A randomized phase III non-inferiority trial assessing lenalidomide, bortezomib and dexame-thasone induction therapy with either intravenous or subcutaneous isatuximab in patients with newly diagnosed multiple myeloma

Prior treatment

• Patient has known hypersensitivity (or contraindication) to dexamethasone, sucrose histidine (as base and hydrochloride salt), boron, mannitol, and polysorbate 80 or any of the components of study therapy that are not amenable to premedication with steroids or H1 blockers that would prohibit further treatment with these agents
• Participation in other interventional clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months
• Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local MM progression. (Note: patients may have received a cumulative dose of up to 160 mg of dexamethasone or equivalent as emergency therapy for MM.)

Other illness

• 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
• Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
• Autoimmune hemolytic anemia with positive indirect Coombs test or immune thrombocytopenia
• 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

Lab values

• Patients with severe renal insufficiency (Creatinine Clearance < 30 mL/min) or requiring hemodialysis
• 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)
• Plasma cell leukemia (as defined by more than 20% circulating plasma cells and/or an absolute count greater than 2 × 10^9/L plasma cells in the peripheral blood smears
• Significant hepatic dysfunction (ASAT and/or ALAT ≥ 3 times normal level and/or serum bilirubin ≥ 1.5 times normal level if not due to hereditary abnormalities as Gilbert’s disease), unless related to MM

Other

• Patients with peripheral neuropathy or neuropathic pain, grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0)
• Unable or unwilling to undergo thromboprophylaxis
• Systemic AL amyloidosis (except for localized AL amyloidosis limited to the skin or the bone marrow)
• Pregnancy and lactation

• Confirmed diagnosis of untreated MM requiring systemic therapy (diagnostic criteria according to IMWG)
• Written informed consent (must be available before enrolment in the trial)
• Patient is eligible for HDM (200 mg/m^2 melphalan) and ASCT
• 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; Serum FLC assay: involved FLC level ≥ 10 mg/dL provided sFLC ratio is abnormal
• Age 18-70 years at trial inclusion
• WHO performance status 0-2
• Negative pregnancy test at inclusion in women of childbearing potential
• For all men and women of childbearing potential: patients must be willing and capable to use adequate contraception during the complete therapy
• All patients must agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
• Ability of patient to understand character and individual consequences of the clinical trial