Study of Oral MLN9708 in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

• Maximum Tolerated Dose (MTD) and Recommended phase 2 dose of MLN9708 (phase 1) [ Time Frame: Dose Limiting Toxcities determined in Cycle 1 to define MTD; MTD and adverse events monitored throughout the study will inform the recommended phase 2 dose, approximately 1 year ] [ Designated as safety issue: Yes ]
  Based on adverse events, serious adverse events, assessments of clinical laboratory values, neurotoxicity grading, and vital sign measurements
• Number of patients with complete response and very partial response rate (phase 2) [ Time Frame: Patients will be assessed after each Cycle 1-4 and then every 2 cycles until disease progression, approximately 2 years ] [ Designated as safety issue: No ]
• Number of grade 3 or higher adverse events, all serious adverse events, and treatment discontinuation (phase 2) [ Time Frame: From screening period through 30 days after the last dose of study drug or until the start of subsequent antineoplastic therapy, approximately 1 year and 30 days ] [ Designated as safety issue: Yes ]

• Number of patients with response (phase 1) [ Time Frame: After each Cycle 1-4 and every two cycles thereafter; at end of treatment; and during progression-free survival follow-up (if applicable), expected duration approximately 2 years ] [ Designated as safety issue: No ]
• Time to response (phase 2) [ Time Frame: From the first dose of study treatment to the date of first documentation of a confirmed response, approximately 1 year ] [ Designated as safety issue: No ]
• Duration of response (phase 2) [ Time Frame: From the date of first documentation of a confirmed response to the date of progressive disease, approximately 1 year ] [ Designated as safety issue: No ]
• Time to progression (phase 2) [ Time Frame: From the first dose of study treatment to the date of first documented progressive disease, approximately 3 years ] [ Designated as safety issue: No ]
• Number of patients with progression free survival (phase 2) [ Time Frame: From the first dose of study treatment to the date of first documented progressive disease or death, approximately 3 years ] [ Designated as safety issue: No ]
• Number of patients with overall survival (phase 2) [ Time Frame: From the first dose of study treatment to date of death, approximately 6 years ] [ Designated as safety issue: No ]
• Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC) (phase 1) [ Time Frame: At multiple time points throughout Cycles 1-3, for approximately 43 days ] [ Designated as safety issue: No ]
• Number of patients with overall response (phase 2) [ Time Frame: After Cycles 1-4 and every other cycle thereafter; at end of treatment; and during progression-free survival follow-up (if applicable), expected duration approximately 2 years ] [ Designated as safety issue: No ]
  Complete response + very good partial response + partial response
• Number of patients with complete response + very good partial response (phase 2) [ Time Frame: After Cycles 4, 8, and 16, approximately 2 years ] [ Designated as safety issue: No ]
• Number of patients with complete response, stringent complete response, very good partial response, near complete response, partial response, and minimal response (phase 2) [ Time Frame: After Cycles 1-4 and every other cycle thereafter; at end of treatment; and during progression-free survival follow-up (if applicable), expected duration approximately 2 years ] [ Designated as safety issue: No ]
• Number of patients with 1-year survival (phase 2) [ Time Frame: 1 year after first dose of study treatment in the last patient treated ] [ Designated as safety issue: No ]

This will be a phase 1/2, multicenter, open-label study using the oral formulation of MLN9708 administered twice weekly in combination with lenalidomide and low-dose dexamethasone. Both phases of the study will include patients who have newly diagnosed multiple myeloma and have not previously received systemic treatment.

Both the phase 1 and the phase 2 portions of the study will include induction therapy consisting of 1 year of therapy followed by maintenance therapy that will continue until progressive disease or unacceptable toxicity. Maintenance therapy will be MLN9708 alone on Days 1,4,8, & 11 of a 21-day cycle.

Inclusion Criteria:

• Male or female patients 18 years or older
• Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria
• Measurable disease as specified in study protocol
• Hematologic, liver, and renal function as specified in the study protocol Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
• 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

• Peripheral neuropathy that is greater or equal to Grade 2
• Female patients who are lactating or pregnant
• Major surgery or radiotherapy within 14 days before the first dose of study drug
• Uncontrolled infection requiring systematic antibiotics within 14 days before the first dose of study drug
• Diarrhea (> Grade 1)
• Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient)
• 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
• Central nervous system involvement
• Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome
• Evidence of current uncontrolled cardiovascular conditions
• Prior or concurrent deep vein thrombosis or pulmonary embolism
• Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
• 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 the first dose 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