Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Isatuximab · 21 trials · 21 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.
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.
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).
The percentage of subjects with 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.
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.
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.
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)
| Arm | Type | Description |
|---|---|---|
| Arm A (Induction and screening) | OTHER | All enrolled participants begin with Step 1 induction for 8 28-day cycles before end-of-induction cohort assignment. PBSC mobilization/collection is planned between Cycles 4-6 for participants without progression. End-of-induction MRD/response and risk status determine whether participants proceed to 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 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 at Step 3 evaluation (unless 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: 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. 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 be 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. |
| 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). |
| 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. |
| 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. |
| Combination Treatment | EXPERIMENTAL | Isatuximab |
| 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, defined as bone marrow infiltration of ≥5% (R/R T-ALL). 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). |
| 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. |
| 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. |
| 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 |
| 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. |
| Name | Type | Description |
|---|---|---|
| Isatuximab | DRUG | Supplied by Sanofi-Aventis (Sanofi); used in induction and maintenance/consolidation strategies in this protocol; administered subcutaneously 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 |
| 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. |
| Carfilzomib | DRUG | Investigational medicinal product; Pharmaceutical form: Powder for solution for infusion; Route of administration: Intravenous |
| Dexamethasone IV | DRUG | Investigational medicinal product/background treatment; ATC code: H02AB02; Pharmaceutical form: Powder for solution for infusion; Route of administration: Intravenous |
| Acetaminophen | DRUG | Background Treatment; ATC code: N02BE01; Pharmaceutical form: As per local commercial product; Route of administration: Oral or intravenous (IV) |
| Isatuximab intravenous (IV) | DRUG | Route of administration: IV infusion; Pharmaceutical form: Vial |
| Cemiplimab (SAR439684) | DRUG | Route of administration: IV infusion; Pharmaceutical form: Vial |
| Lenalidomide | DRUG | Route of administration: Oral; Pharmaceutical form: Capsules |
| 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 |
| Bortezomib | DRUG | Bortezomib (SQ): 1.3 mg/m² on Days 1, 4, 8, 11, 22, 25, 29, and 32. |
| 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. |
| 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 |
| 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 |
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...
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