Isatuximab in Combination With Lenalidomide and Dexamethasone in High-risk Smoldering Multiple Myeloma

NCT ID: NCT04270409

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 337 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-06-16
• Study Completion Date: 2033-10-21

Brief Summary

Primary Objectives:

• Safety run-in Part: 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 Part: 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 Part:

• 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 chromosomal subtype on participant outcome

Randomized Phase 3 Part:

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
• Impact of abnormal chromosomal subtype on participant outcome
• Safety and tolerability
• Pharmacokinetics (PK)
• Potential of isatuximab immunogenicity
• Clinical outcome assessments (COAs)

Detailed Description

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.

Conditions

Plasma Cell Myeloma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Isatuximab, lenalidomide, and dexamethasone (ILd)

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.

Group Type: EXPERIMENTAL

Isatuximab SAR650984

Intervention Type: DRUG

Pharmaceutical for: Solution for infusion Route of administration: Intravenous

Lenalidomide

Intervention Type: DRUG

Pharmaceutical form: Capsules Route of administration: Oral

Dexamethasone

Intervention Type: DRUG

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

Montelukast or equivalent

Intervention Type: DRUG

Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: tablet; Route of administration: Oral;

Acetaminophen

Intervention Type: DRUG

AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: tablet/ampule/capsule; Route of administration: Intravenous (IV) or per os (PO)

Diphenhydramine or equivalent

Intervention Type: DRUG

AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: ampule; Route of administration: Intravenous

Methylprednisolone or equivalent

Intervention Type: DRUG

AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: vial; Route of administration: Intravenous

Lenalidomide and dexamethasone (Ld)

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

Group Type: ACTIVE_COMPARATOR

Lenalidomide

Intervention Type: DRUG

Pharmaceutical form: Capsules Route of administration: Oral

Dexamethasone

Intervention Type: DRUG

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

Interventions

Isatuximab SAR650984

Pharmaceutical for: Solution for infusion Route of administration: Intravenous

Intervention Type: DRUG

Lenalidomide

Pharmaceutical form: Capsules Route of administration: Oral

Intervention Type: DRUG

Dexamethasone

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

Intervention Type: DRUG

Montelukast or equivalent

Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical form: tablet; Route of administration: Oral;

Intervention Type: DRUG

Acetaminophen

AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: tablet/ampule/capsule; Route of administration: Intravenous (IV) or per os (PO)

Intervention Type: DRUG

Diphenhydramine or equivalent

AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: ampule; Route of administration: Intravenous

Intervention Type: DRUG

Methylprednisolone or equivalent

AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: vial; Route of administration: Intravenous

Intervention Type: DRUG

Other Intervention Names

Sarclisa

Eligibility Criteria

Inclusion Criteria

• Participants who are diagnosed within 5 years with SMM (per International Myeloma Working Group [IMWG] criteria), defined as serum M-protein ≥30 g/L or urinary M-protein ≥500 mg per 24 hour or both, and/or clonal bone marrow plasma cells (BMPCs) 10% to <60%, and absence of myeloma defining events or other related conditions and with high-risk SMM
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 or 2
• Capable of giving voluntary written informed consent
• Absolute neutrophil count (ANC) ≥1000/µL (1 × 10^9/L)
• Platelets ≥50,000/µL (50 × 10^9/L)
• Total bilirubin ≤3 mg/dL (except Gilbert syndrome, in which direct bilirubin should be -≤5 mg/dL).
• Alanine aminotransferase ≤3× upper limit of normal (ULN), aspartate aminotransferase ≤ 3 × ULN.

Exclusion Criteria

• Evidence of any of the following calcium, renal failure, anemia, bone lesions (CRAB) criteria or Myeloma Defining Events (SLiM CRAB) detailed below (attributable to the participants SMM involvement):

• Increased calcium levels: Corrected serum calcium >1 mg/dL above the ULN or >11 mg/dL
• Renal insufficiency: Determined by glomerular filtration rate (GFR) <40 mL/min/1.73 m² (Modification of Diet in Renal Disease [MDRD] Formula) or serum creatinine >2 mg/dL
• Anemia (hemoglobin 2 g/dL below lower limit of normal or <10 g/dL or both) transfusion support or concurrent treatment with erythropoietin stimulating agents is not permitted
• ≥ 1 bone lytic lesion
• BMPCs ≥60%
• Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L
• Whole body magnetic resonance imaging (WB-MRI) or positron emission tomography-computed tomography (PET-CT) with more than 1 bone focal lesion (≥5 mm in diameter by MRI)
• Primary systemic amyloid light-chain (AL) amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering myeloma, soft tissue plasmacytoma, symptomatic myeloma
• Uncontrolled infection within 28 days prior to randomization in Phase 3 or first study intervention administration in safety run-in
• Clinically significant cardiac or vascular disease within 3 months prior to randomization, e.g. Myocardial Infarction; Unstable Angina; Coronary (e.g. Coronary Artery Bypass Graft, Percutaneous Coronary Intervention) or peripheral artery revascularization, Left Ventricular Ejection Fraction <40%, Heart Failure NYHA III-IV, Stroke, Transient Ischemic Attack, Pulmonary Embolism, other thromboembolic event, cardiac arrhythmia (Grade 3 or higher by NCI-CTCAE Version 5.0)
• Known acquired immunodeficiency syndrome (AIDS)-related illness or known human immunodeficiency virus (HIV) disease requiring antiviral treatment or active hepatitis A (defined as positive hepatitis A antigen or positive IgM). HIV serology at screening will be tested for German participants and any other country where required as per local regulations and serology hepatitis B and C at screening will be tested for all participants
• Uncontrolled or active hepatitis B virus (HBV) infection: Patients with positive Hepatitis B surface antigen (HBsAg) and/or HBV Deoxyribonucleic acid (DNA)

Of note:

• Patient can be eligible if anti-HBc Immunoglobulin G (IgG) positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. If anti-HBV therapy in relation with prior infection was started before initiation of IMP, the anti-HBV therapy and monitoring should continue throughout the study treatment period.
• Patients with negative HBsAg and positive HBV DNA observed during screening period will be evaluated by a specialist for start of anti-viral treatment: study treatment could be proposed if HBV DNA becomes negative and all the other study criteria are still met.
• Active hepatitis C virus (HCV) infection: positive HCV ribonucleic acid (RNA) and negative anti-HCV

Of note:

• Patients with antiviral therapy for HCV started before initiation of IMP and positive HCV antibodies are eligible. The antiviral therapy for HCV should continue throughout the treatment period until seroconversion.
• Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for HCV are eligible
• Malabsorption syndrome or any condition that can significantly impact the absorption of lenalidomide
• Any of the following within 3 months prior to randomization (or first study intervention administration in safety run-in cohort): treatment resistant peptic ulcer disease, erosive esophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism, or other uncontrolled thromboembolic event
• Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3 years of randomization (or first study intervention administration in safety run-in cohort)
• Prior exposure to approved or investigational treatments for SMM or multiple myeloma (MM) (including but not limited to conventional chemotherapies, immunomodulatory imid drugs, or Proteasome inhibitors); concurrent use of bisphosphonates or receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor denosumab is not permitted; however, prior bisphosphonates or once-a-year intravenous bisphosphonate given for the treatment of osteoporosis is permitted
• Ongoing treatment with corticosteroids with a dose >10 mg prednisone or equivalent per day at the time of randomization (or first study intervention administration in safety run-in cohort)
• Women of childbearing potential or male participant with women of childbearing potential who do not agree to use a highly effective method of birth control
• Vaccination with a live vaccine 4 weeks before the start of the study drug. Seasonal flu vaccines that do not contain live virus are permitted

The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

UCLA Site Number : 8400010

Los Angeles, California, United States

Colorado Blood Cancer Institute Site Number : 8400007

Denver, Colorado, United States

Cancer Specialist of North Florida Site Number : 8400011

Jacksonville, Florida, United States

University of Miami Site Number : 8400012

Miami, Florida, United States

Dana Farber Cancer Institute Site Number : 8400001

Boston, Massachusetts, United States

Presbyterian Hospital Site Number : 8400015

Charlotte, North Carolina, United States

Novant Health Forsyth Medical Center Site Number : 8401015

Winston-Salem, North Carolina, United States

Tennessee Oncology Site Number : 8400006

Nashville, Tennessee, United States

~University of Texas - MD Anderson Cancer Center Site Number : 8400002

Houston, Texas, United States

Investigational Site Number :0360008

Liverpool, New South Wales, Australia

Investigational Site Number :0360005

Waratah, New South Wales, Australia

Investigational Site Number :0360001

Wollongong, New South Wales, Australia

Investigational Site Number :0360002

Fitzroy, Victoria, Australia

Investigational Site Number :0360007

Heidelberg West, Victoria, Australia

Investigational Site Number :0360004

Richmond, Victoria, Australia

Investigational Site Number :0360006

Nedlands, Western Australia, Australia

Investigational Site Number :0760002

São Paulo, São Paulo, Brazil

Investigational Site Number :1240004

Edmonton, Alberta, Canada

Investigational Site Number :1240005

Moncton, New Brunswick, Canada

Investigational Site Number :1240001

Montreal, Quebec, Canada

Investigational Site Number :1560002

Hangzhou, , China

Investigational Site Number :1560003

Hangzhou, , China

Investigational Site Number :1560006

Nanchang, , China

Investigational Site Number :1560004

Shanghai, , China

Investigational Site Number :1560005

Shenyang, , China

Investigational Site Number :1560001

Tianjin, , China

Investigational Site Number : 2030004

Brno, , Czechia

Investigational Site Number : 2030005

Hradec Králové, , Czechia

Investigational Site Number : 2030002

Olomouc, , Czechia

Investigational Site Number : 2030003

Ostrava - Poruba, , Czechia

Investigational Site Number : 2030001

Prague, , Czechia

Investigational Site Number :2080001

Aalborg, , Denmark

Investigational Site Number :2080003

Aarhus N, , Denmark

Investigational Site Number :2080005

Copenhagen, , Denmark

Investigational Site Number :2080002

Roskilde, , Denmark

Investigational Site Number :2500009

Ars-Laquenexy, , France

Investigational Site Number :2500010

Bayonne, , France

Investigational Site Number :2500007

Grenoble, , France

Investigational Site Number :2500006

La Roche-sur-Yon, , France

Investigational Site Number :2500003

Lille, , France

Investigational Site Number :2500005

Paris, , France

Investigational Site Number :2500011

Paris, , France

Investigational Site Number :2500002

Poitiers, , France

Investigational Site Number :2500001

Rennes, , France

Investigational Site Number :2760001

Hamburg, , Germany

Investigational Site Number :2760002

Heidelberg, , Germany

Investigational Site Number :3000002

Athens, , Greece

Investigational Site Number :3000001

Athens, , Greece

Investigational Site Number :3000003

Thessaloniki, , Greece

Investigational Site Number :3480003

Budapest, , Hungary

Investigational Site Number :3480001

Budapest, , Hungary

Investigational Site Number :3480002

Debrecen, , Hungary

Investigational Site Number :3480004

Kaposvár, , Hungary

Investigational Site Number :3720001

Dublin, Dublin, Ireland

Investigational Site Number :3720002

Dublin, Dublin, Ireland

Investigational Site Number :3720003

Dublin, Dublin, Ireland

Investigational Site Number :3760004

Ashdod, , Israel

Investigational Site Number :3760001

Jerusalem, , Israel

Investigational Site Number :3760002

Jerusalem, , Israel

Investigational Site Number :3760005

Petah Tikva, , Israel

Investigational Site Number :3760006

Ramat Gan, , Israel

Investigational Site Number :3760003

Tel Aviv, , Israel

Investigational Site Number :3800006

Meldola, Forlì-Cesena, Italy

Investigational Site Number :3800001

Rozzano, Milano, Italy

Investigational Site Number :3800005

Ancona, , Italy

Investigational Site Number :3800003

Bologna, , Italy

Investigational Site Number :3800002

Terni, , Italy

Investigational Site Number :3920002

Nagoya, Aichi-ken, Japan

Investigational Site Number :3920006

Kamogawa-shi, Chiba, Japan

Investigational Site Number :3920008

Maebashi, Gunma, Japan

Investigational Site Number :3920005

Higashiibaraki-gun, Ibaraki, Japan

Investigational Site Number :3920003

Okayama, Okayama-ken, Japan

Investigational Site Number :3920009

Sunto-gun, Shizuoka, Japan

Investigational Site Number :3920001

Shibuya-ku, Tokyo, Japan

Investigational Site Number :4400001

Vilnius, , Lithuania

Investigational Site Number :5540004

Christchurch, Canterbury, New Zealand

Investigational Site Number :5540001

Hamilton, Waikato Region, New Zealand

Investigational Site Number :5780002

Bergen, , Norway

Investigational Site Number :5780001

Oslo, , Norway

Investigational Site Number :6160006

Bydgoszcz, Kuyavian-Pomeranian Voivodeship, Poland

Investigational Site Number :6160002

Lodz, Lódzkie, Poland

Investigational Site Number :6160008

Gdansk, Pomeranian Voivodeship, Poland

Investigational Site Number :6160005

Chorzów, Silesian Voivodeship, Poland

Investigational Site Number :4100004

Gangnam-gu, Seoul-teukbyeolsi, South Korea

Investigational Site Number :4100003

Seoul, Seoul-teukbyeolsi, South Korea

Investigational Site Number :4100001

Seoul, Seoul-teukbyeolsi, South Korea

Investigational Site Number :4100002

Seoul, , South Korea

Investigational Site Number :7240004

Barcelona, Barcelona [Barcelona], Spain

Investigational Site Number :7240001

Barcelona, Barcelona [Barcelona], Spain

Investigational Site Number :7240006

Pamplona, Navarre, Spain

Investigational Site Number :7240002

Valencia, Valenciana, Comunidad, Spain

Investigational Site Number :7240005

Madrid, , Spain

Investigational Site Number :7240007

Salamanca, , Spain

Investigational Site Number :7240003

Zaragoza, , Spain

Investigational Site Number :7520001

Gothenburg, , Sweden

Investigational Site Number :7520003

Helsingborg, , Sweden

Investigational Site Number : 7920005

Ankara, , Turkey (Türkiye)

Investigational Site Number : 7920001

Ankara, , Turkey (Türkiye)

Investigational Site Number : 7920004

Istanbul, , Turkey (Türkiye)

Investigational Site Number : 7920002

Istanbul, , Turkey (Türkiye)

Investigational Site Number : 7920003

Izmir, , Turkey (Türkiye)

Investigational Site Number :8260002

Bournemouth, Hampshire, United Kingdom

Investigational Site Number :8260003

London, London, City of, United Kingdom

Investigational Site Number :8260001

Leicester, , United Kingdom

Investigational Site Number :8260004

Southampton, , United Kingdom

Countries

United States; Australia; Brazil; Canada; China; Czechia; Denmark; France; Germany; Greece; Hungary; Ireland; Israel; Italy; Japan; Lithuania; New Zealand; Norway; Poland; South Korea; Spain; Sweden; Turkey (Türkiye); United Kingdom

Related Links

https://www.trialsummaries.com/Study/StudyDetails?id=25236&tenant=MT_SNY_9011

EFC15992 Plain Language Results Summaries

Other Identifiers

U1111-1222-7068

Identifier Type: REGISTRY

Identifier Source: secondary_id

2023-507419-37

Identifier Type: REGISTRY

Identifier Source: secondary_id

2019-003139-47

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EFC15992

Identifier Type: -

Identifier Source: org_study_id