Lenalidomide, Bortezomib and Dexamethasone Induction Therapy With Either Intravenous or Subcutaneous Isatuximab in Patients With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The trial aims to demonstrate the non-inferiority of subcutaneos to intravenous isatuximab administration in transplant-eligible patients with newly diagnosed multple myeloma.

Detailed Description
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Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy. Investigational Medicinal Product: Isatuximab, subcutaneous administration via a wearable injector system. Randomization: Patients are randomized in one of 2 study arms (A or B) before induction therapy. Patients randomized in arm A will receive 3 cycles of the monoclonal antibody isatuximab intravenously, combined with RVd regimen (Lenalidomide, Bortezomib, Dexamethasone). Each cycle will last for 42 days. Patients in arm B will receive 3 cycles RVd plus isatuximab subcutaneously. After induction therapy, patients will receive standard intensification (usually cyclophosphamide-based mobilization therapy, stem cell collection and high-dose melphalan followed by autologous stem cell transplantation (HDM/ASCT)). End of study will be after the first HDM/ASCT. There is one primary objective: Demonstration of non-inferiority of subcutaneous (SC) isatuximab compared to intravenous (IV) isatuximab, both in combination with RVd, with respect to rates of VGPR or better after induction therapy (according to standard International Myeloma Working Group (IMWG) response criteria). Key secondary objectives are: Comparison of patient-reported outcomes (PRO) regarding route of administration of isatuximab (SC vs. IV) on induction therapy as assessed by modified CTSQ (modified 9-item questionnaire). Non-inferiority of rates of MRD negativity (assessed by NGS from BMA; sensitivity 10^-5) independent of standard IMWG response after induction therapy. The duration of the trial for each patients is expected to be approximately 10 months (induction and intensification treatment).

Official Title
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A Randomized Phase III Non-inferiority Trial Assessing Lenalidomide, Bortezomib and Dexamethasone Induction Therapy With Either Intravenous or Subcutaneous Isatuximab in Transplant-eligible Patients With Newly Diagnosed Multiple Myeloma.

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Isatuximab
* Drug: Isatuximab
* Drug: Lenalidomide
* Drug: Bortezomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of untreated MM requiring systemic therapy (diagnostic criteria according to IMWG) Patient is eligible for high-dose melphalan (200 mg/m^2 melphalan) and autologous stem cell transplantation Measurable MM disease according to IMWG criteria, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements: serum M-protein ≥ 10 g/L; urine light-chain (M-protein) of ≥ 200 mg/24 hours; involved FLC level ≥ 10 mg/dL provided sFLC ratio is abnormal Age 18-70 years at trial inclusion Exclusion Criteria: Patient has known hypersensitivity (or contraindication) to any of the components of study therapy Systemic amyloid light-chain amyloidosis (except for localized AL amyloidosis limited to the skin or the bone marrow) Plasma cell leukemia Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local MM progression Severe cardiac dysfunction (NYHA classification III-IV) Patients with active or uncontrolled hepatitis B or C or detectable liver disease due to hepatitis B or C HIV positivity Patients with active, uncontrolled infections Patients with severe renal insufficiency or requiring hemodialysis Patients with peripheral neuropathy or neuropathic pain, grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events) Patients with a history of any active malignancy during the past 5 years with the exception of following malignancies after curative therapy: basal cell carcinoma of the skin, squamous cell skin carcinoma, stage 0 cervical carcinoma or any in situ malignancy Platelet count < 75 x 10^9/L Haemoglobin ≤ 8.0 g/dL, unless related to MM Absolute neutrophil count (ANC) < 1.0 x 10^9/L (the use of colony stimulating factors within 14 days before the test is not allowed) Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L) Pregnancy and lactation For further details on inclusion/exclusion criteria please refer to the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A - Intravenous isatuximab<br>Patients in arm A are treated with 3 cycles RVd + i.v. isatuximab, followed by a standard intensification and autologous stem cell transplantation. | Drug: Isatuximab<br>* IV isatuximab will be administered weekly in the first cycle (Cycle 1) on days 1, 8, 15, 22, 29, and biweekly on the 2 subsequent cycles at days 1, 15 and 29, at the dose of 10 mg/kg.<br>* Other names: Sarclisa;Drug: Lenalidomide<br>* Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3<br>Drug: Bortezomib<br>* Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles<br>* Other names: Velcade;Drug: Dexamethasone<br>* 20 mg per os on day 1-2, 4-5, 8-9, 11-12, 15; and 22-23, 25-26, 29-30, 32-33 in induction cycles 1-3.<br>|
| Experimental: Arm B - Subcutaneous isatuximab<br>Patients in arm B are treated with 3 cycles RVd + s.c. isatuximab, followed by a standard intensification and autologous stem cell transplantation. | Drug: Isatuximab<br>* SC isatuximab will be administered on days 1, 8, 15, 22, 29 of cycle 1, and on days 1, 15 and 29 of cycles 2-3, at the dose of 1400 mg<br>* Other names: Sarclisa;Drug: Lenalidomide<br>* Both arms: 25 mg per os on day 1-14 and d22-35 in induction cycle 1-3<br>Drug: Bortezomib<br>* Both arms: 1.3 mg/m^2 subcutaneous on day 1, 4, 8, 11, 22, 25, 29 32 in 3 induction cycles<br>* Other names: Velcade;Drug: Dexamethasone<br>* 20 mg per os on day 1-2, 4-5, 8-9, 11-12, 15; and 22-23, 25-26, 29-30, 32-33 in induction cycles 1-3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Demonstration of non-inferiority of subcutaneous (SC) isatuximab compared to intravenous (IV) isatuximab, both in combination with RVd. | Rates of VGPR or better (according to standard IMWG response criteria), defined as proportion of patients with at least VGPR after induction therapy (according to standard International Myeloma Working Group (IMWG) response criteria). | 18 weeks after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life compared between Arm A and B. | Comparison of PRO (patient-reported outcome) regarding route of administration of isatuximab (SC vs. IV) on induction therapy as assessed by modified CTSQ (modified 9-item questionnaire) | 18 weeks after start of study treatment | 
| Non-inferiority of rates of MRD negativity in Arm B compared to Arm A | Rates of NGS-MRD negativity (sensitivity 10^-5, from bone marrow aspirate) after induction therapy | 18 weeks after start of study treatment | 
| Rates of MRD negativity by NGS and NGF (sensitivity 10^-5, from BMA) independent of standard IMWG response after first HDM/ASCT | defined as proportion of negative patients with the corresponding MRD method (NGS or NGF) at the defined timepoint (after induction therapy or first HDM/ASCT) | 18 weeks (timepoint after induction) or 35 weeks (timepoint after first HDM/ASCT) after start of study treatment | 
| Rates of best overall response to treatment (BOR) | proportion of patients with BOR (at least PR or better) to treatment until end of study (based on timepoints post induction cycle 2 and 3, prior to HDM/ASCT and post first HDM/ASCT) | Depending on the timepoint of best response out of all response assessments, up to 10 months from randomization | 
| Progression-free survival (PFS) | Time from randomization (at study inclusion) to progression or death from any cause whichever occurs first | Until EOS (28 months after start of study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, Paraproteinemias, Lymphoproliferative Disorders, Immunoproliferative Disorders, Lenalidomide, Bortezomib, Dexamethasone, Isatuximab, Monoclonal antibodies