STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA

All patients will be randomized in a 1:1 ratio to receive:

ARM A (enrollment closed):

Bortezomib (V):

• 1.3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29 and 32 in cycles 1-4;
• 1.3 mg/m2 subcutaneously on days 1, 8, 22 and 29 in cycles 5-9.

Melphalan (M):

• 9 mg/m2 orally on days 1, 2, 3 and 4 of each cycle.

Prednisone (P):

• 60 mg/m2 orally on days 1, 2, 3 and 4 of each cycle. Each cycle is to be repeated every 42 days. Duration: Maximum 9 therapy cycles can be performed. After 9 cycles, patients will be observed until progression disease or the start of a new line of therapy.

ARM A2:

Bortezomib (V) 1. 3 mg/m2 subcutaneously twice weekly on weeks 1, 2, 4, and 5 of cycle 1 (days 1,4,8,11,22,25,29,32) and once weekly on weeks 1, 2, 4, and 5 of cycles 2 through 9 (days 1,8,22,29) Melphalan (M):- 9 mg/m2 orally on days 1, 2, 3 and 4 of each cycle.

Prednisone (P):

• 60 mg/m2 orally on days 1, 2, 3 and 4 of each cycle. Daratumumab (Dara) 16 mg per kilogram of body weight or 1800 mg Daratumumab subcutaneous (SC) (according to local clinical practice) with oral or intravenous dexamethasone (to manage infusion reactions) at a dose of 20 mg once weekly in cycle 1 (days 1,8,15,22,29,36), every 3 weeks in cycles 2 through 9 (days 1,22), and every 4 weeks thereafter until disease progression or unacceptable toxic effects. Dexamethasone at a dose of 20 mg was substituted for prednisone on day 1 of each cycle.

ARM B (enrollment closed):

Lenalidomide (R):

• 25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

• 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles. Duration: patients will receive treatment until any sign of progression or intolerance.

ARM B2

Lenalidomide (R):

• 25 mg orally on days 1-21 of each cycle.

Dexamethasone (d):

• 40 mg orally on days 1, 8, 15 and 22 of each cycle. Each cycle is a 28-day cycles. Daratumumab (Dara) intravenous at a dose of 16 mg per kilogram of body weight or 1800 mg Daratumumab subcutaneous (SC) (according to local clinical practice) once weekly during cycles 1 and 2, every 2 weeks during cycles 3 through 6, and every 4 weeks thereafter; preinfusion medications were administered approximately 1 hour before each daratumumab dose.

Inclusion criteria

• Patients has given voluntary written informed consent before the performance of any study related procedure;
• Patients with newly diagnosed symptomatic multiple myeloma (NDMM) based on standard IMWG (International Myeloma Working Group) criteria:
• Clonal bone marrow plasma cells >=10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features and myeloma-defining events:
• evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically

• Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11mg/dL)
• Renal insufficiency: creatinine clearance (CLcr)<40 mL per minute (measured or estimated by validated equations) or serum creatinine > 177 micro mol/L (>2mg/dL)
• Anemia: hemoglobin value of >20g/L below the lower limit of normal, or a hemoglobin value <100g/L
• Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement
• Any one or more of the following biomarkers of malignancy:

• Clonal bone marrow plasma cell percentage >=60% (clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used)
• Involved:uninvolved serum free light chain ratio >=100 (values based on the serum Freelite assay. The involved free light chain must be >=100 mg/L)
• >1 focal lesion detected by MRI (magnetic resonance imaging) studies (each focal lesion must be 5 mm or more in size
• According to physician's opinion, patients can undergo either one of the two standard treatments and procedures;
• Females of childbearing potential (FBCP) must use an effective contraceptive method for 28 days before the study treatment, during the treatment and for at least 3 months after the last dose of study drugs;
• Male subjects must use an effective barrier method if sexually active with FCBP during treatment and for at least 6 months after the last dose of study drug;
• Patients should be ineligible for ASCT, defined as:
• >= 65 years old
• younger than 65 years but who reject the transplant procedure or with abnormal cardiac, pulmonary, hepatic and renal function defined as [1]:

• LVEF (left ventricular ejection fraction) < 40%
• FEV1 (forced expiratory volume-1 second) < 40%
• Bilirubin > 1.5 UNL, AST/ALT >2.5 UNL Creatinine clearance < 60 mL/min.

Exclusion criteria

• Hypersensitivity to any active substance or to any of the excipients (lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, boron, mannitol, nitrogen, crospovidone, colloidal anhydrous silica, hypromellose, titanium dioxide, macrogol, talc, sodium starch glycolate, sodium benzoate, propylene glycol, sodium dihydrogen phosphate, hydroxypropyl beta cyclodextrin, sodium saccharin, sodium EDTA, sodium hydroxide, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 20, sorbitol (E420), recombinant human hyaluronidase (rHuPH20));
• Hereditary intolerance to fructose;
• Pregnant and lactating women;
• FBCP that do not follow the Pregnancy Prevention Plan requirements;
• Acute diffuse infiltrative pulmonary and pericardial disease;
• Acute viral infections (e.g. herpes simplex or ocular herpes simplex, herpes zoster, varicella);
• Systemic mycotic or bacterial infections, unless specific anti-infectious therapy is ongoing;
• Peptic ulcer;
• Psychosis;
• Administration of prophylactic vaccine from 8 to 2 weeks before starting treatment.