Phase 3 Randomized Study of Isatuximab with Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma Patients
- Trial ID
- 2023-507419-37-00
- Protocol
- EFC15992
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the clinical benefit of **isatuximab** in combination with lenalidomide and dexamethasone in patients with high-risk smoldering multiple myeloma. This is assessed by confirming the recommended dose of isatuximab when combined with lenalidomide and dexamethasone, and by demonstrating the prolongation of progression-free survival compared to lenalidomide and dexamethasone alone. This is clinically relevant as it may offer a more effective treatment option for patients with high-risk smoldering multiple myeloma, potentially delaying disease progression.
Secondary objectives include: - Assessing overall response rate (ORR) and duration of response (DOR) in the safety run-in part. - Evaluating minimal residual disease (MRD) negativity in participants achieving very good partial response (VGPR) or complete response (CR). - Assessing time to diagnostic (SLiM CRAB) progression or death, and time to first-line treatment for multiple myeloma (MM). - Evaluating the potential immunogenicity of isatuximab and the impact of abnormal chromosomal subtype on participant outcomes. - In the randomized Phase 3 part, comparing MRD negativity, sustained MRD negativity, second progression-free survival (PFS2), and overall survival between treatment arms. - Evaluating complete response (CR) rate, ORR, DOR, time to diagnostic progression, time to biochemical progression, and time to first-line treatment for MM in both arms. - Assessing the impact of abnormal chromosomal subtype on outcomes, safety and tolerability, pharmacokinetics (PK), potential immunogenicity of isatuximab, and clinical outcome assessments (COAs).
Participants
The clinical trial involves a total of **258 participants** diagnosed with high-risk **smoldering multiple myeloma**. The study population includes both male and female subjects, aged 18 years and older, with an **Eastern Cooperative Oncology Group (ECOG) Performance Status** of 0, 1, or 2. Participants were selected based on their diagnosis within the last five years, meeting specific criteria such as serum M-protein levels and clonal bone marrow plasma cells, without myeloma-defining events. The trial includes individuals capable of providing informed consent and meeting certain hematological and biochemical parameters. The study population is characterized by a diverse age range and includes a vulnerable population. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, multicenter study to evaluate the efficacy and safety of **isatuximab** in combination with **lenalidomide** and **dexamethasone** in patients with high-risk smoldering **multiple myeloma**. The trial consists of two parts: a safety run-in phase and a randomized Phase 3 part. The primary objective of the safety run-in phase is to confirm the recommended dose of isatuximab when combined with lenalidomide and dexamethasone. The randomized Phase 3 part aims to demonstrate the clinical benefit of the combination therapy in prolonging progression-free survival compared to lenalidomide and dexamethasone alone. The trial is expected to conclude by May 30, 2034, with recruitment having started on June 16, 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of smoldering multiple myeloma, and performance status. Follow-up visits will be scheduled to monitor treatment-emergent adverse events, plasma concentration of isatuximab, and progression-free survival. The end-of-study visit will evaluate the overall response rate, duration of response, and minimal residual disease negativity. The expected length of participant involvement varies, with the maximum treatment period for isatuximab being 36 months and for lenalidomide and dexamethasone being 24 months. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or disease progression.
Treatment
The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. The primary experimental medication is **Isatuximab**, a solution for infusion, administered intravenously. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 10 mg/kg and a total maximum dose of 500 mg/kg over a treatment period of up to 36 months. Isatuximab is provided by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR650984.
Another key experimental medication is **Lenalidomide**, available in hard capsule form under the brand names Revlimid and Zelvina, with varying strengths of 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. The capsules are administered orally, with a maximum daily dose of 25 mg and a total maximum dose of 7875 mg over a treatment period of up to 24 months. Lenalidomide is supplied by Bristol-Myers Squibb Pharma EEIG and Adalvo Limited.
**Dexamethasone** is used as a non-experimental treatment in the study. It is available in two forms: as a tablet (Dexamethason JENAPHARM®) and as a solution for injection (Dexamethasone 3.3 mg/ml solution for injection). The tablet form is administered orally, while the solution is administered intravenously. The maximum daily dose for both forms is 40 mg, with a total maximum dose of 2640 mg for the tablet form over a 24-month period and 40 mg for the injectable form over a 1-day period. The tablet is provided by MIBE GmbH Arzneimittel, and the injectable solution is provided by Hameln Pharma Ltd.
Additional non-experimental treatments include **Methylprednisolone acetate** combined with **Lidocaine hydrochloride monohydrate**, administered intravenously, and **Montelukast sodium**, administered orally. These treatments are used as auxiliary medications in the trial. The dosing for these auxiliary treatments is not specified due to the diversity of the ATC level selected.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. All medications are repackaged and relabeled for clinical supplies to maintain consistency and compliance with trial protocols.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint for the Randomized Phase 3 Part is **progression-free survival (PFS)**, which measures the length of time during and after the treatment that a patient lives with the disease without it getting worse. Secondary endpoints include **overall response rate (ORR)**, **duration of response (DOR)**, **minimal residual disease (MRD) negativity**, **time to diagnostic (SLiM CRAB) progression or death**, and **time to first-line treatment for multiple myeloma (MM)**, among others. These endpoints will be evaluated to determine the clinical benefit of isatuximab in combination with lenalidomide and dexamethasone compared to lenalidomide and dexamethasone alone in patients with high-risk smoldering multiple myeloma.
Data collection will involve measuring plasma concentration of isatuximab, receptor density/receptor occupancy, and the incidence of anti-drug antibodies (ADA) against isatuximab. The trial will also assess patient-reported outcomes using tools such as the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-MY20, EQ-5D-5L, and the Patient's Qualitative Assessment of Treatment Version 2 (PQAT-v2). These assessments will be conducted at various timepoints throughout the trial to ensure comprehensive evaluation of the treatment's efficacy and impact on quality of life.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant must be at least 18 years of age inclusive or older
- 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 × 109/L)
- Platelets ≥50,000/µL (50 × 109/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
- 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)
- -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): 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
- 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
- -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): Anemia (hemoglobin 2 g/dL below lower limit of normal or <10 g/dL or both). Transfusionsupport or concurrent treatment with erythropoietin stimulating agents is not permitted
- -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): ≥ 1 bone lytic lesion of ≥5mm in size
- -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): BMPCs ≥60%
- -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): Serum involved/uninvolved FLC ratio ≥100 and an involved FLC ≥100mg/L
- -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): 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)
- 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)
- Primary systemic and localized amyloid light chain (AL) amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), standard risk smoldering myeloma, soft-tissue plasmacytoma, and symptomatic myeloma
- Uncontrolled infection within 28 days prior to randomization in Phase 3 or first study intervention administration in safety run-in
- Patient can be eligible if anti-HBc Immunoglubolin 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
- 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)
- 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 ribonucleic acid (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
- Received treatment (eg surgery, radiotherapy, medication) for a malignancy within 3 years of randomization (or first study intervention administration in safety run-in cohort)
- Active hepatitis C virus (HCV) infection: positive HCV RNA and negative anti-HCV
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Not Recruiting | 16 Jun 2020 | 20 |
 Denmark | Not Recruiting | 16 Jun 2020 | 11 |
 France | Not Recruiting | 16 Jun 2020 | 40 |
 Germany | Not Recruiting | 16 Jun 2020 | 7 |
 Greece | Not Recruiting | 16 Jun 2020 | 36 |
 Hungary | Not Recruiting | 16 Jun 2020 | 12 |
 Italy | Not Recruiting | 16 Jun 2020 | 41 |
 Lithuania | Not Recruiting | 16 Jun 2020 | 10 |
 Norway | Not Recruiting | 16 Jun 2020 | 28 |
 Poland | Not Recruiting | 16 Jun 2020 | 18 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Revlimid 10 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264292 |
DIPHENHYDRAMINE | Other | PHF00245MIG | INTRAVENOUS | 0 | 1 | SCP1159503 |
Revlimid 20 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264307 |
Dexamethasone 3.3 mg/ml solution for injection | Test | SOLUTION FOR INJECTION | INTRAVENOUS USE | 40 | 1 | PRD302046 |
Zelvina 5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD8721745 |
Revlimid 10 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264283 |
Isatuximab | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 10 | 36 | PRD10652636 |
Revlimid 25 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264271 |
Zelvina 25 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD8721744 |
Revlimid 5 mg hard capsules | Test | HARD CAPSULES | ORAL USE | 25 | 24 | PRD9264284 |