In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Overview of Study Design:

In an attempt to reduce relapse risk and improve outcomes following haploidentical transplantation for patients with high risk hematologic malignancies, the investigators will implement several strategies to augment the well documented effect of NK cell alloreactivity seen in HLA-mismatched transplantation. These strategies include (1) choosing potential haploidentical donors for optimal NK-alloreactivity, (2) utilizing proteasome inhibition post-transplant with MLN9708 to both sensitize tumor cells to NK cytotoxicity and protect against graft-versus-host disease (GVHD), and (3) eliminating mycophenolate mofetil from the post-transplant immunosuppression regimen to improve NK cell reconstitution following haploidentical peripheral blood stem cell transplantation.

Patients will receive a nonmyeloablative haploidentical transplant using a T-cell replete allograft and post-transplant cyclophosphamide as previously described at our center (Bashey et al. J Clin Oncol. 2013; 31(10):1310-6). MLN9708 will be administered once weekly for 3 weeks on a 28 day cycle for one-year post-transplant. Post-transplant immunosuppression will consist of tacrolimus only (MLN9708 will substitute for mycophenolate mofetil as the second GVHD prophylactic medication).

The primary endpoint of this trial will be the risk of relapse and/or progression at one-year post-transplant. Experience from the literature suggests that following a nonmyeloablative haploidentical transplant using post-transplant cyclophosphamide (haplo-pCy), the risk of relapse is approximately 50% at one year post-transplant. It is hoped that under this protocol, this rate will be at most 25%. Thus the investigators statistically formalize this study by testing the null hypothesis that p, the PFS rate is 0.25 or less versus the alternative hypothesis that p is greater than 0.5. A sample size of 25 patients gives 90% power with an alpha=0.05, using the formula for a one sample binomial (two-sided) test of a proportion.

Inclusion Criteria:

• Availability of a 3/6 - 5/6 matched (HLA-A, B, DR) related donor
• Donor must have negative HLA cross-match in the host vs. graft direction.
• Donor must be willing to donate mobilized peripheral blood stem cells
• Age ≥ 18 years
• Karnofsky status ≥ 70%
• One of the following high-risk malignancies:
• Chronic Myelogenous Leukemia (chronic phase, resistant and/or intolerant to tyrosine kinase inhibitors (OR) accelerated phase (OR) blast crisis in 2nd chronic phase following induction chemotherapy)
• Acute Myelogenous Leukemia (2nd or subsequent complete remission [CR] (OR) Primary induction chemotherapy failure, but subsequently entered into a CR(OR) 1st CR with poor risk cytogenetics or molecular markers; or arising from preceding hematological disease)
• Myelodysplastic Syndrome (treatment-related, monosomy 7 or complex cytogenetics, IPSS score of 1.5 or greater, Chronic myelomonocytic leukemia [CMML])
• Acute lymphocytic leukemia/lymphoblastic lymphoma (2nd or subsequent CR (OR) Primary induction chemotherapy failure, but subsequently entered into a CR (OR) 1st CR with poor risk cytogenetics)
• Chronic Lymphocytic Leukemia / Prolymphocytic Leukemia (Duration of remission <12 months after receiving chemotherapy with a nucleoside analog (OR) High risk features (i.e. 17p deletion), (OR) Second or subsequent relapse)
• Hodgkin's or Non-Hodgkin's Lymphoma (including low-grade, mantle cell, and intermediate-grade/diffuse) (Previously treated disease that has either relapsed or failed to respond adequately to conventional-dose therapy or autologous transplantation (AND) Chemoresponsive to most recent salvage therapy
• Multiple Myeloma (Presence of a poor risk cytogenetic abnormality [i.e. 17p, t(4;14)], Relapse post autologous transplant)

Exclusion Criteria:

• Poor cardiac function: left ventricular ejection fraction <40%
• Poor pulmonary function: FEV1, FVC, or DLCO <50% predicted
• Poor liver function: bilirubin >2.5 mg/dl (not due to hemolysis, Gilbert's or primary malignancy), AST/ALT > 3X ULN
• Poor renal function: Creatinine >2.0 mg/dl or creatinine clearance (calculated creatinine clearance is permitted) < 40 mL/min
• Ongoing or active systemic infection, active hepatitis B or C virus infection, or known human immunodeficiency virus (HIV) positive.
• Women of childbearing potential who currently are pregnant or who are not practicing adequate contraception
• Patients who have any debilitating medical or psychiatric illness which would preclude their giving informed consent or their receiving optimal treatment and follow-up.
• Systemic treatment, within 14 days before the first dose of MLN9708, with strong strong inhibitors of CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
• Patient has >/= Grade 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 21days of the start of this trial and throughout the duration of this trial.
• Infection requiring systemic antibiotic therapy or other serious infection within 14 days before study enrollment.
• 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 of any agent.
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of MLN9708 including difficulty swallowing

25 of those patients were deemed eligible to participate. 4 additional patients were consented but considered screen failures and were not included in the analysis.

Adverse Events were collected from the first dose of study drug through 30 days after administration of the last dose of MLN9708.

We used the standard definition of adverse events. Only grade 3-4 adverse events were tracked and reported. Grade 3 & 4 AEs are listed in the 'other non-serious' adverse events as they were documented. They did not meet the definition of serious therefore are listed in the separate category.