A Phase 3 Study Comparing Oral MLN9708 Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

• Overall Survival [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: No ]
  To determine whether the addition of oral MLN9708 to lenalidomide and dexamethasone improves OS
• Overall Response Rate (ORR), including Partial Response (PR), Very Good Partial Response (VGPR), and Complete Response (CR) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
  Standard multiple myeloma disease assessments
• CR + VGPR [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
  Standard multiple myeloma disease assessments
• Duration of Response (DOR) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
• Time to Progression (TTP) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
• Number of AEs, SAEs, assessment of clinical laboratory values and evaluate Eastern Cooperative Group (ECOG) performance scores [ Time Frame: From the date of signing of the informed consent form through 30 days after the last dose of study drug ] [ Designated as safety issue: Yes ]
  To determine the safety of addition of MLN9708 to lenalidomide and dexamethasone
• Pain response rate as assessed by the BFI-SF and analgesic use [ Time Frame: BPI-SF will be assessed at screening; Day 1 of each cycle; at EOT and thereafter every 4 weeks until disease progression ] [ Designated as safety issue: No ]
• Change in global health status, as measured by the patient reported outcome questionnaires, EORTC QLQ-C30 and MY-20 [ Time Frame: At the time of screening, Day 1 of Cycle 1 and Cycle 2; every other cycle until EOT; every 4 weeks after EOT until disease progression and thereafter every 12 weeks until OS ] [ Designated as safety issue: No ]
• OS and PFS in high-risk population such as those carrying del(13), del(17), +1q21, t(4;14), or t(14;16) [ Time Frame: At the time of screening; Day 1 of each cycle; at EOT; every 4 weeks until disease progression and thereafter every 12 weeks until death or study termination ] [ Designated as safety issue: Yes ]
• To collect PK data including Cmax, AUC and Tmax to contribute to population PK analyses [ Time Frame: Days 1 & 14 of cycles 1&2. Day 1 of cycles 3-10 ] [ Designated as safety issue: No ]

The purpose of this phase 3, randomized, double-blind, multicenter study is to compare Oral MLN9708 plus Lenalidomide and Dexamethasone versus Placebo plus Lenalidomide and Dexamethasone in adult patients with relapsed and/or refractory multiple myeloma.

• Relapsed Multiple Myeloma
• Refractory Multiple Myeloma

• Drug: MLN9708 + Lenalidomide + Dexamethasone
  Patients will receive single oral dose of MLN9708 (4.0mg) on days 1,8,15 and single oral dose of Lenalidomide (25mg) on days 1-21 and single oral dose of Dexamethasone (40mg) on days 1,8, 15 and 22 every 28 days until disease progression
• Drug: Placebo + Lenalidomide + Dexamethasone
  Patients will receive single oral dose of Placebo on days 1,8,15 and single oral dose of Lenalidomide (25mg) on days 1-21 and single oral dose of Dexamethasone (40mg) on days 1,8, 15 and 22 every 28 days until disease progression

• Active Comparator: MLN9708
  MLN9708 + Lenalidomide + Dexamethasone
  Intervention: Drug: MLN9708 + Lenalidomide + Dexamethasone
• Placebo Comparator: Placebo
  Placebo + Lenalidomide + Dexamethasone
  Intervention: Drug: Placebo + Lenalidomide + Dexamethasone

Inclusion Criteria:

• Male or female patients 18 years or older
• Diagnosed Multiple Myeloma according to standard criteria
• Measurable disease as specified in study protocol
• Eastern Cooperative Oncology Group (ECOG)performance status of 0 to 2
• Patients with relapsed and/or refractory Multiple Myeloma who have received 1 to 3 prior therapies
• Meet the clinical laboratories criteria as specified in the protocol
• Patients who received prior allogenic transplant must have no active graft-versus-host disease (GVHD)
• Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program
• Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse AND must adhere to the guidelines of the lenalidomide pregnancy prevention program
• Must be able to take concurrent aspirin 325 mg daily
• Voluntary written consent

Exclusion Criteria:

• Patient who were refractory to lenalidomide or proteasome inhibitor-based therapy
• Female patients who are lactating or pregnant
• Major surgery or radiotherapy within 14 days before randomization
• Infection requiring systematic antibiotics within 14 days before the first dose of study drug
• Central nervous system involvement
• Failure to have fully recovered from the effects of prior chemotherapy regardless of the interval since last treatment
• Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginko biloba or St. John's wort within 14 days before the first dose of study treatment
• Diagnosis of Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
• Evidence of current uncontrolled cardiovascular conditions
• Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
• Known allergy to any of the study medications
• Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
• Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ
• Ongoing or active systemic infection, active hepatitis B virus infect, active hepatitis C infection, or known human immunodeficiency virus (HIV) positive