Inclusion criteria
1. Male or female patients ≥ 18 years and ≤ 65 years at the time
2. Voluntary written consent must be given 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
3. Patients diagnosed with multiple myeloma
4. Subjects must have symptomatic myeloma with CRAB criteria.
5. Subjects must have measurable disease requiring systemic therapy defined by serum M-component ≥ 5g/l, urine M-component ≥ 200 mg/24h or serum FLC ≥ 100 mg/l.
6. Subjects must not have been treated previously with any systemic therapy for multiple myeloma. 7.Subjects must be eligible for high dose therapy.
8.Life expectancy ≥ 3 months.9.ECOG performance status 0, 1 or 2. 10.Patients must meet the following clinical laboratory criteria
* Adequate hepatic function, with serum ALT and AST ≤ 3 times the upper limit of normal and serum direct bilirubin ≤ 1.5 times the upper limit of normal within 14 days prior to enrolment.
* Absolute neutrophil count (ANC) ≥ 1.0 × 109/L within 14 days prior to enrollment.
* Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to enrollment (subjects may be receiving red blood cell \[RBC\] transfusions in accordance with institutional guidelines with a wash-out period of 7 days).
* Platelet count ≥ 75 × 109/L (≥ 30 × 109/L if myeloma involvement in the bone marrow is \> 50%) within 14 days prior to enrollment. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment.
* Calculated creatinine clearance ≥ 30 mL/minute (MDRD formula should be used for calculating creatinine clearance values: http://mdrd.com/).
11.Female of childbearing potential:must have two negative pregnancy tests : one serum pregnancy test within 10 to 14 days prior to therapy and one urine pregnancy test within 24 hours before starting study drug.
must agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 3 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
12.Male patients, even if surgically sterilized, must agree to not father a child and agree to use a latex condom during therapy and for 3 months after the last dose of study drug, even if they have had a successful vasectomy, if their partner is of childbearing potential.
13.Affiliation number to National Health Care System.
Exclusion Criteria:
1. Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a positive urine pregnancy test within 24 hours before first dose of study drug.
2. Evidence of mucosal or internal bleeding and/or platelet refractory.
3. Prior myeloma systemic therapy.
4. Major surgery within 14 days before first dose of study drug.
5. Radiotherapy within 14 days before first dose of study drug. If the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the MLN9708.
6. Treatment by corticosteroids if exceed the equivalent of 160 mg of dexamethasone within 14 days before first dose of study drug.
7. Subjects not eligible for high dose therapy.
8. Growth factors within 7 days prior to enrolment.
9. Transfusion within 3 days prior to enrolment.
10. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to first dose of study drug.
11. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before first dose of study drug.
12. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, unstable angina, or myocardial infarction within 6 months.
13. Systemic treatment, within 14 days before first dose of study drug, with strong inhibitors of CYP1A2, strong inhibitors of CYP3A or strong CYP3A inducers, or use of Ginkgo biloba or St. John's wort.
14. Ongoing or active systemic infection, known human immunodeficiency virus positive, known active hepatitis B virus hepatitis, or known active hepatitis C virus hepatitis.
15. Co-morbid systemic illnesses or other severe concurrent disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
16. Psychiatric illness/social situation that would limit compliance with study requirements.
17. Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
18. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
19. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral absorption or tolerance of treatment.
20. Diagnosed or treated for another malignancy within 2 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
21. Patient has significant neuropathy within 14 days prior to enrolment.
22. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to enrolment.
23. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
24. Participation in clinical trials with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.
25. Failure to have fully recovered from the reversible effects of prior chemotherapy.
26. Central nervous system involvement
