ELRANATAMAB for Multiple myeloma|Newly diagnosed multiple myeloma

Stratification factors

• Cytogenetics risk (standard versus high-risk) according to IMS/IMWG consensus definition
• Site enrollment capacity (smaller sites grouped together)
• MRD (NGS) < 10-5 status at the end of consolidation
• Randomization 1 arm

Inclusion criteria

• {"criterion_text":"-1.\tMale or female subjects, aged ≥18 but < 70 years old.\n-2.\tPatients have provided voluntary written informed consent before performing any study-related procedure.\n-3.\tPatients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose chemotherapy (melphalan) and autologous stem cell transplantation (ASCT).\n-4.\tPatients with documented symptomatic NDMM according to CRAB and/or SLIM criteria, with measurable disease as defined by: •\tPresence 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: \tHypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than upper limits of normal (ULN) or >2.75 mmol/L (>11 mg/dL). \tRenal insufficiency: creatinine clearance < 40mL/min/1.73 m2 using CKD-EPI or serum creatinine >177 μmol/L (>2 mg/dL). \tAnemia: hemoglobin >2 g/dL below the lower limit of normal (LLN) or hemoglobin <10 g/dL. \tBone lesions: ≥1 osteolytic lesion on skeletal radiography, CT or PET-CT. \tClonal bone marrow plasma cell percentage ≥60%. \tSerum involved/uninvolved free light chain ratio ≥100. \tMore than 1 focal lesion (≥5 mm diameter) on MRI. •\tMeasurable 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.\n-5.\tPatient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.\n-6.\tPatients must have clinical laboratory values (within 15 days of initiating induction therapy) as follows: •\tHemoglobin ≥7.5 g/dL (≥5 mmol/L). Prior red blood cell (RBC) transfusion or the use of recombinant human erythropoietin is permitted. •\tAbsolute neutrophil count (ANC) ≥1.0 G/L (granulocyte colony stimulating factor [G-CSF] use is permitted). •\tAspartate aminotransferase (AST) ≤3 x ULN. •\tAlanine aminotransferase (ALT) ≤ 3 x ULN. •\tTotal bilirubin ≤3 x ULN (except in subjects with congenital bilirubinemia, such as Gilbert syndrome, that require a direct bilirubin ≤3 x ULN). •\tCalculated creatinine clearance ≥40 mL/min/1.73 m² using CKD-EPI.•\tAlbumin corrected serum calcium ≤14 mg/dL (<3.5 mmol/L); or free-ionized calcium ≤6.5 mg/dL (≤1.6 mmol/L). •\tPlatelet 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).\n-7.\tWomen 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.\n-8.\tPatients 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

• {"criterion_text":"-1.\tSubjects 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).\n-10.\tSubject has clinically significant cardiac disease, including: a.\tSubject 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.\tSubject has uncontrolled cardiac arrhythmia (common terminology criteria for adverse events [CTCAE] version 4 grade ≥2) or clinically significant electrocardiography (ECG) abnormalities. c.\tSubject with a baseline QT interval as corrected by Fridericia’s formula (QTcF) >470 msec (12-lead ECG).\n-11.\tSubjects 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.\n-12.\tKnown 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.\n-13.\tKnown allergies to any of the study medications, their analogues, or excipients in the various formulations\n-14.\tSubjects 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.\n-15.\tSubjects 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.\n-16.\tPregnant or breast-feeding women.\n-17.\tWomen 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.\n-18.\tMen 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.\n-19.\tKnown 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.\tIf 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.\n-2.\tSubject with ongoing Grade ≥ 3 peripheral sensory or motor neuropathy.\n-20.\tPatient with an active systemic infection or severe infections requiring parenteral administration of antibiotics\n-21.\tPatients with a gastrointestinal disease/disorder that may significantly impact the absorption of oral treatments.\n-22.\tPatients unable or unwilling to undergo antithrombic prophylaxis.\n-23.\tA person under guardianship, trusteeship, or deprived of freedom by a judicial or administrative decision.\n-3.\tSubject with history of GBS or GBS variants, or history of any Grade ≥3 peripheral motor polyneuropathy.\n-4.\tSubject with a current diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma.\n-5.\tSubject 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.\n-6.\tThe subject has had plasmapheresis within 14 days of initiating induction therapy.\n-7.\tSubject with clinical signs of meningeal involvement of multiple myeloma.\n-8.\tThe 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).\n-9.\tSubject 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."}

Primary endpoints

• {"endpoint_text":"-MRD negativity rate as determined by NGS with a sensitivity of at least 10-5 measured at end of consolidation","definition_or_measurement_approach":"As determined by NGS with a sensitivity of at least 10-5 measured at end of consolidation."}
• {"endpoint_text":"-PFS R2 defined as the time interval from the date of second randomization to the date of confirmed PD (IMWG criteria) or death from any cause, whichever occurs first.","definition_or_measurement_approach":"Time interval from the date of second randomization to the date of confirmed progressive disease (per IMWG criteria) or death from any cause, whichever occurs first."}

Secondary endpoints

• {"endpoint_text":"-PFS R1 defined as the time interval from the date of first randomization to the date of confirmed PD (IMWG criteria) or death from any cause, whichever occurs first.","definition_or_measurement_approach":"Time interval from date of first randomization to confirmed progressive disease (IMWG criteria) or death from any cause, whichever occurs first."}
• {"endpoint_text":"-OS R1 defined as the time interval from the date of first randomization to the date of death from any cause","definition_or_measurement_approach":"Time interval from date of first randomization to date of death from any cause."}
• {"endpoint_text":"-\tOverall response rate (ORR) -\tVery good partial response (VGPR) rate -\tComplete response (CR) rate - Sustained MRD negativity rate at 24 months defined as the proportion of participants with CR per IMWG criteria and MRD negativity at 12 months after R1 which is sustained at 24 months after R1","definition_or_measurement_approach":"ORR, VGPR, CR per IMWG criteria; sustained MRD negativity at 24 months defined as participants with CR per IMWG and MRD negativity at 12 months after R1 sustained at 24 months after R1."}
• {"endpoint_text":"-\tOverall response rate (ORR) in maintenance -\tVery good partial response (VGPR) rate in maintenance -\tComplete response (CR) rate in maintenance -\tPFS of subsequent/next treatment line (PFS2 from R2) -\tOverall survival from second randomization (OS R2)","definition_or_measurement_approach":"Maintenance-phase ORR/VGPR/CR measured per IMWG; PFS2 from R2 is time to progression/death on subsequent line; OS R2 is time from second randomization to death from any cause."}
• {"endpoint_text":"-Incidence and severity of AEs","definition_or_measurement_approach":"Adverse events recorded and graded (incidence and severity)."}
• {"endpoint_text":"-QoL will be assessed using the following instruments: •\tEORTC QLQ-C30, •\tEUROQOL (EQ-5D-5L) •\tReturn to work questionnaires","definition_or_measurement_approach":"Quality of life measured using EORTC QLQ-C30, EQ-5D-5L and return-to-work questionnaires."}

France

Earliest CTIS Part Ii Submission Date

25-02-2025

Latest Decision Or Authorization Date

29-01-2026

Processing Time Days

338

Number Of Sites

70

Number Of Participants

824

Primary sponsor

Full Name

Intergroupe Francophone Du Myelome

Organisation Type

Patient organisation/association

Country Of Registered Address

France

Contract research organisations

Name

PPD Development LP

Responsibilities

Sponsor duty code: 4

Third parties

• {"country":"France","full_name":"Exystat","duties_or_roles":"codes: 10,6","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"CHU Toulouse","duties_or_roles":"code: 4","organisation_type":"Health care"}
• {"country":"France","full_name":"Eurofins Clinical Trial Supplies France","duties_or_roles":"code: 14","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"CHU Nantes","duties_or_roles":"code: 4","organisation_type":"Health care"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"CHU Grenoble Alpes - Hôpital Michallon","duties_or_roles":"code: 8","organisation_type":"Health care"}