Phase 3 Study Evaluating Elranatamab-Lenalidomide Efficacy in Newly Diagnosed Multiple Myeloma Compared to Standard Chemotherapy and Maintenance Therapy
- Trial ID
- 2024-516418-39-00
- Protocol
- IFM2025-01
Trial statistics
Diseases & Conditions
Objectives
The primary objectives of this phase 3, open-label, controlled, randomized study are to evaluate the efficacy of **elranatamab** and **lenalidomide** in the treatment of newly diagnosed **Multiple Myeloma**. Specifically, the study aims to determine if consolidation therapy with elranatamab and lenalidomide is superior to the standard of care in achieving a higher rate of minimal residual disease (MRD) negativity. Additionally, it seeks to assess whether maintenance therapy with elranatamab is superior to the standard of care in terms of progression-free survival (PFS). These objectives are clinically relevant as they address the potential for improved treatment outcomes and long-term disease control in multiple myeloma patients.
Secondary objectives include: - Assessing whether consolidation therapy with elranatamab and lenalidomide is superior in terms of PFS. - Evaluating if this consolidation therapy is superior to the standard of care in terms of overall survival (OS). - Comparing the efficacy of consolidation therapy with elranatamab and lenalidomide to the standard of care. - Assessing the efficacy of maintenance therapy with elranatamab. - Evaluating safety during induction, consolidation, and maintenance therapy. - Evaluating the impact of treatment on health-related quality of life (QoL).
Participants
The clinical trial involves participants diagnosed with **Multiple Myeloma**, specifically those newly diagnosed and eligible for high-dose chemotherapy and autologous stem cell transplantation. The study population includes both male and female subjects aged between 18 and 69 years. Participants are required to have a documented symptomatic condition according to CRAB and/or SLIM criteria, with measurable disease. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group performance status of 2 or less and meet specific clinical laboratory values within 15 days of initiating induction therapy. Lifestyle factors such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is a **randomized**, **controlled**, open-label, phase 3 study designed to evaluate the efficacy and safety of a combination therapy involving **elranatamab** and **lenalidomide** in patients with newly diagnosed **multiple myeloma**. The trial aims to assess whether this combination is superior to the standard of care in terms of minimal residual disease (MRD) negativity rate and progression-free survival (PFS). The study is expected to commence on March 15, 2025, and conclude by March 15, 2036, with an estimated participant involvement duration of up to 11 years.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and laboratory values. Following successful screening, participants will be randomized into treatment groups. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will occur at the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term effects of the treatment.
The trial will involve regular monitoring and assessments, including MRD status using next-generation sequencing (NGS) and PFS evaluations. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will also assess secondary endpoints such as overall response rate (ORR), very good partial response (VGPR) rate, complete response (CR) rate, and quality of life (QoL) using standardized questionnaires. The study will ensure rigorous adherence to ethical standards and regulatory requirements throughout its duration.
Treatment
The clinical trial involves several treatments, including both experimental and comparator medications. **Elranatamab**, marketed as ELREXFIO 40 mg/mL solution for injection, is a test medication in this study. It is a protein-based therapeutic agent administered via **subcutaneous injection**. The maximum daily dose is 32 mg, with a total dose limit of 44 mg over a treatment period of 2 days. Another formulation of ELREXFIO allows for a maximum daily dose of 76 mg and a total dose of 3344 mg over 30 days. This medication is sourced from Pfizer Europe MA EEIG.
**Lenalidomide** is used in two forms: 10 mg and 25 mg hard capsules. Both forms are administered **orally**. The 10 mg capsules have a maximum daily dose of 15 mg and a total dose of 8.5 g over 29 days, while the 25 mg capsules have a maximum daily dose of 25 mg and a total dose of 3150 mg over 6 days. Lenalidomide is provided by Wockhardt UK Ltd.
**Bortezomib**, marketed as a 3.5 mg powder for solution for injection, is administered via **subcutaneous injection**. The maximum daily dose is 1.3 mg/m², with a total dose of 31.2 mg/m² over a 40-day period. This chemical-based medication is supplied by Aspire Pharma (Malta) Limited.
**Human Normal Immunoglobulin**, marketed as Privigen 100 mg/mL solution for infusion, is administered through **intravascular use**. The maximum daily dose is 400 mg/kg, with a total dose of 16000 mg/kg over 120 days. This blood-derived product is provided by CSL Behring GmbH.
**Daratumumab**, marketed as DARZALEX 1800 mg solution for injection, is administered via **subcutaneous injection**. The maximum daily dose is 1800 mg, with a total dose of 28.8 g over 24 days. This protein-based medication is supplied by Janssen-Cilag International NV.
**Dexamethasone** is provided in the form of 20 mg tablets, administered **orally**. The maximum daily dose is 20 mg, with a total dose of 1120 mg over 24 days. This chemical-based medication is sourced from Manx Healthcare Ltd.
These treatments are part of a phase 3, open-label, controlled, randomized study aimed at evaluating the efficacy and safety of the elranatamab-lenalidomide combination in treating newly diagnosed multiple myeloma. The study compares this combination to standard-of-care therapies in both consolidation and maintenance phases.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **MRD negativity rate** as determined by next-generation sequencing (NGS) with a sensitivity of at least 10-5, measured at the end of the consolidation phase, and **PFS R2**, defined as the time interval from the date of second randomization to the date of confirmed progressive disease (PD) according to the International Myeloma Working Group (IMWG) criteria or death from any cause, whichever occurs first.
Secondary endpoints encompass a range of measures, including **PFS R1**, which is the time interval from the date of first randomization to the date of confirmed PD or death from any cause. Additional secondary endpoints include overall survival (OS R1), overall response rate (ORR), very good partial response (VGPR) rate, complete response (CR) rate, and sustained MRD negativity rate at 24 months. The trial will also evaluate ORR, VGPR rate, and CR rate during the maintenance phase, as well as PFS of subsequent treatment lines (PFS2 from R2) and overall survival from the second randomization (OS R2). The incidence and severity of adverse events (AEs) will be monitored, and quality of life (QoL) will be assessed using the EORTC QLQ-C30, EUROQOL (EQ-5D-5L), and return to work questionnaires.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female subjects, aged ≥18 but < 70 years old.
- Patients have provided voluntary written informed consent before performing any study-related procedure.
- Patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose chemotherapy (melphalan) and autologous stem cell transplantation (ASCT).
- Patients with documented symptomatic NDMM according to CRAB and/or SLIM criteria, with measurable disease as defined by: • Presence of ≥10% monoclonal plasma cells in the bone marrow OR presence of a biopsy-proven plasmacytoma. In addition, the patient must have ≥1 of the following myeloma defining events: Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limits of normal (ULN) or >2.75 mmol/L (>11 mg/dL). Renal insufficiency: creatinine clearance < 40mL/min/1.73 m2 using CKD-EPI or serum creatinine >177 μmol/L (>2 mg/dL). Anemia: hemoglobin >2 g/dL below the lower limit of normal (LLN) or hemoglobin <10 g/dL. Bone lesions: ≥1 osteolytic lesion on skeletal radiography, CT or PET-CT. Clonal bone marrow plasma cell percentage ≥60%. Serum involved/uninvolved free light chain ratio ≥100. More than 1 focal lesion (≥5 mm diameter) on MRI. • Measurable disease as defined by serum M-component ≥5 g/L, and/or urine M-component ≥200 mg/24 h and/or serum FLC ≥100 mg/L.
- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.
- Patients must have clinical laboratory values (within 15 days of initiating induction therapy) as follows: • Hemoglobin ≥7.5 g/dL (≥5 mmol/L). Prior red blood cell (RBC) transfusion or the use of recombinant human erythropoietin is permitted. • Absolute neutrophil count (ANC) ≥1.0 G/L (granulocyte colony stimulating factor [G-CSF] use is permitted). • Aspartate aminotransferase (AST) ≤3 x ULN. • Alanine aminotransferase (ALT) ≤ 3 x ULN. • Total bilirubin ≤3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, that require a direct bilirubin ≤3 x ULN). • Calculated creatinine clearance ≥40 mL/min/1.73 m² using CKD-EPI.• Albumin corrected serum calcium ≤14 mg/dL (<3.5 mmol/L); or free-ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L). • Platelet count ≥50 Giga/L for subjects who have <50% of bone marrow nucleated cells as plasma cells. If not, platelet count >30 G/L (platelets transfusions done during the 15 days before initiating induction therapy are not permitted).
- Women of childbearing potential must have a negative serum or urine pregnancy test during the screening period before randomization AND within 3 days before initiating induction therapy.
- 8.Patients must be willing and able to comply with scheduled appointments, treatment plan, laboratory tests, and other study procedures (such as blood transfusion if required, ASCT, IVIG prophylaxis, etc.
Exclusion Criteria
- Subjects previously treated with any systemic therapy for multiple myeloma. Patients are allowed corticosteroids before or during screening , as far as the total dose received is not >160 mg of dexamethasone (or equivalent) within 14 days before initiating induction therapy. Patients with concurrent radiotherapy within the 14 days before initiating induction therapy are not eligible (If possible, in these cases, enrolment should be deferred).
- Subject with ongoing Grade ≥ 3 peripheral sensory or motor neuropathy.
- Subject with history of GBS or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.
- Subject with a current diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.
- Subject has a diagnosis of Waldenström’s macroglobulinemia, or other conditions in which IgM M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
- The subject has had plasmapheresis within 14 days of initiating induction therapy.
- Subject with clinical signs of meningeal involvement of multiple myeloma.
- The subject has plasma cell leukemia (by WHO criterion: ≥5% of plasma cells in the peripheral blood) or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes).
- Subject has any concurrent medical or psychiatric condition or disease (e.g., active systemic infection, uncontrolled diabetes, acute diffuse infiltrative pulmonary disease) that is likely to interfere with the study procedures or results, or that in the opinion of the investigator, would constitute a hazard for participating in this study.
- Subject has clinically significant cardiac disease, including: a. Subject has had myocardial infarction within 1 year before initiating induction therapy, or currently has an unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association [NYHA] class III IV). b. Subject has uncontrolled cardiac arrhythmia (common terminology criteria for adverse events [CTCAE] version 4 grade ≥2) or clinically significant electrocardiography (ECG) abnormalities. c. Subject with a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec (12-lead ECG).
- Subjects taking systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John’s wort (millepertuis) within the 14 days before initiating induction therapy.
- Known intolerance to steroids, mannitol, pregelatinized starch, sodium stearyl fumarate, histidine (as base and hydrochloride salt), arginine hydrochloride, poloxamer 188, sucrose or any of the other components of study intervention that are not amenable to premedication with steroids and H2 blockers or would prohibit further treatment with these agents.
- Known allergies to any of the study medications, their analogues, or excipients in the various formulations
- Subjects who have had major surgery within 2 weeks before study inclusion (signing of the informed consent) OR will not have fully recovered from surgery before initiating induction therapy OR have surgery planned during their study participation. Kyphoplasty and vertebroplasty are not considered as major surgery.
- Subjects with any prior or concurrent malignancy (other than multiple myeloma) within 5 years of study inclusion study, except for adequately treated basal cell or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or localized prostate adenocarcinoma diagnosed ≥3 years ago and without evidence of biological failure, or other cancers for which the subject has undergone potentially curative therapy and has shown no evidence of relapse/recurrence for ≥5 years.
- Pregnant or breast-feeding women.
- Women that refuse to abstain from heterosexual intercourse or refuse to use adequate contraceptives during heterosexual intercourse starting at least 4 weeks before initiating induction therapy and continually until at least 4 weeks after discontinuing lenalidomide, 90 days after discontinuing daratumumab and 6 months after discontinuing elranatamab.
- Men with partners of childbearing potential, even men with a successful vasectomy, that refuse to use a condom during intercourse, from initiating induction therapy to ≥ 4 weeks after discontinuing lenalidomide. Furthermore, men must agree to not donate sperm during this period.
- Known positive for HIV or active hepatitis A, B or C: Uncontrolled or active HBV infection: Patients with positive HBsAg and/or HBV DNA Of note: Patients can be eligible if anti-HBc IgG positive (with or without positive anti-HBs) but HBsAg and HBV DNA are negative. a. If anti-HBV therapy in relation to 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 HCV infection: positive HCV RNA and negative anti-HCV. Of note: Patients with antiviral therapy (Direct-acting antivirals (DAAs)) 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. HIV infection: Of note: In equivocal cases, participants whose viral load is negative may be eligible. HIV seropositive participants who are otherwise healthy and at low risk for AIDS related outcomes could be considered eligible. Potential eligibility for a specific HIV positive protocol candidate should be evaluated and discussed with the sponsor prior to screening, considering current and past CD4+ and T-cell counts, history (if any) of AIDS defining conditions (eg, opportunistic infections), status of HIV treatment and the potential for drug-drug interactions.
- Patient with an active systemic infection or severe infections requiring parenteral administration of antibiotics
- Patients with a gastrointestinal disease/disorder that may significantly impact the absorption of oral treatments.
- Patients unable or unwilling to undergo antithrombic prophylaxis.
- A person under guardianship, trusteeship, or deprived of freedom by a judicial or administrative decision.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 15 Mar 2025 | 824 |
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 |
|---|---|---|---|---|---|---|
DARZALEX 1800 mg solution for injection | Comparator | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1800 | 126 | PRD8157846 |
ELREXFIO 40 mg/mL solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 32 | 2 | PRD10988295 |
Lenalidomide 25mg hard capsules | Comparator | HARD CAPSULES | ORAL | 25 | 6 | PRD10184466 |
Bortezomib 3.5 mg powder for solution for injection | Comparator | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 1.3 | 40 | PRD11124086 |
Lenalidomide 10mg hard capsules | Comparator | HARD CAPSULES | ORAL | 15 | 121 | PRD10184463 |
Dexamethasone 20 mg tablets | Comparator | TABLETS | ORAL | 20 | 24 | PRD11842925 |
Privigen 100 mg/ml solution for infusion | Other | SOLUTION FOR INFUSION | INTRAVASCULAR USE | 400 | 120 | PRD339230 |
ELREXFIO 40 mg/mL solution for injection | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS INJECTION | 76 | 124 | PRD10988294 |