Primary Objective: -To demonstrate the benefit of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone in the prolongation of progression free survival (PFS) as compared to bortezomib, lenalidomide, and dexamethasone, in participants with newly diagnosed multiple myeloma (NDMM) not eligible for transplant. Secondary Objectives: * To evaluate in both randomized (isatuximab, bortezomib, lenalidomide and dexamethasone combination (IVRd) and bortezomib, lenalidomide and dexamethasone combination (VRd)) arms: * Complete response (CR) rate, as defined by the International Myeloma Working Group (IMWG) criteria. * Minimal residual disease (MRD) negativity rate in participants with CR. * Very good partial response or better rate, as defined by the IMWG criteria. * Overall survival (OS). * To evaluate the overall response rate (ORR) as per IMWG criteria. * To evaluate the time to progression (TTP) overall and by MRD status. * To evaluate PFS by MRD status. * To evaluate the duration of response (DOR) overall and by MRD status. * To evaluate time to first response (TT1R). * To evaluate time to best response (TTBR). * To evaluate progression-free survival on next line of therapy (PFS2). * To evaluate the sustained MRD negativity \>12 months rate. * To evaluate safety. * To determine the pharmacokinetic (PK) profile of isatuximab in combination with bortezomib, lenalidomide, and dexamethasone (IVRd arm only). * To evaluate the immunogenicity of isatuximab in participants receiving isatuximab (IVRd and crossover arms). * To assess disease-specific and generic health-related quality of life (HRQL), disease and treatment-related symptoms, health state utility, and health status.
The duration of the study for each participant will include a screening period of up to 4 weeks, an induction period of 24 weeks (4 cycles with a duration of 42 ± 3 days), a continuous treatment period and a crossover period (when applicable). The cycle duration is 28 ± 3 days during the continuous treatment and crossover periods.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
475
Pharmaceutical form: Solution for infusion Route of administration: Intravenous (IV)
Pharmaceutical form: Lyophilized powder for injection Route of administration: Subcutaneous
Pharmaceutical form: Capsules Route of administration: Oral
Pharmaceutical form: Tablets, ampoules or vials for injection Route of administration: Oral/Intravenous
Investigational Site Number: 8400006
Fort Myers, Florida, United States
Investigational Site Number: 8400004
St. Petersburg, Florida, United States
Investigational Site Number: 8400007
Kansas City, Missouri, United States
Investigational Site Number: 8400005
Nashville, Tennessee, United States
Investigational Site Number: 8400001
Houston, Texas, United States
Progression free survival (PFS)
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 frame: Up to approximately 100 months after the First Participant In (FPI)
Complete response rate (CR)
Defined as the proportion of participants with CR and stringent complete response (sCR) as assessed by the IRC using the IMWG criteria.
Time frame: Up to approximately 100 months after the FPI
Minimal residual disease (MRD) negativity rate for participants with CR
Proportion of participants with CR for whom MRD measurement is negative
Time frame: Up to approximately 100 months after the FPI
Very good partial response (VGPR) or better rate
Proportion of participants with sCR, CR and VGPR as assessed by the IRC using the International Myeloma Working Group (IMWG) criteria
Time frame: Up to approximately 100 months after the FPI
Overall survival (OS)
Defined as the time from the date of randomization to death from any cause
Time frame: Up to approximately 110 months after the FPI
Overall response rate (ORR)
Proportion of participants with best overall response (BOR) recorded as sCR, CR, VGPR, or partial response (PR) as assessed by the IRC using the IMWG criteria
Time frame: Up to approximately 100 months after the FPI assessment
Time to progression (TTP)
Defined as the time from randomization to date of first documentation of PD as assessed by the IRC using the IMWG criteria
Time frame: Up to approximately 100 months after FPI
Duration of response (DOR)
Defined as the time from date of first IRC determined response to date of first IRC PD or death, whichever occurs first for participants achieving sCR, CR, VGPR, or PR
Time frame: Up to approximately 100 months after the FPI
Time to first response (TT1R)
Time from randomization to the first IRC determined response (PR or better) that is subsequently confirmed
Time frame: Up to approximately 100 months after the FPI
Time to best response (TTBR)
Defined as the time from randomization to the date of first occurrence of IRC determined best response (PR or better) that is subsequently confirmed
Time frame: Up to approximately 100 months after the FPI
PFS on next line of therapy (PFS2)
Defined as the time from randomization to the date of first documentation of disease progression (as assessed by investigator) after initiation of further anti-myeloma treatment, or death from any cause, whichever occurs first
Time frame: Up to approximately 110 months after the FPI
PFS in MRD negative participants
Defined as the time from the date of randomization to the date of first documentation of PD or the date of death from any cause, whichever comes first in MRD negative participants
Time frame: Up to approximately 100 months after the FPI
Sustained MRD negativity ≥12 months rate
Defined as the proportion of participants with the maintenance of MRD negativity confirmed ≥12 months apart with no MRD positive test in between.
Time frame: Up to approximately 100 months after the FPI
Adverse Events
Treatment-emergent adverse events/serious adverse events (TEAEs/SAEs) including infusion associated reactions (IARs), second primary malignancies, laboratory parameters, vital signs, weight, ECOG PS, and findings from physical examination
Time frame: Up to 30 days after end of treatment (EOT) visit
Assessment of PK parameter: Ctrough
Isatuximab: Pre-dose plasma isatuximab concentration (Ctrough)
Time frame: Cycle 1 Day 8/Day 15/Day 29 (pre-dose) and Day 1 (pre-dose) of Cycle 2, 3, 4, 5, 6, 7, 8, 9 and 10 (Duration of each cycle for Cycles 1-4: 6 weeks; Duration of each cycle for Cycles 5-10: 4 weeks)
Immunogenicity
Presence of anti-drug antibodies against isatuximab
Time frame: Up to approximately 100 months after the FPI
participants reported outcome (PRO): QLQ-C30
Disease-specific HRQL will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30)
Time frame: Up to approximately 100 months after the FPI
PRO: QLQ-MY20
Disease- and treatment-related quality of life will be assessed using the EORTC myeloma module (QLQ-MY20) questionnaire
Time frame: Up to approximately 100 months after the FPI
PRO: EQ-5D-5L
Health state utility and health status will be assessed using the European Quality of Life Group questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L)
Time frame: Up to approximately 100 months after the FPI
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Investigational Site Number : 0360003
Liverpool, New South Wales, Australia
Investigational Site Number : 0360001
Waratah, New South Wales, Australia
Investigational Site Number : 0360002
Wollongong, New South Wales, Australia
Investigational Site Number : 0360007
South Brisbane, Queensland, Australia
Investigational Site Number : 0360005
Clayton, Victoria, Australia
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