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

The study is designed as a Phase II, multi-center double-blind trial that randomizes patients
with high risk Multiple Myeloma to Ixazomib maintenance or placebo 60-120 days after
allogeneic HSCT. The primary objective of this randomized trial is to compare progression
free survival from randomization as a time to event endpoint between patients randomized to
Ixazomib maintenance or placebo. Secondary objectives are to describe for each treatment arm:
rates of grade II-IV and III-IV Graft-Versus-Host-Disease (GVHD), chronic GVHD, best disease
response rates, disease progression, transplant related mortality, overall survival, rates of
Grade ≥ 3 toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE)
Version 4.0, incidence of infections, and health-related quality of life.

Inclusion Criteria:

1. 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 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 (< 1.0 g/dl in serum or < 200 mg/24hrs in
urine) may be considered to have met VGPR criteria if < 5% plasma cells in bone marrow
and ≥ 90% decrease in the difference between involved and uninvolved FLC levels from
baseline (time of progression/relapse).

ii. In patients with IgG kappa MM receiving daratumumab: International Myeloma Working
Group criteria for VGPR may not be achieved since daratumumab is known to increase the
IgG kappa spike. In such cases the FLC and marrow may be used to establish VGPR, as
above, with prior approval from the protocol co-chairs.

c. Patients with standard risk multiple myeloma in VGPR or better (see criteria 2.b.i.
and 2.b.ii. above) at the time of enrollment with 1 prior progression ≤ 24.0 months
from single or planned tandem autologous HCT; or d. Patients with primary plasma cell
leukemia in VGPR or better with no prior disease progression and are ≤ 18.0 months
after autologous HCT, or are ≤ 18.0 months after initiation of anti-myeloma therapy
without prior autologous HCT.

2. Patients must have a related or unrelated peripheral blood stem cell donor that meet
one of the following criteria:

1. A sibling donor who is a 6/6 match at HLA-A and -B (intermediate or higher
resolution) and -DRB1 (at high resolution using DNA-based typing) and must be
willing to donate peripheral blood stem cells and meet institutional criteria for
donation OR

2. A related donor (other than sibling) who is a 8/8 match for HLA-A, -B, -C (at
intermediate or higher resolution) and -DRB1 (at high resolution using DNA-based
typing) and must be willing to donate peripheral blood stem cells and meet
institutional criteria for donation OR

3. An unrelated donor who is an 8/8 match at HLA-A, -B, -C, and -DRB1 (at high
resolution using DNA-based typing) and must be willing to donate peripheral blood
stem cells and meet institutional criteria for donation.

3. Cardiac function: Ejection fraction > 40%

4. Estimated creatinine clearance greater than 40 mL/minute (using the Cockcroft-Gault
formula and actual body weight)

5. Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) ≥ 40%
(adjusted for hemoglobin) and forced expiratory volume in one second (FEV1) ≥ 50%

6. Liver function: total bilirubin < 2x the upper limit of normal and alanine
aminotransferase (ALT)/aspartate aminotransferase (AST) < 2.5x the upper normal limit
(Patients with Gilbert's Disease are permitted to exceed the defined bilirubin value
of 2x the upper limit of normal, however measurements of direct bilirubin should be
done to confirm this diagnosis).

7. Female subjects (unless postmenopausal for at least 1 year before the screening visit,
or surgically sterilized), agree to practice two (2) effective methods of
contraception at the same time, or agree to practice true abstinence when this is in
line with the preferred and usual lifestyle of the subject (Periodic abstinence [eg,
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not
acceptable methods of contraception) through 90 days after the last dose of
maintenance therapy (see Section 2.6.2 for definition of postmenopausal).

8. Male subjects (even if surgically sterilized) must agree to one of the following:
practice effective barrier contraception (see Section 2.6.4.1 for list of barrier
methods), or practice true abstinence when this is in line with the preferred and
usual lifestyle of the subject. Periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of
from the time of signing the informed consent through 90 days after last dose of
maintenance therapy.

9. 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.

10. Able to comply with the study visit schedule and other protocol requirements.

Exclusion Criteria:

1. Karnofsky Performance Score < 70%

2. Prior allogeneic HCT

3. Patient with purely non-secretory multiple myeloma [absence of monoclonal protein (M
protein) in serum as measured by electrophoresis and immunofixation and the absence of
Bence Jones protein in the urine defined by the use of conventional electrophoresis
and immunofixation techniques and the absence of involved serum free light chain > 100
mg/L].

4. Planned pre-emptive/prophylactic administration of donor lymphocytes (as per section
2.5.2)

5. Central Nervous System (CNS) involvement with multiple myeloma defined as CSF
positivity for plasma cells or a parenchymal CNS plasmacytoma

6. Patients with uncontrolled bacterial, viral or fungal infections (currently taking
medication and with progression or no clinical improvement) at time of enrollment.

7. Presence of fluid collection (ascites, pleural, or pericardial effusion) that
interferes with methotrexate clearance or makes methotrexate use contraindicated.

8. Patients seropositive for the human immunodeficiency virus (HIV).

9. Patient with active Hepatitis B or C determined by serology and/or NAAT.

10. Patients with hypersensitivity to bortezomib, boron or mannitol.

11. Known GI disease or GI procedure that could interfere with the oral absorption or
tolerance of MLN9708 (ixazomib) including difficulty swallowing.

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

13. Patients with ≥ grade 2 sensory peripheral neuropathy.

14. 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.

15. Female patients who are lactating or pregnant

16. 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 < 5 years, which is in remission, will be reviewed
on a case-by-case basis by the Protocol Officer or one of the Protocol Chairs.

17. Patients with multi-organ involvement by amyloidosis or evidence of amyloidosis
related organ dysfunction.

18. Failure to have fully recovered (i.e., no toxicities > Grade 1 by CTCAE version 4.0)
from the reversible effects of prior chemotherapy.

19. Patient with serious medical of psychiatric illness likely to interfere with
participation on this clinical study

20. 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.

21. Patients who have received radiation therapy within 3 weeks before transplant.
Enrollment of subjects who require concurrent radiotherapy (which must be localized in
its field size) should be deferred until the radiotherapy is completed and 3 weeks
have elapsed since the last date of therapy.

22. Patients unable or unwilling to adhere to the study assessment schedule.