMWG-URC).
MRD-negative CR rate is defined as the proportion of participants who achieve MRD negativity at a minimum 10\^-5 sensitivity assessed by NGS during the time of confirmed CR or better response per IMWG-URC.
ORR by independent review committee (IRC) using 2016 international myeloma working group (IMWG) criteria:Percentage of participants with complete response (CR),stringent CR (sCR),very good partial response (VGPR) \& partial response (PR).CR:negative immunofixation on serum and urine,disappearance of any soft tissue plasmacytomas (STP),\<5% plasma cells in bone marrow (BM) aspirates \& a normal free light chain(FLC)ratio (0.26-1.65).sCR:CR plus no clonal cells in BM biopsy. VGPR:serum \& urine M-protein detectable by immunofixation, not electrophoresis;\>=90% reduction in serum M-protein plus urine M-protein level\<100mg/24hour(h);\>=90% decrease in sum of maximal perpendicular diameter (SPD) compared to baseline in STP;FLC only:\>=90% decrease in difference between involved and uninvolved FLC levels.PR:\>=50% reduction of serum M-protein and reduction in 24h urine M-protein by \>=90% or to \<200mg/24h.In addition to above, if present at baseline,\>=50% reduction in size SPD of STPs also required.
Ctrough at steady state was the observed plasma concentration collected on pre-dose at Cycle 6 Day 1 (equivalent to prior to Cycle 6 Day 1) of isatuximab administration dose.
For both parts of the trial (A vs B and C vs D), the primary comparison of the 2 strategies will be made with respect to negative MRD rate (10-6 NGS) before maintenance using the chi square test in the ITT population. The observed MRD negative rate will be provided along with its 2-sided 95% Confidence interval (CI). Treatment effect will be described by an Odds Ratio, along with its 2-sided 95% confidence interval, by fitting a logistic regression model adjusted on stratification variables (with high risk cytogenetics and MRD negative rate (10-5 NGS) after induction as fixed effects and center as random effects for A vs B comparison, and high risk cytogenetics as fixed effects and center as random effects for C vs D comparison). In case of missing MRD, data will be imputed as positive in all arms. Sensitivity analyses will be performed using best-worst and worst-best case to check for robustness of the results.
Change in CD38 receptor occupancy from baseline
PFS defined as the time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee (IRC) assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first
Defined as the time from the date of randomization to the date of first documentation of progression disease (PD) as determined by the independent review committee (IRC) or the date of death from any cause, whichever occurs first.
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.
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.
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.
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.
The percentage of subjects with complete response (CR)
To assess hematologic response (VGPR or better i.e. dFLC \< 40 mg/L, CR including modified CR\*, low-dFLC response (dFLC \< 10 mg/L), iFLC \< 10 mg/l) achieved after 6 cycles of Isa-Pd. \*: If iFLC \<ULN and serum and urine immunofixation are negative, then neither a normal uFLC level nor a normal FLC ratio are required for complete response (CR).
Assess the feasibility of approach incorporating the use of isatuximab and dexamethasone with the subsequent addition of lenalidomide from the third cycle onwards in ultra-frail patients with myeloma
Cohort 1: Proportion of patients with complete hematologic response (ORR= CR and CRi) after 2 cycles of induction therapy including Isatuximab.
Cohort 1: Overall incidence and severity of adverse events (CTCAE 5.0).
Cohort 2: Proportion of patients with molecular response (MolCR) after one cycle of Isatuximab.
ORR defined as the proportion of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) according to the 2016 International Myeloma Working Group (IMWG) criteria assessed by Independent Review Committee (IRC).
Change in total lymphocyte count measured from blood sample
To evaluate the Very Good Partial Response (VGPR) or better rate by the end of two cycles of induction treatment, defined as the proportion of patients who have achieved VGPR, according to International Myeloma Working Group (IMWG) criteria, by the end of two cycles of induction treatment.
To demonstrate the benefit of isatuximab in combination with lenalidomide and low-dose dexamethasone followed by isatuximab and lenalidomide maintenance therapy in changing the proportion of patients with MRD negativity as compared to lenalidomide and low-dose dexamethasone followed by lenalidomide maintenance treatment in patients with newly diagnosed multiple myeloma (NDMM).
Responses will be based on the International Myeloma Working Group criteria for response in multiple myeloma.
proportion of patients who have achieved VGPR or better, according to International Myeloma Working Group (IMWG) criteria (Kumar 2016), by the end of two cycles of induction treatment
Renal response defined as a decrease in 24-hour proteinuria by \>50% at any point post therapy.
Evaluate in both arms the occurance after maintenance start of: Very good partial response (VGPR) or better rate, as defined by the International Myeloma Working Group (IMWG) criteria.
Assessment of changes in MRD negativity rate in patients with complete and very good partial response as well as conversion of MRD positivity to MRD negativity.
Use Common Terminology Criteria for Adverse Events (CTCAE) Version 6 to assess the adverse event
Will use the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 for AE collection. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. The incidence of severe (grade 3+) adverse events or toxicities will be described. We will also assess tolerability of the regimen through assessing the number of patients who required dose modifications and/or dose delays. In addition, we will capture the proportion of patients who go off treatment due to adverse reactions.
An event is defined as going off study due to toxicity, death or progression of disease. The events include off-study due to toxicity, death, or progression. The rate will be calculated with an exact 95% confidence interval using the efficacy evaluable population.
Determination or confirmation of the dose will be based on: safety and tolerability in terms of TEAEs/SAEs, dose-limiting toxicity occurrence, and laboratory parameters available information on PK (if appropriate) and biomarkers.
VGPR or better rate is defined as the percentage of participants with a VGPR or better as defined by the 2016 IMWG response criteria, assessed by Investigator based on central laboratory values and local imaging.
ORR, defined as the proportion of participants with stringent complete response (sCR), complete response (CR), VGPR, or partial response (PR), according to the 2016 IMWG criteria assessed by Investigator based on central laboratory values and local imaging.
Number of participants with adverse events
Concentration observed at the end of infusion (Ceoi)
Maximum concentration observed after the first infusion (Cmax)
Time to reach Cmax (tmax)
Last concentration observed above the lower limit of quantification after the first infusion (Clast)
Time of Clast (tlast)
Concentration observed just before treatment administration during repeated dosing (Ctrough)
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time zero to time of the last concentration observed above the lower limit of quantification (ie, Clast) (AUClast)
Area under the plasma concentration versus time curve calculated over the dosing interval T (168h or 336h) (AUC0 T)
To evaluate the maximum observed concentration (Cmax)
To evaluate the time to reach Cmax (tmax)
To evaluate area under the plasma concentration versus time curve over the dosing interval (AUC0-168h)
To evaluate the concentration observed at the end of an IV infusion (Ceoi)
To evaluate concentration observed just before investigational medicinal product (IMP) administration during repeated dosing (Ctrough)
Potential DLTs were defined as the occurrence of any of the following adverse reactions at first treatment cycle, unless due to disease progression or obviously unrelated cause: Hematological DLTs: Grade(G) 4 neutropenia (N) for more than 7 consecutive days, G3 to G4 N complicated by fever (temperature greater than or equal to \[\>=\] 38.5 degree Celsius on more than 1 occasion) or microbiologically/radiographically documented infection, G3 to G4 thrombocytopenia associated with clinically significant bleeding requiring clinical intervention or Non-hematological DLTs: G4 non-hematologic AE, G\>=2 uveitis, G3 non-hematological AE lasting greater than (\>)3 days despite optimal care support, delay in initiation of Cycle 2 \>14 days due to treatment related laboratory abnormalities/AE. Any other AE that the investigator/study committee deemed to be dose-limiting, regardless of grade, was also considered as DLT.
An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered with a pharmaceutical product and which did not necessarily have a causal relationship with study treatment. SAEs were 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 an AE which occurred after the first dose of study treatment administration up to 30 days after the last dose of study treatment administration. The DLT observation period was 1 cycle (28 days). However, all AEs during treatment, unless due to disease progression or an obviously unrelated cause, were taken into consideration by the Study Committee for the determination of the maximum tolerated dose and recommended Phase 2 dose.
ORR by Investigator using international myeloma working group (IMWG) response criteria:percentage of participants with complete response (CR) (including stringent CR \[sCR\]very good partial response \[VGPR\] and partial response \[PR\]).CR:negative immunofixation on serum and urine,disappearance of any soft tissue plasmacytomas,less than (\<)5% plasma cells in bone marrow (BM) aspirates and normal free light chain(FLC)ratio (0.26-1.65).sCR:CR plus no clonal cells in BM biopsy.VGPR:serum and urine M-protein detectable by immunofixation,not electrophoresis;\>=90% reduction in serum M-protein plus urine M-protein level\<100mg/24hour(h);FLC only:\>=90% decrease in difference between involved and uninvolved FLC levels.PR:\>=50% reduction of serum M-protein and reduction in 24h urine M-protein by \>=90% or \<200mg/24h.In addition to above, if present at baseline,\>=50% reduction in size (sum of products of maximal perpendicular diameters of measured lesions \[SPD\]) of soft tissue plasmacytomas required.
DLTs: AEs occurring during 1st treatment cycle, assessed per national cancer institute (NCI) common terminology criteria for adverse events (CTCAE) version 4.03. DLTs included: Hematologic DLTs: Grade(G) 4 neutropenia(N) lasting greater than or equal to (\>=) 5 days; G3 to G4 N with fever or microbiologically or radiographically documented infection; G4 thrombocytopenia lasting for \>=5 days; thrombocytopenia, treatment delay greater than (\>)14 days due to hematologic toxicity. Non-hematologic DLTs: G\>=3 non-hematological AE, excluding G3 fatigue, G 3 to 4 electrolyte abnormalities, G3 nausea/vomiting/diarrhea if responsive to optimal medical management within 48 hours or allergic reaction/ hypersensitivity attributed to isatuximab; AE that required treatment delay for \>14 days. Any other toxicity deemed by Investigator or sponsor to be dose-limiting, regardless of the grade, was also considered DLT.
Percentage of participants with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) assessed by International Myeloma Working Group (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% 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 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.
Treatment-related Adverse events resulting in a DLT will be summarized by maximum toxicity grade for each dose level of isatuximab.
The MTD is defined as the dose level below the lowest dose that induces dose- limiting toxicity in at least one-third of patients Adverse events will be summarized by maximum toxicity grade and by dose level for each ARM of the trial using NCI CTCAE v4.03
Overall response rate (ORR) as define by the International Myeloma Working Group (IMWG) uniform response criteria of patients obtaining Stringent Complete Remission (sCR), Complete Remission (CR), Very Good Partial Remission (VGPR), Partial Remission (PR), or Minimal Remission (MR)
Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily have to have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of study treatment until 30 days after the last dose of study treatment.
OR defined as participants with stringent complete response (sCR) or complete response (CR) or very good partial response (VGPR) or partial response (PR) . Based on IMWG, CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; sCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein and urine M-protein level \<100 mg/24 hours; PR: \>=50% reduction of serum M-Protein and reduction in urinary M-protein by \>=90% or to \<200 mg/24 hours; \>=50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein criteria or a \>=50% reduction in plasma cells in place of M-protein if present at baseline.
OR: participants with sCR or CR or VGPR or PR. As per updated IMWG, CR: Negative immunofixation on serum and urine, disappearance of any soft tissue plasmacytomas and \<=5% plasma cells in bone marrow; normal FLC ratio of 0.26-1.65 in participants with only FLC disease; sCR: CR and normal FLC ratio and no clonal cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or \>=90% reduction in serum M-protein and urine M-protein level \<100 mg/24 hours, \>90% decrease in the difference between involved and uninvolved FLC levels; PR: \>=50% reduction of serum M-Protein and reduction in urinary M-protein by \>=90% or to \<200 mg/24 hours; \>=50% decrease in the difference between involved and uninvolved FLC levels in place of M-protein criteria or \>=50% reduction in plasma cells in place of M-protein if present at baseline.
| Arm | Type | Description |
|---|---|---|
| Arm A (Induction and screening) | OTHER | All enrolled participants begin with Step 1 induction that consists of eight 28-day cycles before end-of-induction cohort assignment. Peripheral Blood Stem Cells (PBSC) mobilization/collection is planned after completion of 4-6 cycles of induction for participants without disease progression. End-of-induction MRD/response and cytogenetic risk status determine whether participants proceed to post-induction Cohort 1 or Cohort 2. |
| Arm B (Cohort 1 Maintenance Therapy Part 1) | OTHER | Participants assigned to Cohort 1 enter Arm B and receive isatuximab + iberdomide maintenance for 36 cycles. Maintenance should begin within 28 days of the last induction cycle. |
| Arm C: Cohort 1 Maintenance Therapy (Part 2), Single-Agent Iberdomide | OTHER | After completion of Arm B, participants with MRD-negative Complete Response (CR) status at Step 3 are assigned to Arm C and continue single-agent iberdomide until progression. Isatuximab is not administered in Arm C. |
| Arm D: Cohort 1 Maintenance Therapy (Part 2), Iberdomide + Isatuximab | OTHER | After completion of Arm B, participants with MRD-positive or MRD-indeterminate disease, or \<VGPR (very good partial response) at Step 3 evaluation \[unless Progressive Disease (PD)\], continue iberdomide + isatuximab until progression. |
| Arm E: Cohort 2 Randomized Consolidation and Maintenance (HDM-ASCT) Strategy | ACTIVE_COMPARATOR | Eligible Cohort 2 participants are randomized to Arm E: High-Dose Melphalan followed by Autologous Stem Cell Transplantation (HDM-ASCT) consolidation followed by isatuximab + iberdomide maintenance until progression. The protocol identifies Arm E as the control arm and describes HDM-ASCT-based therapy as the SOC comparator for Cohort 2. Consolidation should begin preferably within 30 days, and no later than 42 days, after induction completion. Maintenance begins 60-110 days after PBSC infusion. |
| Arm F: Cohort 2 Randomized Consolidation and Maintenance (Linvoseltamab Strategy) | EXPERIMENTAL | Eligible Cohort 2 participants are randomized to Arm F: linvoseltamab consolidation for 8 cycles followed by isatuximab + iberdomide maintenance until progression. The protocol explicitly identifies Arm F as the experimental arm and hypothesizes superior efficacy versus Arm E. Maintenance should begin within 2-4 weeks after the last linvoseltamab dose. |
| Arm G: Cohort 2 Non-randomized 3-Drug Maintenance | OTHER | Participants in Cohort 2 who do not meet criteria for consolidation therapy may enter Arm G. Standard Risk (SR) MRD-indeterminate participants may also enter Arm G or, with Sponsor-Investigator approval, may be randomized in Cohort 2. Arm G is a 3-drug maintenance regimen continued in 28-day cycles until progression. The protocol explicitly states that dexamethasone is excluded from Arm G. |
| Isatuximab Subcutaneous (SC) | EXPERIMENTAL | Isatuximab dose will administered SC weekly for 4 weeks during Cycle 1 (Days 1, 8, 15, and 22) and Day 1 and 15 of subsequent cycles. Each cycle will be 28 days in duration. Pomalidomide dose will be taken orally on Day 1 to Day 21 of each cycle at the time that is the most convenient for the participants prior to or after isatuximab administration, preferably at the same time every day. Dexamethasone will be taken orally on Day 1, 8, 15 and 22 (to be repeated every 28 days). Participants may receive other treatments as background treatment and/or rescue medication. |
| Isatuximab Intravenous (IV) | ACTIVE_COMPARATOR | Isatuximab dose will be administered via IV infusion weekly for 4 weeks during Cycle 1 (Days 1, 8, 15, and 22) and Day 1 and 15 of subsequent cycles. Each cycle will be 28 days. Pomalidomide dose will be taken orally on Day 1 to Day 21 of each cycle at the time that is the most convenient for the participants prior to or after isatuximab administration, preferably at the same time every day. Dexamethasone will be taken orally on Day 1, 8, 15 and 22 (to be repeated every 28 days). Participants may receive other treatments as background treatment and/or rescue medication. |
| MRD Standard-risk patients (post induction MRD <10-5, MRD SR) (1:1 Randomization) : Arm A | EXPERIMENTAL | Arm A: consolidation with 6 additional cycles of Isa-KRD (cycles 7 to 12; 28-day cycle; Isa-KRD = Isatuximab Carfilzomib Lenalidomide Dexamethasone): * Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 12) * Carfilzomib: 56 mg/m2 I.V on days 1, 8 and 15 (cycles 7 to 12) * Lenalidomide: 25 mg per day orally from days 1 to 21 * Dexamethasone: 40 mg orally on day 1, 8, 15, 22 |
| MRD Standard-risk patients (post induction MRD <10-5, MRD SR) (1:1 Randomization): Arm B | EXPERIMENTAL | Arm B: consolidation with ASCT followed by 2 cycles of Isa-KRD (cycles 7 and 8; Isa-KRD = Isatuximab Carfilzomib Lenalidomide Dexamethasone; 28-day cycle) Melphalan 200 mg/m2 followed by autologous stem cell transplantation (please refer to section 6.3.2) * Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 8) * Carfilzomib: 56 mg/m2 I.V on days on days 1, 8 and 15 (cycles 7 to 8) * Lenalidomide: 25 mg per day orally from days 1 to 21 * Dexamethasone: 40 mg orally on days 1, 8, 15, 22 (cycles 7 to 8) |
| MRD High-risk patients (post induction MRD >10-5, MRD HR) (1:1 Randomization): Arm C | EXPERIMENTAL | Arm C: ASCT followed by 2 cycles of Isa-KRD (cycles 7 and 8; Isa-KRD = Isatuximab Carfilzomib Lenalidomide Dexamethasone; 28-day cycle) Melphalan 200 mg/m2 followed by autologous stem cell transplantation. * Isatuximab: 10 mg/kg I.V. on days 1 and 15 (cycles 7 to 8) * Carfilzomib: 56 mg/m2 I.V on days on days 1, 8 and 15 (cycle 7 to 8) * Lenalidomide: 25 mg per day orally from day 1 to day 21 * Dexamethasone: 40 mg orally on days 1, 8, 15, 22 (cycle 7 to 8) |
| MRD High-risk patients (post induction MRD >10-5, MRD HR) (1:1 Randomization): Arm D | EXPERIMENTAL | Tandem ASCT Melphalan 200 mg/m2 followed by autologous stem cell transplantation. |
| Isatuximab, lenalidomide, and dexamethasone (ILd) | EXPERIMENTAL | Participants will receive isatuximab \[intravenous (IV) administration\] in combination with lenalidomide \[per os (PO) administration\] and dexamethasone \[IV on Day 1 of Cycle 1 for participants receiving isatuximab IV only and PO otherwise for subsequent cycles\] for 24 cycles followed by isatuximab monotherapy for 12 cycles for a total duration of 36 cycles. 1 cycle = 28 days. Participants may receive other treatments as pre-medication. |
| Lenalidomide and dexamethasone (Ld) | ACTIVE_COMPARATOR | Lenalidomide \[PO administration\] in combination with dexamethasone \[PO administration\] for 24 cycles. 1 cycle = 28 days |
| Isatuximab/Bortezomib/Lenalidomide/Dexamethasone = IVRd arm | EXPERIMENTAL | 1. Induction treatment with 4x6-week cycles with intravenous (IV) isatuximab + subcutaneous (SC) bortezomib + oral lenalidomide + IV or oral dexamethasone 2. Continuous treatment with 4-week cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone |
| Bortezomib/Lenalidomide/Dexamethasone = VRd arm | ACTIVE_COMPARATOR | 1. Induction treatment with 4x6-week cycles with SC bortezomib + oral lenalidomide + IV or oral dexamethasone 2. Continuous treatment with 4-week cycles with oral lenalidomide + IV or oral dexamethasone |
| Isatuximab/Lenalidomide/Dexamethasone = IRd crossover arm | OTHER | 4-weeks cycles with IV isatuximab + oral lenalidomide + IV or oral dexamethasone |
| Isatuximab + Carfilzomib + Dexamethasone (IKd) | EXPERIMENTAL | 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. |
| Carfilzomib + Dexamethasone (Kd) | ACTIVE_COMPARATOR | 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. |
| Pd (pomalidomide + dexamethasone) | ACTIVE_COMPARATOR | Participants received pomalidomide 4 milligrams (mg) Per os (PO) on Days 1 to 21 of each 28-day treatment cycle plus dexamethasone 40 mg (participants greater than or equal to (\>=) 75 years of age received 20 mg dexamethasone) PO on Days 1, 8, 15 and 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 306.6 weeks). |
| IPd (isatuximab + pomalidomide + dexamethasone) | EXPERIMENTAL | Participants received isatuximab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion on Days 1, 8, 15, and 22 at Cycle 1, and then on Days 1 and 15 of subsequent cycles plus pomalidomide 4 mg PO on Days 1 to 21 of each 28-day treatment cycle and dexamethasone 40 mg (participants \>= 75 years of age received 20 mg dexamethasone), PO or IV on Day 1, 8, 15, 22 of each 28-day treatment cycle until disease progression or unacceptable toxicity or participant's wish to discontinue study treatment, or any other reason, whichever comes first (maximum exposure: 311.0 weeks). |
| Isatuximab and Cemiplimab combined therapy | EXPERIMENTAL | Drug : Isatuximab 1 cycle : 10mg/kg IV every week. It is administered on Day 2, Day 9, Day 16, Day 23. 2\~6 cycle : 10mg/kg every 2 weeks . It is administered on Day 2, Day 16. 7th cycle and beyond : 10mg/kg IV every 3 weeks. It is administered on Day 2. Drug : Cemiplimab 1st - 6th cycle : 250mg IV every 2 weeks. It is administered on Day 1, Day 15. 7th cycle and beyond : 350mg every 3 weeks. It is administered on Day 1. |
| Single-stage | EXPERIMENTAL | Patient eligible to enter the study will receive 9 to 12 cycles (according to response) of intravenous Isatuximab (10 mg/kg) and oral Pomalidomide 4 mg from day 1 to day 21 and Dexamethasone 10-20 mg weekly on days 1, 8, 15 and 22. Each cycle will be of 28 days duration. During cycle 1, Isatuximab will be administered weekly on days 1, 8, 15, and 22 then days 1 and 15 in subsequent cycles from cycle 2 to 9 or 12. For each individual patient, the treatment period will be 12 months, unless CR at the completion of 9 cycles, disease progression or unacceptable toxicity occurs. The duration of follow-up for overall survival will be 1 year after the last patient enters overall survival follow-up. |
| Combination Treatment | EXPERIMENTAL | Isatuximab |
| Isatuximab in combination with weekly carfilzomib and dexamethasone | EXPERIMENTAL | Participants will receive isatuximab via SC-OBDS administration in combination with weekly carfilzomib and dexamethasone. Isatuximab will be administered on days 1, 8, 15 and 22 for Cycle 1 and then on days 1, 15 for subsequent cycles. Carfilzomib will be administered intravenously (IV) at a starting dose on Day 1 of Cycle 1 and then escalated dose on Days 8 and 15 of Cycle 1, followed by Days 1, 8 and 15 of subsequent cycles. Dexamethasone will be given on Days 1, 8, 15, and 22 of Cycle 1 and then on Days 1, 8 and 15 of subsequent cycles. Dexamethasone will be administered IV on Cycle 1 Day 1, and IV or PO in the subsequent administrations. 1 cycle = 28 days. |
| GMALL-Isatuximab | EXPERIMENTAL | Cohort 1: In this Cohort, Isatuximab shall be implemented as part of a combination therapy for patients with R/R T-ALL/T-LBL, defined as bone marrow infiltration of ≥5% (R/R T-ALL) or ≥1% minimal residual disease (MRD). Cohort 2: In this Cohort, Isatuximab shall be implemented as single drug treatment for patients with molecular failure/relapse. Cohort 2 will include patients with hematologic remission (bone marrow blast count \<5%) of T-cell ALL, but with molecular failure or molecular relapse (MRD+ T-ALL) - terminated with protocol version 3.2. |
| Cohort 1: manual administration | EXPERIMENTAL | Isatuximab will be administered manually for 8 minutes on Day 1 of Cycle 1 followed by 6 minutes from Day 8 of Cycle 1 and thereafter, in combination with carfilzomib and dexamethasone. Participants may receive other treatments as rescue medication or background medication. |
| Part 1 Cohort 2: manual administration | EXPERIMENTAL | Isatuximab will be administered manually for 6 minutes on Day 1 of Cycle 1 and thereafter, in combination with carfilzomib and dexamethasone. Participants may receive other treatments as rescue medication or background medication. |
| Part 2 Cohort 3 Randomized Cohort: OBDS to manual | EXPERIMENTAL | Isatuximab will be administered in combination with carfilzomib and dexamethasone. Isatuximab will be administered via OBDS from Cycle 1 to 3. For Cycle 4 to 6, the method of administration will be switched for each participant from OBDS to manual administration. From Cycle 7 and onwards, participants can choose manual or OBDS. Participants may receive other treatments as rescue medication or background medication. |
| Part 2 Cohort 3 Randomized Cohort: Manual to OBDS | EXPERIMENTAL | Isatuximab will be administered in combination with carfilzomib and dexamethasone. Isatuximab will be administered manually from Cycle 1 to 3. For Cycle 4 to 6, the method of administration will be switched for each participant from manual to OBDS administration. From Cycle 7 and onwards, participants can choose manual or OBDS. Participants may receive other treatments as rescue medication or background medication. |
| Part 3 Cohort 4 Randomized Cohort: OBDS to manual | EXPERIMENTAL | Isatuximab will be administered in combination with carfilzomib and dexamethasone. Isatuximab will be administered via OBDS from Cycle 1 to 3. For Cycle 4 to 6, the method of administration will be switched for each participant from OBDS to manual administration. From Cycle 7 and onwards, participants can choose manual or OBDS. Participants may receive other treatments as rescue medication or background medication. |
| Part 3 Cohort 4: Randomized Cohort: manual to OBDS | EXPERIMENTAL | Isatuximab will be administered in combination with carfilzomib and dexamethasone. Isatuximab will be administered manually from Cycle 1 to 3. For Cycle 4 to 6, the method of administration will be switched for each participant from manual to OBDS administration. From Cycle 7 and onwards, participants can choose manual or OBDS. Participants may receive other treatments as rescue medication or background medication. |
| Part 3 Cohort 5 Randomized Cohort: OBDS to manual administration in Chinese participants | EXPERIMENTAL | Isatuximab will be administered in combination with carfilzomib and dexamethasone. Isatuximab will be administered via OBDS from Cycle 1 to 3. For Cycle 4 to 6, the method of administration will be switched for each participant from OBDS to manual administration. From Cycle 7 and onwards, participants can choose manual or OBDS. Participants may receive other treatments as rescue medication or background medication. |
| Part 3 Cohort 5 Randomized Cohort: manual to OBDS administration in Chinese participants | EXPERIMENTAL | Isatuximab will be administered in combination with carfilzomib and dexamethasone. Isatuximab will be administered manually from Cycle 1 to 3. For Cycle 4 to 6, the method of administration will be switched for each participant from manual to OBDS administration. From Cycle 7 and onwards, participants can choose manual or OBDS. Participants may receive other treatments as rescue medication or background medication. |
| Isatuximab | EXPERIMENTAL | Participants will receive isatuximab as monotherapy or in a combination regimen, according to the treatment the participant received on the parental protocol |
| Isatuximab and Standard Procedures | EXPERIMENTAL | Subjects will receive the study drug Isatuximab in addition to standard procedures for transplant |
| Standard procedures | EXPERIMENTAL | Subjects will receive standard procedures for transplant. |
| Treatment (isatuximab, carfilzomib, pomalidomide) | EXPERIMENTAL | Patients receive isatuximab IV over 30-60 minutes on days 1, 8, 15, and 22 of cycle 1, and days 1 and 15 of subsequent cycles, carfilzomib IV over 10 to 30 minutes on days 1, 8, 15, and pomalidomide PO QD on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Isa-RVD | EXPERIMENTAL | Isatuximab (IV): 10 mg/kg on Days 1, 8, 15, 22, 29 in Cycle 1; from Cycle 2 onwards, it will be given on Days 1, 15, 29. Bortezomib (SQ): 1.3 mg/m² on Days 1, 4, 8, 11, 22, 25, 29, and 32. Lenalidomide (PO): 25 mg/day (10 mg/day for patients with creatinine clearance \[CrCl\] ≥30 to \<60 mL/min) from Day 1 to Day 14 and from Day 22 to Day 35 of each cycle. Dexamethasone (IV on the days of Isatuximab and PO on other days): 20 mg/day on Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23, 25, 26, 29, 30, 32, and 33. If patients are ≥75 years old, dexamethasone will be administered on Days 1, 4, 8, 11, 15, 16, 22, 25, 29 and 32. |
| IRd followed by IR | EXPERIMENTAL | Induction: 8 cycles isatuximab+lenalidomide+dexamethasone; Maintenance: up to 24 cylces isatuximab+lenalidomide |
| Rd followed by R | OTHER | Induction: 8 cycles lenalidomide+dexamethasone; Maintenance: up to 24 cylces lenalidomide |
| Treatment (isatuximab, carfilzomib, pomalidomide, steroid) | EXPERIMENTAL | INDUCTION: Patients receive isatuximab IV on days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of subsequent cycles carfilzomib IV over 30 minutes on days 1, 8, and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1,8, 15, and 22. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive isatuximab IV days 1 and 15, carfilzomib IV over 30 minutes on days 1 and 15, pomalidomide PO QD on days 1-21, and dexamethasone PO or IV on days 1, 8, 15, and 22. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. All patients undergo bone marrow aspirate and biopsy during screening, skeletal x-ray, CT, PET-CT, or MRI, bone marrow and blood sample collection throughout the study. |
| Isatuximab for MGRS | EXPERIMENTAL | Subjects will receive Isatuximab for 6 months and will be followed for an additional one year post therapy for outcome follow-up. |
| A - Isatuximab/CellProtect | EXPERIMENTAL | Isatuximab will be given intravenously (IV) at the dose of 10 mg/kg on Days 1, 8, 15, 22 (cycle 1), 36, 50 (cycle 2), 64, 78 (cycle 3) and monthly thereafter (cycles 4-36). CellProtect will be given IV infusion at the dose of 3x10\^7 cells/kg day 29 , 43 and 3-10x10\^7 on day 57. Each cycle will be 28 days, after completion of third cycles, patients will continue with Isatuximab alone until disease progression, unacceptable AE, death, completion of 3 years of treatment or patient's decision to discontinue, whichever occurs first. |
| B - Isatuximab | ACTIVE_COMPARATOR | Isatuximab will be given intravenously (IV) at the dose of 10 mg/kg on Days 1, 8, 15, 22 (cycle 1), 36, 50 (cycle 2), 64, 78 (cycle 3) and monthly thereafter (cycles 4-36). Each cycle will be 28 days, after completion of third cycles, patients will continue with Isatuximab alone until disease progression, unacceptable AE, death, completion of 3 years of treatment or patient's decision to discontinue, whichever occurs first. |
| Treatment (cyclophosphamide, dexamethasone, TiNK, isatuximab) | EXPERIMENTAL | Patients receive cyclophosphamide IV on day 1, dexamethasone PO on days 1-4, TiNK IV on day 8, and isatuximab IV on days 8 and 15 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and biopsy during screening and on study, as well as optionally during follow up. Patients undergo ECHO during screening and blood sample collection throughout the study. |
| Treatment (isatuximab, chemotherapy) | EXPERIMENTAL | All patients will receive Isatuximab plus dexamethasone 4 mg PO/IV days weekly. Based on tolerance, patients will add to their treatment subcutaneous Velcade (earliest time to add Velcade is cycle 1 day 15) and intravenous cyclophosphamide (earliest time to add cyclophosphamide is cycle 4 day 1) Patients then receive dexamethasone and isatuximab as maintenance treatment twice per month for 12 months in the absence of disease progression or unacceptable toxicity. |
| Control Arm: isatuximab + pomalidomide + dexamethasone (Substudy 01) | ACTIVE_COMPARATOR | * Isatuximab, intravenous (IV) doseweekly (QW) × 4 weeks (Cycle 1), followed by every two weeks (Q2W) (subsequent cycles). * Pomalidomide dose by mouth daily Day 1 to Day 21. * Dexamethasone dose by mouth QW. |
| isatuximab + SAR439459 + dexamethasone (Substudy 02) | EXPERIMENTAL | SAR439459 in combination with isatuximab and dexamethasone Part 1: 2 dose levels (DLs) of IV SAR439459: * DL1 SAR439459 dose Q2W. * DL2 SAR439459 dose Q2W. * Isatuximab dose IV QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8). Part 2: * SAR439459 IV dose Q2W. * Isatuximab IV dose QW × 5 weeks (Cycle 1), followed by Q2W administrations (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth. In Cycle 1, the first administration of SAR439459 (Day 1) will precede isatuximab by 1 week (first dose of isatuximab will be at Cycle 1 Day 8). |
| isatuximab + dexamethasone + belantamab mafodotin (Substudy 03) | EXPERIMENTAL | Belantamab mafodotin in combination with isatuximab and dexamethasone Part 1: 1 DL of IV belantamab mafodotin in Part 1 and de-escalation dose DL-1: * DL1 belantamab mafodotin IV dose QW4 or de-escalation dose DL-1 QW8 * Isatuximab dose, IV QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). * Dexamethasone fixed dose and schedule: QW by mouth. Part 2: * Isatuximab IV dose QW × 4 weeks (Cycle 1), followed by Q2W (subsequent cycles). * Belantamab mafodotin IV dose Q4W or Q8W * Dexamethasone fixed dose and schedule: QW by mouth. |
| Isatuximab + pegenzileukin (Substudy 04) | EXPERIMENTAL | Pegenzileukin in combination with isatuximab Part 1- dose escalation: * Up to 3 DLs of IV pegenzileukin are planned to be evaluated: * DL1 will explore pegenzileukin at Q2W. * DL2 will explore pegenzileukin at Q2W. * DL3 will explore pegenzileukin at Q2W. * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). Part 1 - dose optimization: * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). * Pegenzileukin at potential doses (DL A and DL B) Q2W. Part 2 (dose expansion): * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles). * Pegenzileukin IV dose Q2W. |
| Experimental: Isatuximab + Dexamethasone + Belumosudil (Substudy 05) | EXPERIMENTAL | Isatuximab in combination with belumosudil and dexamethasone Part 1- dose escalation: During the first cycle, belumosudil will be evaluated in monotherapy during 2 to 4 weeks, then isatuximab and dexamethasone will be added, and continued for the subsequent cycles. * Belumosudil by mouth at Dose Level (DL) 1, DL2, DL3, and DL4 * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization: * Belumosudil at potential doses (DL A and DL B), daily by mouth * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 2- dose expansion: * Belumosudil dose daily, by mouth * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth |
| Isatuximab + evorpacept + dexamethasone (Substudy 06) | EXPERIMENTAL | Isatuximab in combination with evorpacept and dexamethasone Part 1- dose escalation: * Evorpacept IV dose Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 1- dose optimization * Evorpacept IV at potential doses (DL A and DL B), Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth Part 2- dose expansion: * Evorpacept IV dose Q2W * Isatuximab IV dose QW × 4 weeks, followed by Q2W (subsequent cycles) * Dexamethasone fixed dose and schedule: QW by mouth |
| Dose regimen 1 | EXPERIMENTAL | Isatuximab SC administration dose level 1 once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle |
| Dose regimen 2 | EXPERIMENTAL | Isatuximab SC administration dose level 2 once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle |
| Dose regimen 3 | EXPERIMENTAL | Isatuximab SC administration dose level 3 using the investigational injector device once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle |
| Dose regimen 4 | EXPERIMENTAL | Isatuximab IV administration once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle |
| Dose regimen 5 | EXPERIMENTAL | Isatuximab IV administration once weekly for 4 weeks (Cycle 1) and on Day 1 and Day 15 of each subsequent cycle |
| Isatuximab/cemiplimab (Regimen 1) | EXPERIMENTAL | Isatuximab on Days 1, 8, 15, and 22, then Days 1 and 15 in 28-day cycles up to disease progression. Cemiplimab on Days 1 and 15 in 28-day cycle up to disease progression. |
| Isatuximab/cemiplimab (Regimen 2) | EXPERIMENTAL | Isatuximab on Days 1, 8, 15, and 22, then Days 1 and 15 in 28-day cycles up to disease progression. Cemiplimab on Day 1 in 28-day cycle up to disease progression. |
| Phase 1, Cohort 1: Isatuximab 10 mg/kg | EXPERIMENTAL | Participants received Isatuximab 10 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then every 2 weeks (Q2W) (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 112 weeks). |
| Phase 1, Cohort 2: Isatuximab 20 mg/kg | EXPERIMENTAL | Participants received Isatuximab 20 mg/kg IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then Q2W (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 137 weeks). |
| Phase 2: Isatuximab 20 mg/kg | EXPERIMENTAL | Participants received Isatuximab 20 mg/kg IV infusion, QW for 4 weeks (i.e., on Day 1, Day 8, Day 15 and Day 22 of Cycle 1), and then Q2W (i.e., on Day 1 and 15) for subsequent treatment cycles (each cycle of 28 days) until unacceptable adverse events, disease progression, or any other reason for discontinuation whichever occurs first (maximum duration of exposure: 248 weeks). |
| PomdeSAR | EXPERIMENTAL | Part A: Isatuximab (escalating dose) on Day 1, 8, 15, and 22, then Day 1 and 15 + pomalidomide 4 mg on Day 1 to 21 + dexamethasone 40 mg (20 mg in patients of 75 years or older) on Day 1, 8, 15, 22 in 28-day cycles up to disease progression Part B: Isatuximab 10 mg/kg on Day 1, 8, 15, and 22, then Day 1 and 15 + pomalidomide 4 mg on Day 1 to 21 + dexamethasone 40 mg (20 mg in patients of 75 years or older) on Day 1, 8, 15, 22 in 28-day cycles up to disease progression |
| Arm I (20 mg dexamethasone, isatuximab, carfilzomib) | EXPERIMENTAL | 20 mg dexamethasone IV given on days 1, 8, 15, 22 (pre- SAR650984 and carfilzomib), then dexamethasone 4 IV or PO mg Day 2, 9, 16. All patients will receive a fixed dose of Isatuximab (SAR650984) according to their assigned dose cohort. Patients receive isatuximab IV over 4-6 hours on days 1 and 15 of every cycle for the starting cohort, and days 1, 8, 15, and 22 of cycle 1 and days 1 and 15 of subsequent cycles. Carfilzomib IV will be administered over 10 minutes on days 1, 2, 8, 9, 15, and 16 . Treatment repeats every 28 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may continue treatment after 8 courses if clinical benefit is present at the investigator's discretion (carfilzomib may be switched to days 1, 2, 15, and 16 after 8 cycles per investigator discretion). |
| Arm II (40 mg dexamethasone, isatuximab, carfilzomib) | EXPERIMENTAL | 40 mg dexamethasone IV given on Days 1, 8, 15 and 22 (use as premed to isatuximab). All patients will receive a fixed dose of Isatuximab (SAR650984) according to the assigned dose. Patients receive isatuximab IV over 4-6 hours on day 1, 3-4 hours on Day 8, 15, and 22 of cycle 1 and then on days 1 and 15 of subsequent cycle (patients may be eligible for rapid siatuximab given over 75 minutes), and carfilzomib IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. |
| SAR650984 (isatuximab) | EXPERIMENTAL | SAR650984 (isatuximab) (escalating dose) plus lenalidomide 25 mg on Days 1 to 21 plus dexamethasone 40 mg on Days 1, 8, 15, 22 in 28-day cycles for all cohorts up to disease progression. For Q2W cohorts: SAR650984 (isatuximab) on Days 1 and 15 of every cycle. For QW/Q2W cohorts: SAR650984 (isatuximab) on Days 1, 8, 15, and 22 of first cycle and Days 1 and 15 of every subsequent cycle. |
| Phase 1:Isatuximab <=1 mg/kg Q2W | EXPERIMENTAL | Participants with CD38+ hematological malignancies (HM), received Isatuximab at any one of the dose less than or equal to (\<=) 1 milligram per kilogram (mg/kg) (i.e. either 0.0001 mg/kg or 0.001 mg/kg or 0.01 mg/kg or 0.03 mg/kg or 0.1 mg/kg or 0.3 mg/kg or 1 mg/kg) as intravenous (IV) infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal by participant, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 1: Isatuximab 3mg/kg Q2W | EXPERIMENTAL | Participants with CD38+ HM, received Isatuximab 3 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 1: Isatuximab 5 mg/kg Q2W | EXPERIMENTAL | Participants with CD38+ HM, received Isatuximab 5 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase1:Isatuximab (CD38+HM and Standard Risk Multiple Myeloma) | EXPERIMENTAL | Participants with CD38+ HM along with participants with standard risk multiple myeloma were included this arm and, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 1:Isatuximab (CD38 + HM and High Risk Multiple Myeloma) | EXPERIMENTAL | Participants with CD38+ HM along with participants with high risk multiple myeloma, received Isatuximab 10 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 1: Isatuximab 10 mg/kg QW | EXPERIMENTAL | Participants with CD38+ HM, received Isatuximab 10 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 1: Isatuximab 20 mg/kg Q2W | EXPERIMENTAL | Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion on Day 1 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 1: Isatuximab 20 mg/kg QW | EXPERIMENTAL | Participants with CD38+ HM, received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1 and 8 of each 14-day treatment cycle until occurrence of unacceptable toxicity, disease progression, death, consent withdrawal, investigator's decision, and/or availability of study drug (maximum exposure: 120 weeks). |
| Phase 2 Stage 1a: Isatuximab 3 mg/kg Q2W | EXPERIMENTAL | Participants with multiple Myeloma received Isatuximab 3 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable adverse event (AE), disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). |
| Phase 2 Stage 1a: Isatuximab 10 mg/kg Q2W | EXPERIMENTAL | Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion on Day 1 and Day 15 of each 28-day cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). |
| Phase2 Stage1a:Isatuximab 10mg/kg Q2W; Then Q4W | EXPERIMENTAL | Participants with multiple Myeloma received Isatuximab 10 mg/kg, as IV infusion Q2W, i.e. on Day 1 and Day 15 of Cycle 1 and 2 (each cycle 28 days), then every 4 week (Q4W), i.e. on Day 1 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 414 weeks). |
| Phase 2 Stage 1b: Isatuximab 20mg/kg QW and Then Q2W | EXPERIMENTAL | Participants with multiple Myeloma received Isatuximab 20 mg/kg, as IV infusion QW, i.e. on Day 1, 8, 15 and 22 of Cycle 1 and 2 (each cycle 28 days), then Q2W, i.e. on Day 1 and Day 15 of each 28-days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination or lost to follow up (maximum exposure: 92 weeks). |
| Phase 2 Stage 2: Isatuximab Alone | EXPERIMENTAL | Participants with relapsed or relapsed/refractory multiple myeloma (RRMM), received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks). |
| Phase 2 Stage 2: Isatuximab + Dexamethasone | EXPERIMENTAL | Participants with relapsed or RRMM, received Isatuximab 20 mg/kg, as IV infusion on Day 1, 8, 15 and Day 22 of Cycle 1 (28 days) and then on Day 1 and 15 of each subsequent 28-day cycles along with dexamethasone: tablet or as IV infusion (40 mg/day for less than \[\<\] 75 years of age; 20 mg/day \[greater than or equal to \[\>=\] for 75 years of age) on Days 1, 8, 15 and 22 of each 28 days cycle until unacceptable AE, disease progression, poor compliance to the study protocol, study termination, lost to follow up or investigator's decision (maximum exposure: 301 weeks). |
| Name | Type | Description |
|---|---|---|
| Isatuximab | DRUG | Supplied by Sanofi-Aventis (Sanofi); used in induction and maintenance/consolidation strategies in this protocol; administered subcutaneously (SC) in the maintenance tables provided; not administered in Arm C. |
| Iberdomide | DRUG | Supplied by Bristol Myers Squibb/Celgene (BMS); used across induction and maintenance phases; administered orally. |
| Bortezomib (B) | DRUG | Commercial supply; used in induction and Arm G maintenance; administered subcutaneously in Arm G on Days 1 and 15 of each 28-day cycle. |
| Dexamethasone | DRUG | Commercial supply; used in induction; may be administered intravenously or orally at investigator discretion; excluded from Arm G. |
| Melphalan | DRUG | Commercial supply; used as conditioning therapy for Arm E before PBSC infusion/ASCT; administered intravenously. |
| Linvoseltamab | DRUG | Supplied by Regeneron; used in Arm F consolidation for 8 cycles before maintenance therapy. |
| On Body Delivery System (OBDS) | DEVICE | Device: On Body Delivery System (OBDS) - Sanofi-Aventis device used with isatuximab administration; abdominal/periumbilical single-site application with post-dose needle retraction and lock-out. |
| Isatuximab IV | DRUG | Pharmaceutical form: Concentrate solution for IV infusion; Route of administration: Intravenous |
| Isatuximab SC | DRUG | Pharmaceutical form: Solution for subcutaneous administration; Route of administration: Subcutaneous (SC) |
| Pomalidomide | DRUG | Pharmaceutical form: hard capsules; Route of administration: Oral |
| Montelukast | DRUG | Pharmaceutical form: As per local commercial product; Route of administration: Oral; AxMP i.e., background treatment; ATC code: R03DC03 |
| Paracetamol / Acetaminophen | DRUG | Pharmaceutical form: As per local commercial product; Route of administration: Oral; AxMP i.e., background treatment; ATC code: N02BE01 |
| Diphenhydramine | DRUG | Pharmaceutical form: As per local commercial product; Route of administration: As premedication- oral; for management of infusion reactions-IV (or oral equivalent); AxMP i.e., background treatment and rescue medication (in case of infusion reactions); ATC code: R06AA02 |
| Methylprednisolone | DRUG | Pharmaceutical form: As per local commercial product; Route of administration: As premedication-IV; for management of infusion reactions- IV (or oral equivalent); AxMP i.e., background treatment and rescue medication (in case of infusion reactions); ATC code: H02AB04 |
| ASCT | PROCEDURE | ASCT for ams B, C and D during consolidation |
| Isatuximab SAR650984 | DRUG | Pharmaceutical for: Solution for infusion Route of administration: Intravenous |
| Lenalidomide | DRUG | Pharmaceutical form: Capsules Route of administration: Oral |
| Montelukast or equivalent | DRUG | Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: tablet; Route of administration: Oral; |
| Acetaminophen | DRUG | AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: tablet/ampule/capsule; Route of administration: Intravenous (IV) or per os (PO) |
| Diphenhydramine or equivalent | DRUG | AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: ampule; Route of administration: Intravenous |
| Methylprednisolone or equivalent | DRUG | AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: vial; Route of administration: Intravenous |
| Bortezomib | DRUG | Pharmaceutical form: Lyophilized powder for injection Route of administration: Subcutaneous |
| carfilzomib | DRUG | Pharmaceutical form: solution for infusion Route of administration: intravenous |
| Cemiplimab | DRUG | The treatment cycle will be repeated up to 2 years. If a patient shows disease progression or unacceptable toxicity, the study treatment will be discontinued and followed up for efficacy and safety after the discontinuation of study treatment. |
| Isatuximab SC-OBDS | DRUG | Pharmaceutical form:Solution for SC-OBDS administration-Route of administration:SC-OBDS |
| Dexamethasone IV | DRUG | Investigational medicinal product/background treatment; ATC code: H02AB02; Pharmaceutical form: Powder for solution for infusion; Route of administration: Intravenous |
| Isatuximab intravenous (IV) | DRUG | Route of administration: IV infusion; Pharmaceutical form: Vial |
| Cemiplimab (SAR439684) | DRUG | Route of administration: IV infusion; Pharmaceutical form: Vial |
| Isatuximab subcutaneous (SC) | DRUG | Route of administration: SC injection with the investigational isatuximab injector device; Pharmaceutical form: Vial |
| Standard Procedures | OTHER | Standard procedures (standard of care) for transplant |
| Dexamethasone (IV) | DRUG | Dexamethasone (IV on the days of Isatuximab and PO on other days): 20 mg/day on Days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22, 23, 25, 26, 29, 30, 32, and 33. If patients are ≥75 years old, dexamethasone will be administered on Days 1, 4, 8, 11, 15, 16, 22, 25, 29 and 32. |
| Isatuximab-Irfc 20 MG/ML [Sarclisa] | DRUG | Induction: 10mg/kg on day 1,8,15,22 in cycle 1, subsequently on day 1, 15; every 28 days (q28 days) Maintenance: 10mg/kg, day1, q28 days until progression or intolerance but for a maximum of 24 cycles from start of maintenance |
| Dexamethasone Oral | DRUG | Induction: Patients aged \<75 years: 40mg, once weekly; Patients aged ≥75 years: 20mg, once weekly |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow biopsy |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow aspiration |
| Skeletal Survey X-Ray | PROCEDURE | Undergo skeletal x-ray |
| Computed Tomography | PROCEDURE | Undergo CT |
| Positron Emission Tomography | PROCEDURE | Undergo PET-CT |
| Magnetic Resonance Imaging | PROCEDURE | Undergo MRI |
| Bortezomib Injection | DRUG | SQ Oral, predetermined dosage and predetermined days during each cycle |
| CellProtect | DRUG | In vitro expanded and activated autologous NK cells |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Bone Marrow Aspiration and Biopsy | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Cyclophosphamide | DRUG | Given IV |
| Echocardiography | PROCEDURE | Undergo echocardiography |
| Questionnaire Administration | OTHER | Ancillary study |
| Universal Donor Expanded TGF-beta-imprinted NK Cells | BIOLOGICAL | Given IV |
| Belantamab mafodotin | DRUG | Pharmaceutical form: Solution for infusion; Route of administration: Intravenous |
| Pegenzileukin | DRUG | Pharmaceutical form: Solution for infusion; Route of administration: Intravenous |
| SAR439459 | DRUG | Pharmaceutical form: Solution for injection; Route of administration: Intravenous |
| Belumosudil | DRUG | Pharmaceutical form: tablet; route of administration: oral |
| Evorpacept | DRUG | Pharmaceutical form: Solution for infusion; Route of administration: Intravenous |
| isatuximab SAR650984 IV | DRUG | Pharmaceutical form: solution Route of administration: intravenous |
| isatuximab SAR650984 SC | DRUG | Pharmaceutical form: solution Route of administration: subcutaneous |
| Investigational injector device | DEVICE | Subcutaneous administration |
| Cemiplimab REGN2810 | DRUG | Pharmaceutical form: solution for infusion Route of administration: intravenous |
Inclusion Criteria: * N- NDMM based on IMWG criteria with clonal bone marrow plasma cells ≥10% or biopsy proven bony or extramedullary disease/plasmacytoma (EMD) with any one or more CRAB-features or myeloma defining events (Rajkumar, 2024) (See Appendix E) * \- Age 18 - 75 years. (Patients aged 71...
Isatuximab is being studied in multiple myeloma, AL amyloidosis, aplastic anemia, lymphoma, monoclonal gammopathy, and other hematological malignancies. It is also being evaluated in relapsed or refractory CD38 positive T-cell acute lymphoblastic leukemia. The drug is an investigational monoclonal antibody and is not yet approved for these uses.
Isatuximab targets CD38, a protein found on the surface of myeloma cells and other immune cells. By binding to CD38, isatuximab acts as an inhibitor of CD38-mediated signaling and can trigger immune-mediated destruction of CD38-expressing cells. This mechanism underlies its development across plasma cell disorders and other hematological malignancies.
Isatuximab is being developed by Sanofi, which trades under the ticker SNY. Sanofi is the sponsor of the clinical trials evaluating isatuximab in multiple myeloma, AL amyloidosis, aplastic anemia, and other hematological conditions.
Isatuximab is in Phase 2 development for the indications listed, with additional Phase 1 and Phase 3 trials ongoing. It is an investigational agent and has not been approved by the FDA for these uses. The clinical program includes both completed and active studies.
Isatuximab is being evaluated in several clinical trials, including NCT07714512, a Phase 1/2 study in refractory severe aplastic anemia; NCT07624513, a Phase 3 study in transplant-eligible newly diagnosed multiple myeloma; NCT06648889, a Phase 2 study in relapsed/refractory CD38 positive T-cell acute lymphoblastic leukemia; and NCT06517017, a Phase 2 study in ultra-frail multiple myeloma patients.
Yes, isatuximab is also known by several alternative names, including isatuximab-irfc, SAR650984, and isatuximab SAR650984. These refer to the same monoclonal antibody developed by Sanofi. The different names reflect various formulations, routes of administration, or developmental codes used in research and clinical settings.