Trial Outcomes & Findings for Allogeneic Hematopoietic Stem Cell Transplantation With Ixazomib for High Risk Multiple Myeloma (BMT CTN 1302) (NCT NCT02440464)

Last Updated: 2023-01-04

Results Overview

The primary endpoint compares progression-free survival as a time to event endpoint from randomization between patients randomized to ixazomib and placebo maintenance in high risk multiple myeloma. Participants are considered a failure of the primary endpoint if they die or suffer from disease progression or if they initiate non-protocol anti-myeloma therapy. Disease progression was evaluated using the International Uniform Response Criteria. Participants must meet one of the criteria for disease progression specified in the protocol. The time to this event is the time from randomization to progression, death, or initiation of non-protocol anti myeloma therapy whichever comes first. The Kaplan-Meier estimator was used to estimate progression-free survival during the 2 year post-transplant follow-up period. Participants who were event-free at two years post-transplant are censored at that time.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

57 participants

Primary outcome timeframe

12 months and 21 months post-randomization

Results posted on

2023-01-04

Participant Flow

The study opened to accrual on August 17, 2015 and closed to accrual on September 14, 2018 with 57 participants enrolled from 15 participating centers in the United States.

Five enrolled participants were not transplanted and an additional 9 participants dropped out of the study prior to randomization for a total of 43 participants who received a transplant and proceeded to randomization. The reasons for no transplant include progression (n=2), toxicity (n=2) and withdrew from study (n=1). The reasons for dropout prior to randomization include death (n=5), progression (n=1), neuropathy (n=1), severe infection (n=1) and withdrew from study (n=1).

Participant milestones

Participant milestones
Measure	Ixazomib Maintenance Allogeneic hematopoietic stem cell transplantation (HSCT) and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For graft-versus-host disease (GVHD) prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Overall Study STARTED	21	22
Overall Study COMPLETED	18	20
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Ixazomib Maintenance Allogeneic hematopoietic stem cell transplantation (HSCT) and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For graft-versus-host disease (GVHD) prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Overall Study Withdrawal by Subject	3	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.	Total n=43 Participants Total of all reporting groups
Age, Continuous	52.6 years n=5 Participants	57.5 years n=7 Participants	55.9 years n=5 Participants
Sex: Female, Male Female	12 Participants n=5 Participants	11 Participants n=7 Participants	23 Participants n=5 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	11 Participants n=7 Participants	20 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants	19 Participants n=7 Participants	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	20 Participants n=7 Participants	38 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Disease Classification High Risk Multiple Myeloma	12 Participants n=5 Participants	12 Participants n=7 Participants	24 Participants n=5 Participants
Disease Classification Standard Risk Multiple Myeloma	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Disease Classification Primary Plasma Cell Leukemia	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Karnofsky Performance Score (KPS) 100	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants
Karnofsky Performance Score (KPS) 90	12 Participants n=5 Participants	9 Participants n=7 Participants	21 Participants n=5 Participants
Karnofsky Performance Score (KPS) 80	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Karnofsky Performance Score (KPS) 70	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants
Disease Response Very Good Partial Response (VGPR)	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Disease Response Partial Response (PR)	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Disease Response Stable Disease or Progression	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: 12 months and 21 months post-randomization

Population: All randomized participants were included in the primary endpoint analysis.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Progression-Free Survival 12 Months Post-randomization	65.3 percentage of participants Interval 50.0 to 77.0	72.7 percentage of participants Interval 58.4 to 82.8
Percentage of Participants With Progression-Free Survival 21 Months Post-randomization	55.3 percentage of participants Interval 40.0 to 68.1	59.1 percentage of participants Interval 44.5 to 71.1

SECONDARY outcome

Timeframe: 100 days post-randomization

Population: All randomized subjects were included in the analysis.

Cumulative incidences of grade III-IV acute GVHD were determined using the Aalen-Johansen estimator. Death prior to acute GVHD is treated as the competing risk. Cumulative incidences are compared between treatment arms using Gray's test. Grading of acute GVHD was derived by consensus grading per BMT Clinical Trials Network (CTN) manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Grade 4 is the worst outcome.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Acute GVHD (Grades III-IV)	9.5 percentage of participants Interval 2.2 to 23.4	0.0 percentage of participants Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: 12 months and 21 months post-randomization

Population: All randomized participants were included in the analysis.

Cumulative incidences of chronic GVHD were determined using the Aalen-Johansen estimator. Death prior to chronic GVHD is treated as the competing risk. Cumulative incidences are compared between treatment arms using Gray's test. Data of chronic GVHD were collected from providers and chart review according to the recommendations of the 2014 NIH Consensus Criteria. Eight organs are scored on a 0-3 scale to reflect degree of chronic GVHD involvement; 3 indicates the worst symptom. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD are also recorded.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Chronic GVHD 12 Months Post-randomization	68.6 percentage of participants Interval 46.8 to 82.9	63.6 percentage of participants Interval 43.3 to 78.3
Percentage of Participants With Chronic GVHD 21 Months Post-randomization	68.6 percentage of participants Interval 46.8 to 82.9	63.6 percentage of participants Interval 43.3 to 78.3

SECONDARY outcome

Timeframe: 2 years post-transplant

Response was assessed using the International Uniform Response Criteria. Best response is the best of all the disease response status at each assessment time point after randomization. The order from best to worst is: Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). All disease classifications are relative to the patient's disease status prior to allogeneic transplant (i.e. study entry). This outcome was compared between treatment groups using all response data up to 2 years post-transplant. These response data were summarized separately for patients in sCR/CR at the time of randomization vs. those who were not in sCR/CR at the time of randomization. Within each group (in sCR/CR vs not in sCR/CR at randomization), best response to treatment was compared between treatment groups using a Fisher's Exact test instead of a chi-square test because of the small sample size.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Best Response to Treatment After Randomization Participants in sCR/CR at Randomization · Stringent Complete Response (sCR)	6 Participants	5 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants in sCR/CR at Randomization · Complete Response (CR)	2 Participants	4 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants in sCR/CR at Randomization · Very Good Partial Response (VGPR)	0 Participants	1 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants in sCR/CR at Randomization · Partial Response (PR)	0 Participants	0 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants in sCR/CR at Randomization · Stable Disease (SD)	0 Participants	0 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants in sCR/CR at Randomization · Progressive Disease (PD)	1 Participants	1 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants Not in sCR/CR at Randomization · Stringent Complete Response (sCR)	3 Participants	4 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants Not in sCR/CR at Randomization · Complete Response (CR)	2 Participants	3 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants Not in sCR/CR at Randomization · Very Good Partial Response (VGPR)	4 Participants	4 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants Not in sCR/CR at Randomization · Partial Response (PR)	2 Participants	0 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants Not in sCR/CR at Randomization · Stable Disease (SD)	0 Participants	0 Participants
Percentage of Participants With Best Response to Treatment After Randomization Participants Not in sCR/CR at Randomization · Progressive Disease (PD)	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 18 months and 24 months post-transplant

Population: All randomized participants were included in the analysis. Participants were divided into those in sCR/CR at the time of randomization vs. those who were not in sCR/CR at the time of randomization. Reasons participants were not evaluable were either they withdrew from study or missed an assessment.

Response was assessed using the International Uniform Response Criteria. All disease classifications are relative to the patient's disease status prior to allogeneic transplant (i.e. study entry). Response to treatment after randomization (sCR, CR, VGPR, or PR) is summarized in each arm post-transplant at 18 months and 24 months post-transplant. These response data were summarized separately for patients in sCR/CR at the time of randomization vs. those who were not in sCR/CR at the time of randomization.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Stringent Complete Response (sCR)	3 Participants	3 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Complete Response (CR)	2 Participants	3 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Very Good Partial Response (VGPR)	1 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Partial Response (PR)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Stable Disease (SD)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Progressive Disease (PD)	1 Participants	1 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Died Before Evaluation	1 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants in sCR/CR at Randomization · Not Evaluable	1 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Stringent Complete Response (sCR)	2 Participants	3 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Complete Response (CR)	1 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Very Good Partial Response (VGPR)	3 Participants	4 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Partial Response (PR)	1 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Stable Disease (SD)	1 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Progressive Disease (PD)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Died Before Evaluation	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 18 Months Post-transplant for Participants Not in sCR/CR at Randomization · Not Evaluable	4 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Stringent Complete Response (sCR)	2 Participants	1 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Complete Response (CR)	3 Participants	6 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Very Good Partial Response (VGPR)	1 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Partial Response (PR)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Stable Disease (SD)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Progressive Disease (PD)	1 Participants	1 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Died Before Evaluation	1 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants in sCR/CR at Randomization · Not Evaluable	1 Participants	1 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Stringent Complete Response (sCR)	2 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Complete Response (CR)	1 Participants	2 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Very Good Partial Response (VGPR)	3 Participants	4 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Partial Response (PR)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Stable Disease (SD)	1 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Progressive Disease (PD)	0 Participants	0 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Died Before Evaluation	0 Participants	1 Participants
Percentage of Participants With Response to Treatment Response to Treatment at 24 Months Post-transplant for Participants Not in sCR/CR at Randomization · Not Evaluable	5 Participants	2 Participants

SECONDARY outcome

Timeframe: 12 months and 21 months post-randomization

Population: All randomized participants were included in the analysis.

Disease progression was evaluated using the International Uniform Response Criteria. Participants in sCR/CR must meet at least one of the criteria for disease progression specified in the protocol for sCR/CR participants; those not in sCR/CR must meet at least one of the disease progression criteria specified in the protocol for those not in sCR/CR. The cumulative incidence of progression from randomization will be estimated for each treatment arm using the Aalen-Johansen estimator, with death in remission treated as a competing risk. Initiation of anti-myeloma therapy will be considered evidence of progression. Participants who were event-free at two years post-transplant are censored at that time.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Disease Progression 12 Months Post-randomization	34.7 percentage of participants Interval 17.8 to 52.3	27.3 percentage of participants Interval 13.0 to 43.8
Percentage of Participants With Disease Progression 21 Months Post-randomization	44.7 percentage of participants Interval 25.6 to 62.1	36.4 percentage of participants Interval 19.8 to 53.3

SECONDARY outcome

Timeframe: 12 months and 21 months post-randomization

Population: All randomized participants are included in the analysis.

Overall survival (OS) is defined as freedom from death from any cause. OS post-randomization is estimated for each arm using the Kaplan-Meier estimator and compared between arms using the log rank test. Participants who are alive at two years post-transplant are censored at that time. Confidence intervals for values of 100% were not calculated and are shown as 100%.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Overall Survival (OS) 12 Months Post-randomization	100.0 percentage of participants Interval 100.0 to 100.0	90.9 percentage of participants Interval 73.7 to 97.1
Percentage of Participants With Overall Survival (OS) 21 Months Post-randomization	94.7 percentage of participants Interval 75.6 to 99.0	86.4 percentage of participants Interval 68.4 to 94.5

SECONDARY outcome

Timeframe: 12 months and 21 months post-randomization

Population: All randomized participants were included in the analysis.

Treatment-related mortality is defined as death occurring in a patient from causes other than disease relapse or progression. The cumulative incidence of treatment-related mortality (TRM) post-randomization is estimated for each treatment arm using the Aalen-Johansen estimator, with progression treated as a competing risk. Participants who were event-free at two years post-transplant are censored at that time. Confidence intervals for values of 0% were not calculated.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Treatment-Related Mortality (TRM) 12 Months Post-randomization	0 percentage of participants Because there were no events, the confidence interval was not calculated.	0 percentage of participants Because there were no events, the confidence interval was not calculated.
Percentage of Participants With Treatment-Related Mortality (TRM) 21 Months Post-randomization	0 percentage of participants Because there were no events, the confidence interval was not calculated.	4.5 percentage of participants Interval 0.5 to 16.5

SECONDARY outcome

Timeframe: 2 years post-randomization

Population: All randomized participants are included in the analysis.

Toxicities are graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Higher grades correspond to worse symptoms with the minimum grade being a 0 and the maximum grade being a 5. Toxicities post-randomization are described for each treatment arm by the type of toxicity as well as peak overall grade.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Intestinal Obstruction	1 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Maximum Toxicity Grade : 0 - 2	8 Participants	6 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Maximum Toxicity Grade : 3	13 Participants	14 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Maximum Toxicity Grade : 4	0 Participants	1 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Maximum Toxicity Grade : 5	0 Participants	1 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Abnormal Liver Symptoms	3 Participants	2 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Dysgeusia	1 Participants	2 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Encephalopathy	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Allergic Reaction	0 Participants	1 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Anaphylaxis	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Blood/Lymphatic Toxicity	5 Participants	8 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Cardiac Toxicity	6 Participants	7 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Fatigue	3 Participants	3 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Fever	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 GI Toxicity	6 Participants	7 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Hearing Loss	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Hemorrhage	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Hepatobiliary/Pancreas	1 Participants	7 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Hyperthyroidism	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Hypothyroidism	0 Participants	1 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Metabolic Toxicity	4 Participants	6 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Musculoskeletal Toxicity	1 Participants	3 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Nervous System Toxicity	4 Participants	4 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Ocular Toxicity	0 Participants	2 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Renal Toxicity	0 Participants	5 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Respiratory Toxicity	2 Participants	8 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Skin/Subcutaneous Tissue Toxicity	1 Participants	5 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Grade 3-5 Vascular Toxicity	2 Participants	3 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Hepatitis	0 Participants	1 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Liver Failure	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Severe Muscle Weakness/Paralysis	0 Participants	1 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Sudden Vision Loss	0 Participants	0 Participants
Percentage of Participants With Toxicities Post-randomization by Toxicity Type Tumor Lysis Syndrome	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 6, 12 and 18 months post-randomization

Population: All randomized participants were included in the analysis.

Toxicities are graded using NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Higher grades correspond to worse symptoms with the minimum grade being a 0 and the maximum grade being a 5. The cumulative incidence of Grade ≥ 3 toxicity was estimated at 6, 12 and 18 months post randomization using Aalen-Johansen estimators for each treatment group. Death from a cause other than toxicity was treated as a competing risk. Comparison of cumulative incidence between the two treatment arms was done using a Z test at fixed time points.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Toxicities Post-randomization by Time Point 6 Months Post-randomization	57.1 percentage of participants Interval 36.9 to 73.1	63.6 percentage of participants Interval 43.4 to 78.3
Percentage of Participants With Toxicities Post-randomization by Time Point 12 Months Post-randomization	61.9 percentage of participants Interval 41.3 to 77.1	68.2 percentage of participants Interval 47.7 to 82.0
Percentage of Participants With Toxicities Post-randomization by Time Point 18 Months Post-randomization	61.9 percentage of participants Interval 41.3 to 77.1	72.7 percentage of participants Interval 52.1 to 85.6

SECONDARY outcome

Timeframe: 2 years post-randomization

Population: All randomized participants are included in the analysis.

All Grade 2 and 3 infections are reported according to the BMT CTN MOP (Manual of Procedures) where a higher grade corresponds to more severe symptoms. The number of participants with post-randomization infections in each treatment arm is described by severity and type of infection.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Infections Post-randomization by Infection Type Participants with Infections	8 Participants	11 Participants
Percentage of Participants With Infections Post-randomization by Infection Type Maximum Severity: Grade 2	6 Participants	10 Participants
Percentage of Participants With Infections Post-randomization by Infection Type Maximum Severity: Grade 3	2 Participants	1 Participants
Percentage of Participants With Infections Post-randomization by Infection Type Participants with Bacterial Infection	3 Participants	2 Participants
Percentage of Participants With Infections Post-randomization by Infection Type Participants with Viral Infection	6 Participants	11 Participants
Percentage of Participants With Infections Post-randomization by Infection Type Participants with Fungal Infection	0 Participants	1 Participants
Percentage of Participants With Infections Post-randomization by Infection Type Participants with Other Infection	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 6, 12 and 18 months post-randomization

Population: All randomized participants were included in the analysis.

All Grade 2 and 3 infections are reported according to the BMT CTN MOP (Manual of Procedures) where a higher grade corresponds to more severe symptoms. The cumulative incidence of severe, life-threatening, or fatal infections (Grade 3), treating death as a competing event, are estimated at 6, 12 and 18 months post randomization using Aalen-Johansen estimators for each treatment group. Comparison of cumulative incidence between the two treatment arms was done using a Z test at fixed time points.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Percentage of Participants With Infections Post-randomization by Time Point 6 Months Post-randomization	4.8 percentage of participants Interval 0.6 to 17.0	0.0 percentage of participants Because there were no events, the confidence interval was not calculated.
Percentage of Participants With Infections Post-randomization by Time Point 12 Months Post-randomization	4.8 percentage of participants Interval 0.6 to 17.0	0.0 percentage of participants Because there were no events, the confidence interval was not calculated.
Percentage of Participants With Infections Post-randomization by Time Point 18 Months Post-randomization	4.8 percentage of participants Interval 0.6 to 17.0	0.2 percentage of participants Interval -10.6 to 11.1

SECONDARY outcome

Timeframe: Randomization, 6-months post-randomization, 24 months post-transplant

Population: Randomized participants who completed the questionnaire are included.

The FACT-BMT version 4.0 instrument is comprised of the Functional Assessment of Cancer Therapy - General (FACT-G), which evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer, and the BMT Concerns module, that addresses disease and treatment-related questions specific to bone marrow transplant. This scale goes from 0 to 196 where higher scores indicate better functioning. The FACT-BMT Total, which has all items in the FACT-G and BMT modules, was used as the outcome measure. This self-reported questionnaire was completed at transplant, randomization, 6 months following the start of maintenance therapy (which corresponds to 6 months post-randomization), and 24 months post-transplant. Comparisons between treatment groups were performed prior to maintenance, 6 months post-randomization and at 24 months after transplant. Only English and Spanish speaking patients were eligible to participate in the quality of life component of this trial.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Functional Assessment of Cancer Therapy (FACT) - Bone Marrow Transplant (BMT) Total Score Randomization	100.0 score on a scale Interval 61.2 to 148.0	110.0 score on a scale Interval 86.0 to 146.0
Functional Assessment of Cancer Therapy (FACT) - Bone Marrow Transplant (BMT) Total Score 6 Months Post-randomization	121.4 score on a scale Interval 58.5 to 148.0	114.0 score on a scale Interval 76.7 to 141.0
Functional Assessment of Cancer Therapy (FACT) - Bone Marrow Transplant (BMT) Total Score 24 Months Post-transplant	121.5 score on a scale Interval 72.5 to 147.0	109.0 score on a scale Interval 68.0 to 133.0
Functional Assessment of Cancer Therapy (FACT) - Bone Marrow Transplant (BMT) Total Score Change from Randomization to 6 Months Post-randomization	5.0 score on a scale Interval -46.0 to 50.0	7.0 score on a scale Interval -33.3 to 29.0
Functional Assessment of Cancer Therapy (FACT) - Bone Marrow Transplant (BMT) Total Score Change from Randomization to 24 Months Post-transplant	12.6 score on a scale Interval -15.0 to 49.0	3.0 score on a scale Interval -42.0 to 32.8

SECONDARY outcome

Timeframe: Randomization, 6 months post-randomization, 24 months post-transplant

Population: Randomized participants who completed the questionnaire are included.

The MOS SF-36 instrument is a general assessment of health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. The scale is 0 to 100 where 0 is maximum disability and 100 is no disability, so the higher the score the more positive the outcome. The Physical Component Summary (PCS) and Mental Component Summary (MCS) were used as the outcome measures in summarizing the SF-36 data for this study. This self-reported questionnaire was completed at transplant, randomization, 6 months following the start of maintenance therapy (which corresponds to 6 months post-randomization), and 24 months post-transplant. Comparisons between treatment groups were performed prior to maintenance, 6 months post-randomization and at 24 months after transplant. Only English and Spanish speaking patients were eligible to participate in the quality of life component of this trial.

Outcome measures

Outcome measures
Measure	Ixazomib Maintenance n=21 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 Participants Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score PCS: Randomization	38.7 score on a scale Interval 22.9 to 57.5	41.5 score on a scale Interval 22.8 to 55.0
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score PCS: 6 Months Post-randomization	47.9 score on a scale Interval 23.4 to 58.4	41.2 score on a scale Interval 23.3 to 58.6
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score PCS: 24 Months Post-transplant	45.1 score on a scale Interval 30.9 to 58.9	45.7 score on a scale Interval 36.6 to 58.5
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score PCS: Change from Randomization to 6 Months Post-randomization	3.3 score on a scale Interval -3.7 to 22.4	1.0 score on a scale Interval -15.7 to 12.1
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score PCS: Change from Randomization to 24 Months Post-transplant	4.7 score on a scale Interval -19.8 to 29.4	7.8 score on a scale Interval -10.4 to 19.4
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score MCS: Randomization	51.5 score on a scale Interval 23.4 to 64.3	49.9 score on a scale Interval 37.7 to 63.3
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score MCS: 6 Months Post-randomization	54.8 score on a scale Interval 26.8 to 63.4	54.5 score on a scale Interval 43.2 to 60.8
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score MCS: 24 Months Post-transplant	56.1 score on a scale Interval 29.4 to 66.0	49.5 score on a scale Interval 22.8 to 58.5
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score MCS: Change from Randomization to 6 Months Post-randomization	-0.6 score on a scale Interval -18.1 to 16.7	5.3 score on a scale Interval -10.6 to 8.2
Medical Outcomes Study (MOS) - Short Form 36 (SF-36) Score MCS: Change from Randomization to 24 Months Post-transplant	4.9 score on a scale Interval -7.5 to 16.6	-2.5 score on a scale Interval -32.0 to 11.0

Adverse Events

Ixazomib Maintenance

Serious events: 11 serious events

Other events: 4 other events

Deaths: 1 deaths

Placebo

Serious events: 12 serious events

Other events: 7 other events

Deaths: 3 deaths

Enrolled Not Randomized

Serious events: 7 serious events

Other events: 2 other events

Deaths: 5 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Ixazomib Maintenance n=21 participants at risk Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by Ixazomib maintenance Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Ixazomib: Between 60 and 120 days following HSCT, patients randomized to the experimental arm will receive Ixazomib maintenance. Maintenance will begin at 3-mg oral doses on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule, following successful completion of 3 cycles at the previous dosage, for a total of 12 cycles.	Placebo n=22 participants at risk Allogeneic HSCT and Fludarabine/Melphalan/Bortezomib conditioning followed by placebo maintenance. Allogeneic HSCT: Eligible patients with a Human Leukocyte Antigen (HLA)-matched related or unrelated donor will undergo allogeneic hematopoietic stem cell transplant at Day 0. For GVHD prophylaxis, patients will be given Tacrolimus from Day -3 until at least 6 months following initiation, at an intravenous daily dose of 0.015 mg/kg. This will be combined with an intravenous administration of Methotrexate at 5 mg/m2 on Days +1, +3, +6, and +11. Fludarabine: Patients will receive conditioning treatment before and after HSCT. Fludarabine will be given at 30 mg/m2 intravenously on Day -6 through Day -3. Melphalan: Melphalan will be given at 70 mg/m2 intravenously on Days -4 and -3. Bortezomib: Bortezomib will be administered at 1.3 mg/m2 intravenously on Day -3. Placebo: Between 60 and 120 days following HSCT, patients randomized to the control group will be given 3 mg of placebo orally on Days 1, 8, and 15 of a 28-day cycle. This will increase to 4-mg doses on the same cycle schedule following successful completion of 3 cycles of placebo maintenance at the 3-mg dose. This will continue for a total of 12 cycles.	Enrolled Not Randomized n=14 participants at risk Participants who enrolled in the study but were not randomized to treatment.
Gastrointestinal disorders Ileus	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
General disorders Influenza like illness	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
General disorders Pyrexia	14.3% 3/21 • Number of events 3 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Immune system disorders Graft versus host disease in gastrointestinal tract	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Infections and infestations Upper respiratory tract infection	4.8% 1/21 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/22 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Musculoskeletal and connective tissue disorders Myalgia	4.8% 1/21 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/22 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Nervous system disorders Posterior reversible encephalopathy syndrome	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	7.1% 1/14 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Renal and urinary disorders Acute kidney injury	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	7.1% 1/14 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.
Vascular disorders Deep vein thrombosis	0.00% 0/21 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	4.5% 1/22 • Number of events 1 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.	0.00% 0/14 • 2 years post-randomization Adverse event (AE) reporting was done using the BMT CTN's Manual of Procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals as defined on the Form Submission Schedule and reported in the secondary outcome "Toxicities". All fatal (Grade 5) expected adverse events were reported in an expedited manner.

Additional Information

Adam Mendizabal, PhD

The Emmes Company

Phone: (301) 251-1161

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place