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 SMMSecondary 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 outcomeRandomized Phase 3 Part:Key Secondary Objectives:To compare between the arms - MRD negativity - Sustained MRD negativity - Second progression-free survival (PFS2) - Overall survivalOther 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)
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.
Drug: Isatuximab SAR650984
Pharmaceutical for: Solution for infusion Route of administration: Intravenous
Other Name: Sarclisa
Drug: Lenalidomide
Pharmaceutical form: Capsules Route of administration: Oral
Drug: Dexamethasone
Pharmaceutical form: Tablets and solution for injection Route of administration: Oral and
intravenous
Drug: Montelukast or equivalent
Auxiliary Medicinal Product (AxMP)/pre-medication; ATC code: R03DC03; Pharmaceutical
form: tablet; Route of administration: Oral;
Drug: Acetaminophen
AxMP/pre-medication ATC code: N02BE01 Pharmaceutical form: tablet/ampule/capsule; Route
of administration: Intravenous (IV) or per os (PO)
Drug: Diphenhydramine or equivalent
AxMP/pre-medication ATC code: R06AA02 Pharmaceutical form: ampule; Route of
administration: Intravenous
Drug: Methylprednisolone or equivalent
AxMP/pre-medication; ATC code: H02AB04; Pharmaceutical form: vial; Route of
administration: Intravenous
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.
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
Sao 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 Kralove, Czechia
Investigational Site Number : 2030002
Olomouc, Czechia
Investigational Site Number : 2030003
Ostrava - Poruba, Czechia
Investigational Site Number : 2030001
Praha 2, 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 Cedex 9, 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 Cedex, France
Investigational Site Number :2500001
RENNES Cedex 09, 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 :3720003
Dublin 7, Dublin, Ireland
Investigational Site Number :3720002
Dublin 8, Dublin, Ireland
Investigational Site Number :3720001
Dublin 9, 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-shi, Aichi, Japan
Investigational Site Number :3920006
Kamogawa-shi, Chiba, Japan
Investigational Site Number :3920008
Maebashi-shi, Gunma, Japan
Investigational Site Number :3920005
Higashiibaraki-gun, Ibaraki, Japan
Investigational Site Number :3920003
Okayama-shi, Okayama, Japan
Investigational Site Number :3920009
Sunto-gun, Shizuoka, Japan
Investigational Site Number :3920001
Shibuya-ku, Tokyo, Japan
Investigational Site Number :4100004
Gangnam-gu, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :4100003
Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :4100001
Seoul, Seoul-teukbyeolsi, Korea, Republic of
Investigational Site Number :4100002
Seoul, Korea, Republic of
Investigational Site Number :4400001
Vilnius, Lithuania
Investigational Site Number :5540004
Christchurch, Canterbury, New Zealand
Investigational Site Number :5540001
Hamilton, Waikato, New Zealand
Investigational Site Number :5780002
Bergen, Norway
Investigational Site Number :5780001
Oslo, Norway
Investigational Site Number :6160006
Bydgoszcz, Kujawsko-pomorskie, Poland
Investigational Site Number :6160002
Lodz, Lódzkie, Poland
Investigational Site Number :6160008
Gdansk, Pomorskie, Poland
Investigational Site Number :6160005
Chorzow, Slaskie, Poland
Investigational Site Number :7240004
Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number :7240001
Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number :7240006
Pamplona, Navarra, 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
Göteborg, Sweden
Investigational Site Number :7520003
Helsingborg, Sweden
Investigational Site Number : 7920005
Ankara, Turkey
Investigational Site Number : 7920001
Ankara, Turkey
Investigational Site Number : 7920004
Istanbul, Turkey
Investigational Site Number : 7920002
Istanbul, Turkey
Investigational Site Number : 7920003
Izmir, Turkey
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
Clinical Sciences & Operations, Study Director
Sanofi