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 (ITHACA)

  • End date
    Oct 1, 2033
  • participants needed
  • sponsor
Updated on 8 July 2022
bone marrow procedure
neutrophil count


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

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 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 10 years, including a 28-day screening period, followed by an up to 36-month treatment period, and a follow-up period of approximately 7 years.

Condition Plasma Cell Myeloma
Treatment Dexamethasone, Lenalidomide, isatuximab SAR650984
Clinical Study IdentifierNCT04270409
Last Modified on8 July 2022


Yes No Not Sure

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

Exclusion Criteria

≥ 1 bone lytic lesion
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
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)
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
Primary systemic amyloid light-chain (immunoglobulin light chain) amyloidosis
monoclonal gammopathy of undetermined significance (MGUS), standard risk
BMPCs ≥60%
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 disease, including
Myocardial infarction within 6 months with left ventricular dysfunction or uncontrolled ischemic cardiac disease before Cycle 1 Day 1, or unstable or uncontrolled disease/condition related to or affecting cardiac function (eg, unstable angina, congestive heart failure, New York Heart Association Class III-IV)
Uncontrolled cardiac arrhythmia (Grade 2 or higher by NCI-CTCAE Version 5.0) or clinically significant electrocardiogram (ECG) abnormalities
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
throughout the study treatment period
at screening will be tested for all participants
Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA
Of note
Patient can be eligible if anti-HBc 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
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 HCV infection: positive HCV 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
Prior exposure to approved or investigational treatments for SMM or 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
The above information is not intended to contain all considerations relevant to a potential
participation in a clinical trial
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
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