Daratumumab-bortezomib-dexamethasone (Dara-VCd) vs Bortezomib-Thalidomide-Dexamethasone (VTd), Then Maintenance With Ixazomib (IXA) or IXA-Dara

INDUCTION AND CONSOLIDATION REGIMEN:

Arm Dara-VCd:

Daratumumab: 16 mg/Kg given by IV infusion on days 1, 8, 15, 22, on cycles 1-2 and on days 1, 15 on cycles 3-4.

Bortezomib: 1.3 mg/m2 given subcutaneous (SC) injection on days 1, 8,15, 22; Cyclophosphamide: 300 mg/ m2 given orally or by IV infusion on days 1, 8, 15, 22; Dexamethasone: 40 mg given orally or by IV infusion on days 1, 8, 15, 22 Repeat for four 4-week induction cycles. After induction all patients will be given Cyclophosphamide at the dose of 3 g/m2, followed by Granulocyte Colony-Stimulating Factor (G-CSF) for stem cell collection. Cyclophosphamide will start 4-6 weeks after start of the fourth cycle of therapy.

Stem cell collection will be performed as soon as CD34+ cells are present in peripheral blood, which is usually between 9-14 days after first day of Cyclophosphamide. Stem cells will be harvested at a minimum of 4 x 106 CD34+ cells/kg and cryopreserved. In case insufficient stem cells are collected the procedure may be repeated or alternatively bone marrow stem cell collection may be performed or Plerixafor may be used.

4-6 weeks after cyclophosphamide patients will be treated with High Dose Melphalan followed by autologous stem cell reinfusion according to the schedule below:

• Melphalan 200 mg/ m² day - 2 i.v. rapid infusion
• Stem cell infusion Minimum of 2 x 10^6CD34+cells/kg day 0 90-120 days after Melphalan administration consolidation treatment will be administered: Daratumumab: 16 mg/Kg given by IV infusion on days 1, 15; Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 8, 15, 22; Cyclophosphamide: 300 mg/ m2 given orally or by IV infusion on days 1, 8, 15, 22; Dexamethasone: 40 mg given orally or by IV infusion on days 1, 8, 15, 22. Repeat for 2 4-week consolidation cycles.

Arm VTd:

Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 4, 8, 11 of 28-day cycle; Thalidomide: 100 mg given orally on days 1-28. Dexamethasone: 20 mg given orally or by IV injection on days 1, 2, 3, 4, 8, 9, 10 and 11 of every 28-day cycle.

Repeat for 4 4-week induction cycles. After induction all patients will be given Cyclophosphamide at the dose of 3 g/m2, followed by G-CSF for stem cell collection. Cyclophosphamide will start 4-6 weeks after start of the fourth cycle of therapy.

Stem cell collection will be performed as soon as cluster of differentiation 34 (CD34)+ cells are present in peripheral blood, which is usually between 9-14 days after first day of Cyclophosphamide. Stem cells will be harvested at a minimum of 4 x 106 CD34+ cells/kg and cryopreserved. In case insufficient stem cells are collected the procedure may be repeated by using also Plerixafor or alternatively bone marrow stem cell collection may be performed.

4-6 weeks after cyclophosphamide patients will be treated with High Dose Melphalan followed by autologous stem cell reinfusion according to the schedule below:

• Melphalan 200 mg/ m² day -2 i.v. rapid infusion
• Stem cell infusion Minimum of 2 x 10^6CD34+cells/kg day 0 90-120 days after Melphalan administration consolidation treatment will be administered: Bortezomib: 1.3 mg/m2 given by SC injection on days 1, 4, 8, 11 of 28-day cycle; Thalidomide: 100 mg given orally on days 1-28; Dexamethasone: 20 mg given orally or by IV injection on days 1, 2, 3, 4, 8, 9, 10 and 11 of every 28-day cycle.

Repeat for 2 4-week consolidation cycles.

MAINTENANCE TREATMENT:

All patients in ≥ PR after consolidation will be randomized to receive:

Arm I Ixazomib 3 mg on days 1, 8, 15 of cycle 1-4, followed by ixazomib 4 mg on days 1, 8, 15 cycles from cycle 5*.

Repeat each cycle every 28 days. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.

Arm II Ixazomib 3 mg on days 1, 8, 15 of cycle 1-4, followed by ixazomib 4 mg on days 1, 8, 15 cycles from cycle 5*.

Daratumumab 16 mg/kg on day 1. Repeat each cycle every 28 days. Patients will receive treatment until any sign of progression or intolerance, up to 24 months.

*The dose escalation is admitted only in case there have been no non-hematologic Adverse Events (AEs) ≥ Grade 2 related to study drug and no dose interruptions related to study drug toxicities.

Patients in the first randomization will be stratified according to fluorescent in situ hybridization (FISH) (standard/missing vs high risk, defined as del17, t 4;14, t 14;16) and International Staging System (ISS) (I vs II and III) Patients randomized to maintenance treatment will be stratified according to induction treatment and Minimal Residual Disease (MRD) status by nerve growth factor (NGF) (positive and not evaluable vs negative).

STATISTICAL DESIGN A total of 400 patients will be needed, in according to the study design, to provide a power of at least 85% to the statistical analysis with a two sided alpha error of 0.05 (see study protocol for details).

The statistical analysis will be performed in according to the intention to treat principle and will include summary of descriptive statistics (arithmetic mean and standard deviation, minimum and maximum, median with the interquartile range as appropriate) for continuous variables, absolute frequencies and percentages will be reported for qualitative variables. 95% Confidence intervals will be provided for variables subjected to statistical inference.

Proportions will be compared between treatment groups by use of the chi-square test or Fisher's exact test.

Kaplan-Meier method will be used for survival analyses to estimate and compare survival outcomes.

The log-rank test will be adopted to compare survival curves. Multivariable analysis, using semi parametric Cox proportional hazard regression model, will be performed to assess factors significantly affecting the progression free survival.

The safety analysis will include all patients randomized who will receive at least one dose of study treatment and the toxicity will be compared between treatment groups with chi-squared test.

All tests will be considered significant with p values less than 0.05.

Inclusion criteria

• Patient at least 18 years of age and ≤ 65 years.
• Patient eligible for autologous stem cell transplantation (ASCT).
• Left Ventricular Ejection Fraction (LVEF) ≥ 40%. 2-D transthoracic echocardiogram (ECHO) is the preferred method of evaluation. Multigated Acquisition Scan (MUGA) is acceptable if ECHO is not available.
• Newly diagnosed multiple myeloma patient.
• Patient has given voluntary written informed consent before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Patient with documented multiple myeloma and measurable disease as defined by:
• Monoclonal plasma cells in the bone marrow ≥10% or presence of a biopsy proven plasmacytoma
• Measurable disease as defined by at least one of the following:

• serum M-protein level ≥1 g/dL or urine M-protein level ≥200 mg/24 hours; or
• Light chain multiple myeloma: Serum immunoglobulin free light chain ≥10 mg/dL and abnormal serum immunoglobulin kappa lambda free light chain ratio.
• Evidence of end organ damage/presence of biomarkers of malignancies, specifically:
• Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
• Renal insufficiency: creatinine clearance (CLcr)<40 mL per minute (measured or estimated by validated equations) or serum creatinine >177 μmol/L (>2 mg/dL)
• Anaemia: haemoglobin value of >20 g/L below the lower limit of normal, or haemoglobin value <100 g/L
• Bone lesions: one or more osteolytic lesions 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 κ/λ-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 ration ≥ 100 (values based on the serum Free light assay. The involved free light chain must be ≥100 mg/L)

-> 1 focal lesion on MRI (magnetic resonance imaging) studies (each focal lesion must be 5 mm or more in size) Patient is, in the investigator(s) opinion willing and able to comply with the protocol requirements.

• Women of childbearing potential must commit to either abstain continuously from heterosexual intercourse or to use 2 methods of reliable birth control simultaneously. This includes one highly effective form of contraception (tubal ligation, intrauterine device, hormonal [birth control pills, hormonal patches, vaginal rings or implants] or partner's vasectomy) and one additional effective contraceptive method (male latex or synthetic condom, diaphragm, or cervical cap). Contraception must begin prior to dosing through 90 days after the last dose of study drug. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or bilateral oophorectomy.
• Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) during study drug therapy (including dose interruption) and for 90 days after the last dose of study drug.
• Patient with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 or Karnofsky performance status ≥ 60%.
• Pretreatment clinical laboratory values within 30 days of enrolment:
• Platelet count ≥75 x 109/L;
• Absolute neutrophil count (ANC) ≥ 1 x 109/L (G-CSF use is permitted);
• Corrected serum calcium <14 mg/dL (<3.5 mmol/L);
• Aspartate transaminase (AST) ≤ 2.5 x the upper limit of normal (ULN);
• Alanine transaminase (ALT) ≤ 2.5 x the ULN;
• Total bilirubin ≤ 1.5 x the ULN;
• Calculated or measured creatinine clearance ≥ 30 mL/minute.
• Patient has a life-expectancy >3 months.

Exclusion criteria

• Patient with a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance, smoldering MM or Plasma Cell Leukemia (PCL). Monoclonal gammopathy of undetermined significance is defined by presence of serum M-protein <3 g/dL, clonal bone marrow plasma cells <10%, and absence of end-organ damage or amyloidosis that can be attributed to the plasma cell proliferative disorder. Smoldering multiple myeloma is defined as serum monoclonal protein ≥ 30 g/L or urinary monoclonal protein ≥ 500 mg per 24 h and/or clonal bone marrow plasma cell 10-60% with absence of related organ or tissue impairment or end-organ damage or amyloidosis. Plasma cell leukemia is defined as presence of circulating plasmacells (PCs) >2×109/L in peripheral blood or a peripheral blood plasmacytosis >20%
• Patient with a diagnosis of Waldenström's disease, or other conditions in which immunoglobulin M (IgM) M-protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions.
• Patient has prior or current systemic therapy or SCT for multiple myeloma, with the exception of an emergency use of a short course (equivalent of dexamethasone 40 mg/day for a maximum 4 days) of corticosteroids before treatment.
• Patient has peripheral neuropathy of grade 2 or higher as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.0.
• Patient is exhibiting clinical signs of meningeal involvement of multiple myeloma.
• Clinical active infectious hepatitis type A, B, C or HIV.
• Subject has known chronic obstructive pulmonary disease (COPD) (defined as a Forced Expiratory Volume In 1 second (FEV1) <60% of predicted normal), persistent asthma, or a history of asthma within the last 2 years. Subjects with known or suspected COPD or asthma must have a FEV1 test during screening.
• Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within the past 6 months.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations.
• Contraindication to any of the required concomitant drugs or supportive treatments.
• Pregnant or lactating females.