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Smoldering Multiple Myeloma

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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 \[PO administration\] in combination with dexamethasone \[PO administration\] for 24 cycles. 1 cycle = 28 days

Pharmaceutical for: Solution for infusion Route of administration: Intravenous

Isatuximab SAR650984

Pharmaceutical form: Capsules Route of administration: Oral

Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and intravenous

Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: As per local commercial product; Route of administration: Oral;

Montelukast or equivalent

AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: As per local commercial product; Route of administration: Oral

AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: As per local commercial product; Route of administration: Intravenous

Diphenhydramine or equivalent

AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: As per local commercial product; Route of administration: Intravenous

Methylprednisolone or equivalent

Clinical Sciences & Operations

Primary Objectives:

* Safety run-in: To confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone in participants with high-risk smoldering multiple myeloma (SMM)
* Randomized Phase 3: To demonstrate the clinical benefit of isatuximab in combination with lenalidomide and dexamethasone in the prolongation of progression-free survival when compared to lenalidomide and dexamethasone in subjects with high-risk SMM

Secondary Objectives:

Safety run-in

* To assess overall response rate (ORR)
* To assess duration of response (DOR)
* To assess minimal residual disease (MRD) negativity in participants achieving very good partial response (VGPR) or complete response (CR)
* To assess time to diagnostic (SLiM CRAB) progression or death
* To assess time to first-line treatment for multiple myeloma (MM)
* To assess the potential immunogenicity of isatuximab
* Impact of abnormal cytogenetic subtype on participant outcome

Randomized Phase 3 - Key Secondary Objectives:

To compare between the arms

* MRD negativity
* Sustained MRD negativity
* Second progression-free survival (PFS2)
* Overall survival

Other Secondary Objectives:

To evaluate in both arms

* CR rate
* ORR
* DOR
* Time to diagnostic (SLiM CRAB) progression
* Time to biochemical progression
* Time to first-line treatment for MM
* Safety and tolerability
* Pharmacokinetics (PK)
* Potential of isatuximab immunogenicity
* Clinical outcome assessments (COAs)

Study duration is expected to be approximately 12 years, including a 42-day screening period, followed by an up to 36-month treatment period, and a follow-up period of approximately 9 years.

A Phase 3 Randomized, Open-label, Multicenter Study of Isatuximab (SAR650984) in Combination With Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients With High-risk Smoldering Multiple Myeloma

A Phase 3 Randomized, Open Label, Multicenter Study of Isatuximab (SAR650984) in Combination With Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Patients With High-risk Smoldering Multiple Myeloma

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Maximum concentration observed after the first infusion (Cmax)

Change in CD38 receptor occupancy from baseline

Time from randomization to MM (SLiM CRAB criteria) or other related conditions based on independent review committee assessment according to 2014 International Myeloma Working Group (IMWG) criteria or death from any cause, whichever happens first

Proportion of participants with best overall response recorded as partial response or better according to 2016 IMWG criteria

Time from the date of the first response to date of progressive disease or death, whichever happens first

Number of participants for whom MRD is negative

Time from randomization to diagnosis of SLiM-CRAB or other related conditions, progression, or death from any cause

Time from randomization to first-line treatment for MM

Number of participants with anti-drug antibodies against isatuximab

Number of participants with sustained MRD negativity (sample is still negative at least 1 year after the first negativity assessment)

Time from randomization to date of second objective progressive disease or death from any cause

Time from date of randomization to death from any cause

Association of cytogenetic abnormalities with survival outcomes

Percentage of particpants with a CR as defined by 2016 IMWG response criteria

Time to biochemical progression is defined as the time from randomization to the date of biochemical progression based on IRC assessment.

Concentration observed just before treatment administration during repeated dosing (Ctrough) after IV administration

Mean change from baseline scores will be assessed, with responses ranging from 1=not at all to 4=very much or 1=very poor to 7=excellent; higher scores represent a better level of physical functioning

Mean change from baseline in scores will be assessed using a 4-point scale, with responses ranging from 1=not at all to 4=very much; higher scores represent better perspectives of the future and higher level of symptomatology

Mean change from baseline scores will be assessed from 5 items, with responses ranging from 'no' to 'extreme problems'; health state utility values (HSUVs) are generated by multiplying the item scores by country specific value sets; health status is assessed via a VAS; higher scores = higher HSUV/health status

Mean change from baseline in Health resource utilization and productivity questionnaire (HRUPQ) scores. HRUPQ will assess health care resource utilization of HRSM and the impact of HRSM on employment/work higher scores = greater impact on work/productivity, resources

Patient's qualitative assessment of treatment will be assessed using a 10 point visual analogue/numeric rating scale with response anchors of 'not beneficial at all' to 'extremely beneficial'; higher scores represent greater patient-perceived benefits of treatment

Spots Global Cancer Trial Database for montelukast or equivalent