Daratumumab-bortezomib-dexamethasone (Dara-VCd) vs Bortezomib-Thalidomide-Dexamethasone (VTd), Then Maintenance With Ixazomib (IXA) or IXA-Dara
Daratumumab-bortezomib-dexamethasone (Dara-VCd) vs Bortezomib-Thalidomide-Dexamethasone (VTd), Then Maintenance With Ixazomib (IXA) or IXA-Dara
This protocol is a phase II multicenter, randomized, open label study designed to assess the
 efficacy and safety of daratumumab combined with bortezomib, cyclophosphamide and
 dexamethasone (Dara-VCd) versus the association of bortezomib, thalidomide and dexamethasone
 (VTd) as pre transplant induction and post transplant consolidation, followed by maintenance
 with ixazomib alone or in combination with daratumumab, in newly diagnosed multiple myeloma
 (MM) patients eligible for autologous stem cell transplantation.

 Patients enrolled in the Dara-VCd arm will receive: 4 cycles of
 daratumumab-bortezomib-cyclophosphamide-dexamethasone induction, followed by transplantation
 and 2 cycles of daratumumab-bortezomib-cyclophosphamide-dexamethasone consolidation. The
 choice of cyclophosphamide in combination with bortezomib and dexamethasone is suggested by
 the better safety profile of cyclophosphamide, in comparison with thalidomide and the
 efficacy of the alkylator agent, when combined with bortezomib.

 Once-weekly bortezomib seems to be equally effective and better tolerated than the standard
 twice weekly schedule. The outcomes and response rate did not appear to be affected by the
 bortezomib dosing schedule.

 Patients enrolled in the VTd arm will receive: 4 cycles of
 bortezomib-thalidomide-dexamethasone induction, followed by autologous transplantation and 2
 cycles of bortezomib-thalidomide dexamethasone as consolidation. The VTd drug association is
 the current standard first line induction therapy for multiple myeloma patients who are
 eligible to stem cell transplantation.

 At the end of consolidation phase patients with at least a partial response (≥ PR) will be
 rerandomized (assigned by chance) to one of 2 treatment groups to receive maintenance
 treatment with ixazomib alone or in combination with daratumumab. Patients will receive
 treatment until any sign of progression or intolerance, up to 24 months.
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.