STUDY THAT COMPARE 3 ARM: MLN9708 DEXAMETHASONE, MLN9708 CYCLOPHOSPHAMIDE AND DEXAMETHASONE, MLN9708 THALIDOMIDE AND DEXAMETHASONE FOLLOWED BY MAINTENANCE WITH MLN9708 IN NEWLY DIAGNOSED ELDERLY MULTIPLE MYELOMA PATIENTS

Inclusion Criteria:

* Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
* Patient has given voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
* Female patient is either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intrauterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.
* Male patient agrees to use an acceptable method for contraception (i.e., condom or abstinence) for the duration of the study.
* Newly diagnosed MM based on standard CRAB criteria (see Appendix 12.2).
* Age ≥ 65 years old or younger not eligible for transplantation.
* Patient has measurable disease, defined as follows: any quantifiable serum monoclonal protein (M-protein) value (, ≥ 0.5 g/dL of M-protein) and, where applicable, urine light-chain excretion of \>200 mg/24 hours. For patients with oligo or non-secretory MM, it is required that they have measurable plasmacytoma \> 2 cm as determined by clinical examination or applicable radiographs (i.e. MRI, CT-Scan) or an abnormal free light chain ratio (n.v.: 0.26-1.65). We anticipate that less than 10% of patients admitted to this study will be oligo- or non-secretory MM with free light chains only in order to maximize interpretation of benefit results
* Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2
* Clinical laboratory values within 30 days of enrolment:

  * platelet count ≥ 75 x 109/L (Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment)
  * haemoglobin ≥ 8 g/dL
  * absolute neutrophil count (ANC) ≥ 1.0 x109/L
  * AST and ALT ≤ 3 times the upper limit of normal
  * total bilirubin ≤ 1.5 times the upper limit of normal
  * clearance creatinine ≥ 30 ml/min

Exclusion Criteria:

* Pregnant or lactating females.
* Serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the enrolment or place the subject at unacceptable risk.
* Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid \< to the equivalent of dexamethasone 40 mg/day for 4 days)
* Clinical active infectious hepatitis type A, B, C or HIV (HBV-DNA and HCV-RNA will be analysed to evaluate the cell proliferation of virus; anti-HIV antibody must be negative).
* Acute active infection requiring antibiotics or infiltrative pulmonary disease
* Peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 4.03
* Contraindication to any of the required drugs or supportive treatments
* Invasive malignancy within the past 3 years
* Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of St. John's wort within 14 days before the first dose of study treatment (see Appendix 12.12).
* Diagnosis of Waldenstrom's macroglobulinemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome.
* 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.
* Female patients who are lactating or have a positive serum pregnancy test during the screening period.