A Phase III Trial on the Effect of Elotuzumab in VRD Induction /Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma

Prospective, multicentre, randomised, parallel group, open, phase III clinical trial, for patients with confirmed diagnosis of untreated multiple myeloma requiring systemic therapy .

Investigational Medicinal Products:Elotuzumab, lenalidomide

Patients are randomized in one of 4 study arms (A1, A2, B1, B2). Patients randomized in arm A1 or A2 will receive 4 cycles VRD (Bortezomib (Velcade®), Lenalidomide (Revlimid®), Dexamethasone). Patients in arm B1 or B2 will additionally receive the monoclonal antibody Elotuzumab in the 4 cycles VRD. After induction therapy patients undergo intensifying therapy according to GMMG standard (usually mobilization therapy followed by stem cell collection and autologous stem cell transplantation). After intensification a consolidation therapy will be performed with two cycles VRD (A1 und B1) or VRD+ Elotuzumab (A2 und B2), followed by Lenalidomide maintenance therapy with (arm A2 and B2) or without (arm A1 and B1) additional Elotuzumab. Maintenance therapy will be performed for 2 years.

Primary objective is the determination of the best of four treatment strategies regarding progression-free survival (PFS), defined as time from randomisation to progression or death from any cause whichever occurs first.

The duration of the trial for each patients is expected to be 36-39 months (induction and intensification treatment: 7-10 months, 3 months rest between intensification and start of consolidation, consolidation 2 months, maintenance phase 24 months).

Inclusion criteria

• Patients meeting all of the following criteria will be considered for admission to the trial:
• Confirmed diagnosis of untreated multiple myeloma requiring systemic therapy (diagnostic criteria (IMWG updated criteria (2014) )
• Measurable disease, defined as any quantifiable monoclonal protein value, defined by at least one of the following three measurements:

• Serum M-protein ≥ 10g/l (for IgA ≥ 5g/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 inclusive
• WHO performance status 0-3 (WHO=3 is allowed only if caused by MM and not by co-morbid conditions)
• Negative pregnancy test at inclusion (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. Patients must agree on the requirements regarding the lenalidomide pregnancy prevention programme described in chapter 6.
• All patients must

• agree to abstain from donating blood while taking lenalidomide and for 28 days following discontinuation of lenalidomide therapy
• agree not to share study drug lenalidomide with another person and to return all unused study drug to the investigator or pharmacist
• Ability of patient to understand character and individual consequences of the clinical trial
• Written informed consent (must be available before enrollment in the trial)

Exclusion criteria

• Patients presenting with any of the following criteria will not be included in the trial:
• Patient has known hypersensitivity to any drugs given in the protocol, notably bortezomib, lenalidomide, dexamethasone and elotuzumab or to any of the constituent compounds (incl. boron and mannitol).
• Systemic AL amyloidosis (except for AL amyloidosis of the skin or the bone marrow)
• Previous chemotherapy or radiotherapy during the past 5 years except local radiotherapy in case of local myeloma progression.
• Severe cardiac dysfunction (NYHA classification III-IV)
• Significant hepatic dysfunction (serum bilirubin ≥ 1,8mg/dl and/or ASAT and/or ALAT ≥ 2.5 times normal level), unless related to myeloma.
• Patients with renal insufficiency requiring hemodialysis
• HIV positivity
• Patients with active or history of hepatitis B or C
• Patients with active, uncontrolled infections
• Patients with peripheral neuropathy or neuropathic pain, CTC grade 2 or higher (as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0)
• Patients with a history of active malignancy during the past 5 years with the exception of basal cell carcinoma of the skin or stage 0 cervical carcinoma treated with curative intent
• Patients with acute diffuse infiltrative pulmonary and/or pericardial disease
• Autoimmune hemolytic anemia with positive Coombs test or immune thrombocytopenia
• Platelet count < 75 x 109/l, or, dependent on bone marrow infiltration by plasma cells, platelet count < 30 x 109/l (patients with platelet count < 75 x 109/l, but > 30 x 109/l may be eligible if percentage of plasma cells in bone marrow is ≥ 50%), (transfusion support within 14 days before the test is not allowed)
• Haemoglobin ≤ 8.0 g/dl, unless related to myeloma
• 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), unless related to myeloma
• Pregnancy and lactation
• Participation in other clinical trials. This does not include long-term follow-up periods without active drug treatment of previous studies during the last 6 months.

No patients will be allowed to enrol in this trial more than once.