Combination Chemotherapy and Donor Stem Cell Transplant Followed by Ixazomib Citrate Maintenance Therapy in Treating Patients With Relapsed High-Risk Multiple Myeloma

PRIMARY OBJECTIVES:

I. Safety of BEAM (carmustine, cytarabine, etoposide, melphalan) allogeneic transplant within
100 days, defined as the day 100 transplant related mortality (TRM).

II. Safety of oral ixazomib maintenance therapy from day 100 post allogeneic transplant up to
2 years, defined by the incidence of grade III-IV acute (or overlap) graft-versus-host
disease (GvHD) and grade III-IV ixazomib related toxicity.

SECONDARY OBJECTIVES:

I. To assess the proportion of patients who are eligible to start ixazomib maintenance
therapy.

II. To determine the incidence of discontinuation of ixazomib maintenance therapy at one and
two years post initiation.

III. To determine response rates (complete response [CR], very good partial response [VGPR]
and partial response [PR]) by day 100 and at 12 and 24 months after transplant.

IV. To determine two year progression-free survival and overall survival rate. V. To evaluate
time to engraftment (defined by absolute neutrophil count [ANC] > 500 and platelets >
20,000).

TERTIARY OBJECTIVES:

I. To determine rates of minimal residual disease by deep sequencing (by ClonoSEQ, Adaptive
Biotechnologies).

II. To estimate the cumulative incidence of disease progression rates. III. To determine
rates of >= grade 3 toxicities using the Common Terminology Criteria for Adverse Events
(CTCAE) version 4.03.

IV. To determine the incidence of treatment emergent peripheral neuropathy (all grades).

V. To determine the cumulative incidence and severity of chronic GvHD. VI. To determine the
cumulative incidence of grades III-IV acute GvHD. VII. To evaluate health related quality of
life. VIII. To determine donor and recipient chimerism. IX. To evaluate immune
reconstitution.

OUTLINE:

BEAM CONDITIONING REGIMEN: Patients receive carmustine on day -6, cytarabine and etoposide on
days -5 to -2, and melphalan on day -1.

PERIPHERAL BLOOD STEM CELL TRANSPLANT: Patients undergo allogeneic peripheral blood stem cell
transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive tacrolimus intravenously (IV) or orally (PO) on days -2 to
at least 6 months with a taper as early as 3 months post-transplant and methotrexate IV on
days 1, 3, 6, and 11.

MAINTENANCE THERAPY: Beginning between days 100 and 180 post-transplant, patients receive
ixazomib PO on days 1 and 14 or days 1, 8, and 15 if the principal investigator deems it
medically important. Treatment repeats every 28 days for up to 24 courses in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year.

Inclusion Criteria:

- Relapsed multiple myeloma in patients that have been treated previously with
autologous hematopoietic stem cell transplantation (auto-HCT), bortezomib and an
imunomodulatory agent, AND with at least one of the following high-risk criteria

- High-risk multiple myeloma defined by cytogenetic or fluorescence in situ
hybridization (FISH) detection of any one or more of the following:

- Deletion 17p

- Translocation t(4;14)

- Translocation t(14;16)

- Translocation t(14;20)

- Chromosome 1q gain

- Chromosome 1p deletion

- Deletion 13q by conventional karyotyping (FISH only not acceptable)

- Hypodiploidy

- High-risk gene expression profiling (GEP) at the time of relapse (by Signal
Genetics Myeloma Prognostic Risk Signature [MyPRS] score)

- Beta-2 (B2) microglobulin > 5.5mg

- Plasmablastic morphology (> 2%)

- OR relapsed plasma cell leukemia

- Chemo-sensitive disease; patients with relapsed plasma cell leukemia may have received
systemic therapy including an autologous transplant but it is not required; patients
with relapsed multiple myeloma (MM) must have received prior systemic therapy
including an autologous transplant; patient must be in at least a PR at the time of
transplant; early relapse (VGPR) from complete response will be allowed

- Measurable disease at the time of relapse, defined as a monoclonal immunoglobulin
spike on serum electrophoresis of >= 1 gm/dL (immunoglobulin [IG]G) or >= 0.5 gm/dL
(IGA) and/or urine monoclonal immunoglobulin spike of > 200 mg/24 hours and/ or
involved free light chain (FLC) level >= 10 mg/dl and the serum FLC ratio is abnormal

- Non-secretors must have measurable disease such as plasmacytomas, or positron emission
tomography (PET) avid lytic lesions or bone marrow plasmacytosis >= 30% at the time of
relapse to be eligible

- The patient must have an available sibling or matched unrelated donor with at least a
7/8 human leukocyte antigen (HLA) match

- Creatinine =< 2.0 mg/dL

- Ejection Fraction >= 45%

- Diffusing capacity of the lungs for carbon monoxide (DLCO) >= 50%

- Forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) >= 50%
predicted

- Both men and women and members of all races and ethnic groups will be included

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

- Willing to use adequate contraception for the duration of time on the study and for 6
months after the last therapy

- Female patients must meet one of the following:

- Postmenopausal for at least 1 year before the screening visit, OR

- Surgically sterile, OR

- If they are of childbearing potential:

- Agree to practice 2 effective methods of contraception, at the same time,
from the time of signing the informed consent form through 90 days after the
last dose of study drug, AND

- Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred
and usual lifestyle of the subject; (periodic abstinence [e.g., calendar,
ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception)

- Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree
to one of the following:

- Agree to practice effective barrier contraception during the entire study
treatment period and through 6 months after the last dose of study drug, OR

- Must also adhere to the guidelines of any treatment-specific pregnancy prevention
program, if applicable, OR

- Agree to practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject; periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods
of contraception

- Voluntary written consent must be given before performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care

- DONOR: HLA genotypically identical sibling matched relative

- DONOR: HLA matched unrelated donor according to Standard Practice HLA matching
criteria:

- Matched HLA-A, -B, -C, and -DRB1 alleles by high resolution typing

- Only a single allele disparity will be allowed for HLA-A, B, or C as defined by
high resolution typing

Exclusion Criteria:

- Previous allogeneic stem cell transplant

- POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein [protein] and skin changes)

- Impaired kidney function requiring dialysis or glomerular filtration rate (GFR) <
40mL/min (estimated or calculated)

- Bilirubin > 1.5 x the upper limit of normal

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 2.5 x the upper
limit of normal

- Patients with >= grade III or grade II with pain peripheral neuropathy (National
Cancer Institute [NCI] CTCAE version [v.] 4.03 criteria)

- Receiving steroids > the equivalent of 10 mg prednisone daily for other medical
conditions, e.g., asthma, systemic lupus erythematosis, rheumatoid arthritis

- Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment

- Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive

- 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

- Second malignancy requiring concurrent treatment or those with non-hematological
malignancies (except non-melanoma skin cancers); cancer treated with curative intent <
5 years previously will not be allowed unless approved by the Protocol Chair; cancer
treated with curative intent > 5 years previously is allowed

- Other serious medical or psychiatric illness that could potentially interfere with the
completion of treatment according to this protocol

- Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent

- Radiotherapy within 14 days before enrollment; if the involved field is limited to a
single site, 7 days will be considered a sufficient interval between treatment and
administration of the ixazomib

- Systemic treatment, within 14 days before the first dose of ixazomib, with 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

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral
absorption or tolerance of ixazomib including difficulty swallowing

- Female patients who are lactating or have a positive serum pregnancy test during the
screening period

- Failure to have fully recovered (i.e., =< grade 1 toxicity) from the reversible
effects of prior chemotherapy

- Major surgery within 14 days before enrollment

- Central nervous system involvement

- Participation in other clinical treatment trials, including those with other
investigational agents not included in this trial, within 21 days of the start of this
trial and throughout the duration of this trial

- DONOR: Identical twin

- DONOR: Donors unwilling to donate PBSC

- DONOR: Pregnancy

- DONOR: Infection with HIV

- DONOR: Inability to achieve adequate venous access

- DONOR: Known allergy to filgrastim (G-CSF)

- DONOR: Current serious systemic illness

- DONOR: Failure to meet institutional criteria for stem cell donation

- DONOR: Patient and donor pairs must not be homozygous at mismatched allele