Allogeneic Hematopoietic Stem Cell Transplantation With Ixazomib for High Risk Multiple Myeloma (BMT CTN 1302)

Inclusion Criteria

• Patients must meet one of the following disease criteria:

a. Patients with high risk multiple myeloma in partial response (PR) or better with no prior progression and are ≤ 24.0 months after autologous hematopoietic cell transplantation (HCT) (single or planned tandem), or are ≤ 24.0 months after initiation of systemic anti-myeloma therapy for patients without prior autologous HCT; or

i. High risk is defined by the presence of any one of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional cytogenetics, hypodiploidy, abnormality in chromosome 1(1q amplification or 1p deletion), t(4;14), t(14;16), t(14;20) or deletion of 17p by fluorescence in situ hybridization (FISH) or conventional karyotyping; high risk criteria based on commercially available gene expression profiling (GEP)

b. Patients with high risk multiple myeloma (see criterion 2.a.i. above) in very good partial response (VGPR) or better with 1 prior progression which occurred ≤ 24.0 months after autologous HCT (single or planned tandem), or ≤ 24.0 months after initiation of systemic anti-myeloma therapy for patients without prior autologous HCT; or

i. Patients with one prior progression without measurable monoclonal paraprotein at the time of disease progression or relapse ( 40%

• Estimated creatinine clearance greater than 40 mL/minute (using the Cockcroft-Gault formula and actual body weight)
• Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40% (adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%
• Liver function: total bilirubin 100 mg/L].
• Planned pre-emptive/prophylactic administration of donor lymphocytes (as per section 2.5.2)
• Central Nervous System (CNS) involvement with multiple myeloma defined as cerebrospinal fluid (CSF) positivity for plasma cells or a parenchymal CNS plasmacytoma
• Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment.
• Presence of fluid collection (ascites, pleural, or pericardial effusion) that interferes with methotrexate clearance or makes methotrexate use contraindicated.
• Patients seropositive for the human immunodeficiency virus (HIV).
• Patient with active Hepatitis B or C determined by serology and/or nucleic acid amplification test (NAAT).
• Patients with hypersensitivity to bortezomib, boron or mannitol.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 (ixazomib) including difficulty swallowing.
• Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent.
• Patients with ≥ grade 2 sensory peripheral neuropathy.
• Myocardial infarction within 6 months prior to enrollment or New York Heart Association (NYHA) Class III or IV heart failure (see Appendix D), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Female patients who are lactating or pregnant
• Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent ≥ 5 years previously will be allowed. Cancer treated with curative intent Grade 1 by CTCAE version 4.0) from the reversible effects of prior chemotherapy.
• Patient with serious medical of psychiatric illness likely to interfere with participation on this clinical study
• Participation in clinical trials with other investigational agents not included in this trial, ≤ 14.0 days of enrollment on this trial and throughout its duration.
• Patients who have received radiation therapy within 3 weeks before transplant. Enrollment of subjects w