Trial Outcomes & Findings for Combination Chemotherapy, Rituximab, and Ixazomib Citrate in Treating Patients With Non-Hodgkin Lymphoma (NCT NCT02481310)

Last Updated: 2022-02-21

Results Overview

The RP2D will be determined by the evaluation of dose-limiting toxicities (DLT) to find the Maximum Tolerated Dose (MTD) which will constitute the RP2D. DLTs will be defined as the occurrence of ≥ Grade 3 toxicity experienced during the first cycle (3 weeks or 21 days) of study treatment, will be determined, except for cytopenias. The dose of ixazomib will start at 2.3 mg weekly (for phase I patients) when given concurrently with DA-EPOCH-R. Single-subject cohorts (escalating in ixazomib dose) will be enrolled until the MTD is encountered, after which expansion to 3-subject cohorts will be undertaken. The MTD from phase I will equate the RP2D for ixazomib given in conjunction with DA-EPOCH-R.

Recruitment status

UNKNOWN

Study phase

PHASE1/PHASE2

Target enrollment

38 participants

Primary outcome timeframe

The first 21 days of treatment

Results posted on

2022-02-21

Participant Flow

The study opened to accrual on Aug 24, 2015 with the first patient being enrolled and starting treatment on 10.28.2015. The study closed to any further accrual on October 1sts 2019 with 38 patients enrolled on study. The study closed prior to reaching full accrual goal of up to 55 patients.

First patient was enrolled to Cohort 1. Second patient enrolled to Cohort 2. Third patient enrolled to Cohort 3. Forth and fifth patient enrolled to Cohort 2. All further patients enrolled to phase II (same dose as Cohort 2).

Participant milestones

Participant milestones
Measure	Treatment- Cohort 1(Combination Chemotherapy, Rituximab, Ixazomib 2.3 mg) INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Treatment Cohort 2 and Phase II (Combination Chemotherapy, Rituximab, Ixazomib 3 mg) NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Treatment - Cohort 3 (Combination Chemotherapy, Rituximab, Ixazomib 4 mg) NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
Induction Treatment (6 Cycles) STARTED	1	36	1
Induction Treatment (6 Cycles) Reached First Evaluable Response	1	34	1
Induction Treatment (6 Cycles) Complete 6 Cycles	1	30	1
Induction Treatment (6 Cycles) COMPLETED	1	30	1
Induction Treatment (6 Cycles) NOT COMPLETED	0	6	0
Maintenance Treatment STARTED	1	21	1
Maintenance Treatment Started Maintenance Treatment	1	21	1
Maintenance Treatment COMPLETED	1	21	1
Maintenance Treatment NOT COMPLETED	0	0	0
Follow up STARTED	1	32	1
Follow up COMPLETED	1	29	1
Follow up NOT COMPLETED	0	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment- Cohort 1(Combination Chemotherapy, Rituximab, Ixazomib 2.3 mg) INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Treatment Cohort 2 and Phase II (Combination Chemotherapy, Rituximab, Ixazomib 3 mg) NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Treatment - Cohort 3 (Combination Chemotherapy, Rituximab, Ixazomib 4 mg) NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
Follow up Still in follow up	0	3	0

Baseline Characteristics

Combination Chemotherapy, Rituximab, and Ixazomib Citrate in Treating Patients With Non-Hodgkin Lymphoma

Baseline characteristics by cohort

PRIMARY outcome

Timeframe: The first 21 days of treatment

Population: 1 patient enrolled at 2.3 mg of ixazomib, 3 patients enrolled at 3 mg of ixazomib, 1 patient enrolled at 4 mg ixazomib in phase I were evaluable for this endpoint.

Outcome measures

Outcome measures
Measure	Treatment (Combination Chemotherapy, Rituximab, Ixazomib) n=5 Participants INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
To Determine the Recommended Phase II Dose (RP2D) of Ixazomib in Combination With DA-EPOCH-R.	3 mg

PRIMARY outcome

Timeframe: Up to 12 months from initiation of treatment

Population: Only patients included in the phase II dose are included in this endpoint per protocol.

12-month PFS will be defined as the percentage of patients alive and progression free 12 months from start of therapy. Patients lost to follow up will be censored from last point of contact. PFS was calculated using a Kplan-meier estimation with the probability of patients being progression free at 12 months, presented as the percentage based on this probability.

Outcome measures

Outcome measures
Measure	Treatment (Combination Chemotherapy, Rituximab, Ixazomib) n=36 Participants INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
12-month PFS (Progression Free Survival) of Treatment With Ixazomib in Combination With DA-EPOCH-R (Phase II)	75.84 probability (%) of patients alive Interval 62.5 to 92.03

SECONDARY outcome

Timeframe: Assessed at the beginning each cycle with up to 6 cycles of induction treatment and up to 13 cycles of maintenance treatment (1 cycle =21 days) and at approximately 21 days after the last treatment.

Adverse events will be assessed using CTCAE v 4.03. In general grading will be as follows: Mild (grade 1): the event causes discomfort without disruption of normal daily activities. Moderate (grade 2): the event causes discomfort that affects normal daily activities. Severe (grade 3): the event makes the patient unable to perform normal daily activities or significantly affects his/her clinical status. Life-threatening (grade 4): the patient was at risk of death at the time of the event. Fatal (grade 5): the event caused death.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to approximately 30 months

OS will be defined as freedom from death by any cause and measured from time of treatment initiation and completion of follow up or death from any cause.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: After 2 cycles, then after 6 cycles and then at the discretion of the investigator for up to 13 maintenance cycles (1 cycle = 21 days)

Anti-tumor activity will be defined as the detection of SD (Stable Disease), Partial Response (PR), or CR (Complete Remission) by CT or PET/CT scan, and/or resolution of marrow-only involvement. CR and PR will each be assessed according to the Revised Response Criteria for Malignant Lymphoma. Assessments will be performed after cycles 2 and 6, then at the discretion of the investigator. In general: CR-Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms PR-At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. No increase should be observed in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease should be observed. SD-fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive disease

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to 1 year after treatment stopped

Patients will be categorized as either FDG-PET (+) or (-) at interim and end-of treatment imaging.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 1 year

Impact of COO defined as germinal center B-cell (GCB) and non-GCB via the Hans algorithm upon response rate, PFS, and OS (applicable only to patients with DLBCL).

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 1 year

Feasibility and outcomes of consolidation SCT will be assessed. Patients will be grouped by whether consolidative SCT was performed in first remission, with PFS compared across groups (SCT vs. non-SCT).

Outcome measures

Outcome data not reported

Adverse Events

Treatment (Combination Chemotherapy, Rituximab, Ixazomib)

Serious events: 20 serious events

Other events: 38 other events

Deaths: 6 deaths

Serious adverse events

Serious adverse events
Measure	Treatment (Combination Chemotherapy, Rituximab, Ixazomib) n=38 participants at risk INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
Infections and infestations Cholecystitis	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Lung infection	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Blood and lymphatic system disorders Febrile Neutropenia	18.4% 7/38 • Number of events 8 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Esophageal perforation	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Thromboembolic event	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations duodenitis	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Injury, poisoning and procedural complications Spinal fracture (lumbar)	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Sepsis	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders COPD Exacerbation	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations parainfluenza 3	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Thromboembolic event - pulmonary embolism	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hyponatremia	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Acute kidney injury	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Cardiac Arrest	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Urinary tract infection	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Small intestine and colonic perforation	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) gastric adenocarcinoma	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Blood and lymphatic system disorders Febrile neutropenia	2.6% 1/38 • Number of events 1 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).

Other adverse events

Other adverse events
Measure	Treatment (Combination Chemotherapy, Rituximab, Ixazomib) n=38 participants at risk INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV
Blood and lymphatic system disorders Anemia	100.0% 38/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Lymphocyte count decreased	100.0% 38/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Platelet count decreased	100.0% 38/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypoalbuminemia	97.4% 37/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Fatigue	92.1% 35/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Hypertension	89.5% 34/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypocalcemia	89.5% 34/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations White blood cell decreased	89.5% 34/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypokalemia	86.8% 33/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Neutrophil count decreased	86.8% 33/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Constipation	84.2% 32/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Peripheral sensory neuropathy	78.9% 30/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Nausea	76.3% 29/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Alkaline phosphatase increased	63.2% 24/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hyperglycemia	63.2% 24/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypophosphatemia	63.2% 24/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Alanine aminotransferase increased	57.9% 22/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Mucositis oral	57.9% 22/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Weight loss	57.9% 22/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Aspartate aminotransferase increased	55.3% 21/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Cough	52.6% 20/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Edema limbs	52.6% 20/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Headache	52.6% 20/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hyponatremia	52.6% 20/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Diarrhea	50.0% 19/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Dyspnea	47.4% 18/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Psychiatric disorders Anxiety	42.1% 16/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Back pain	42.1% 16/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Vomiting	42.1% 16/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Dysgeusia	39.5% 15/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Nasal congestion	39.5% 15/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Pain	39.5% 15/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Abdominal pain	36.8% 14/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Dizziness	36.8% 14/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Psychiatric disorders Insomnia	36.8% 14/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders - Other, specify	36.8% 14/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Anorexia	34.2% 13/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Investigations - Other, specify	34.2% 13/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Creatinine increased	31.6% 12/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Psychiatric disorders Depression	31.6% 12/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Sinus tachycardia	31.6% 12/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders - Other, specify	28.9% 11/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Bone pain	26.3% 10/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Chills	26.3% 10/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Generalized muscle weakness	26.3% 10/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypernatremia	26.3% 10/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypomagnesemia	26.3% 10/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Cardiac disorders - Other, specify	23.7% 9/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Fever	23.7% 9/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders General disorders and administration site conditions - Other, specify	23.7% 9/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Pain in extremity	23.7% 9/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Renal and urinary disorders - Other, specify	23.7% 9/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Sore throat	23.7% 9/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Blood bilirubin increased	21.1% 8/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Gastrointestinal disorders - Other, specify	21.1% 8/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hyperkalemia	21.1% 8/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Localized edema	21.1% 8/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Paresthesia	21.1% 8/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Urinary frequency	21.1% 8/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Alopecia	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Injury, poisoning and procedural complications Bruising	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Hemorrhoids	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypoglycemia	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Infections and infestations - Other, specify	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, specify	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	18.4% 7/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Dry mouth	15.8% 6/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypercalcemia	15.8% 6/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hyperuricemia	15.8% 6/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Myalgia	15.8% 6/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Abdominal distension	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Blurred vision	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Dry skin	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Eye disorders - Other, specify	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Infusion related reaction	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Postnasal drip	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Rash maculo-papular	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Sleep apnea	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Thromboembolic event	13.2% 5/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Dehydration	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Dyspepsia	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Dysphagia	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Epistaxis	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Gastroesophageal reflux disease	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Hoarseness	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Hypotension	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Neck pain	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Non-cardiac chest pain	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Obesity	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Peripheral motor neuropathy	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Productive cough	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Reproductive system and breast disorders Reproductive system and breast disorders - Other, specify	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Ear and labyrinth disorders Tinnitus	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Tremor	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Urinary tract infection	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Weight gain	10.5% 4/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Atelectasis	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Bloating	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Blood and lymphatic system disorders Blood and lymphatic system disorders - Other, specify	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Cataract	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Ear and labyrinth disorders Ear and labyrinth disorders - Other, specify	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Blood and lymphatic system disorders Febrile neutropenia	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Flatulence	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Hot flashes	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Hyperhidrosis	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Endocrine disorders Hypothyroidism	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations INR increased	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Lethargy	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Blood and lymphatic system disorders Lymph node pain	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Nail loss	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Oral pain	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Pleural effusion	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Pruritus	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Sepsis	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Skin ulceration	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Upper respiratory infection	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Urinary incontinence	7.9% 3/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Acute kidney injury	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Arthralgia	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Bullous dermatitis	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Chest wall pain	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Cholesterol high	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Psychiatric disorders Confusion	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Flu like symptoms	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Gait disturbance	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Hematuria	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Hypermagnesemia	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Immune system disorders Immune system disorders - Other, specify	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Blood and lymphatic system disorders Leukocytosis	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Lung infection	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Malaise	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Pain of skin	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Palpitations	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Psychiatric disorders Psychiatric disorders - Other, specify	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Rash acneiform	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Respiratory failure	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Retinal detachment	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Sinusitis	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Toothache	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Renal and urinary disorders Urinary retention	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Watering eyes	5.3% 2/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Acidosis	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Alkalosis	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Anal hemorrhage	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Aphonia	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Arthritis	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Atrial fibrillation	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Reproductive system and breast disorders Breast pain	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Cerebrospinal fluid leakage	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Chest pain - cardiac	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Hepatobiliary disorders Cholecystitis	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Psychiatric disorders Delirium	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Dysesthesia	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Dysphasia	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Ear and labyrinth disorders Ear pain	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Edema face	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Encephalopathy	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Endocrine disorders Endocrine disorders - Other, specify	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Enterocolitis infectious	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Reproductive system and breast disorders Erectile dysfunction	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Erythema multiforme	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Esophageal infection	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Eye pain	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Facial pain	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Injury, poisoning and procedural complications Fall	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Fecal incontinence	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Hematoma	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Hepatobiliary disorders Hepatobiliary disorders - Other, specify	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Hiccups	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Hypersomnia	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Hypoxia	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
General disorders Infusion site extravasation	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Injury, poisoning and procedural complications Injury, poisoning and procedural complications - Other, specify	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Left ventricular systolic dysfunction	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Lower gastrointestinal hemorrhage	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Lymphedema	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Lymphocyte count increased	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Memory impairment	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Musculoskeletal and connective tissue disorders Musculoskeletal deformity	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Skin and subcutaneous tissue disorders Nail discoloration	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Nervous system disorders - Other, specify	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Pregnancy, puerperium and perinatal conditions Pregnancy, puerperium and perinatal conditions - Other, specify	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Presyncope	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Pulmonary edema	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Cardiac disorders Sinus bradycardia	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Sinus pain	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Skin infection	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Sneezing	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Metabolism and nutrition disorders Tumor lysis syndrome	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Gastrointestinal disorders Upper gastrointestinal hemorrhage	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Investigations Urine output decreased	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Injury, poisoning and procedural complications Vascular access complication	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Vascular disorders Vascular disorders - Other, specify	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Nervous system disorders Vasovagal reaction	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Eye disorders Vitreous hemorrhage	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Respiratory, thoracic and mediastinal disorders Wheezing	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).
Infections and infestations Wound infection	2.6% 1/38 • Adverse events were collected at the beginning of each cycle for up to 6 induction cycles and up to 13 maintenance cycles (1 cycle = 21 days) and 21 days after the last study treatment Secondary endpoints are written to have phase I \& II patient data combined in analysis. Due to the way that adverse event data collected was analysed (i.e. phase I/II data was analysed combined regardless of dose) all patients data here is shown as one cohort regardless of initial dose of ixazomib given. This is due to the way the protocol was written and that only 2 patients out of 38 received a different initial starting dose (and the starting dose for all in maintenance was 4 mg).

Additional Information

Barbara Pro, MD

Northwestern University

Phone: 312-695-6832

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Treatment- Cohort 1(Combination Chemotherapy, Rituximab, Ixazomib 2.3 mg) n=1 Participants INDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Treatment Cohort 2 and Phase II (Combination Chemotherapy, Rituximab, Ixazomib 3 mg) n=36 Participants NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Treatment - Cohort 3 (Combination Chemotherapy, Rituximab, Ixazomib 4 mg) n=1 Participants NDUCTION: Patients receive ixazomib citrate PO on day 1 and day 8 or 15; etoposide IV, vincristine sulfate IV, and doxorubicin hydrochloride IV continuously over 96 hours on days 1-4; prednisone PO BID on days 1-5; rituximab IV should be started at 50 mg/hr, and increased in 50-mg/hr increments every 30 minutes to a maximum rate of 400 mg/hr on day 1; and cyclophosphamide IV over 90 minutes on day 5. CNS PROPHYLAXIS: Patients with a negative LP receive methotrexate IT once per course. Patients with a positive LP receive methotrexate IT or intraventricularly OR cytarabine IT or intraventricularly OR methotrexate IT or intraventricularly, cytarabine IT or intraventricularly, and therapeutic hydrocortisone IT or intraventricularly. MAINTENANCE: Patients not treated with consolidative SCT, receive ixazomib citrate PO BID on days 1, 8, and 15. Treatment repeats every 28 days for up to one year in the absence of disease progression or unacceptable toxicity. Cyclophosphamide: Given IV Cytarabine: Given IT or intraventricularly Doxorubicin Hydrochloride: Given IV Etoposide: Given IV Ixazomib Citrate: Given PO Laboratory Biomarker Analysis: Correlative studies Methotrexate: Given IT or intraventricularly Prednisone: Given PO Rituximab: Given IV Therapeutic Hydrocortisone: Given IT or intraventricularly Vincristine Sulfate: Given IV	Total n=38 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	25 Participants n=7 Participants	0 Participants n=5 Participants	25 Participants n=4 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants	11 Participants n=7 Participants	1 Participants n=5 Participants	13 Participants n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	11 Participants n=7 Participants	0 Participants n=5 Participants	11 Participants n=4 Participants
Sex: Female, Male Male	1 Participants n=5 Participants	25 Participants n=7 Participants	1 Participants n=5 Participants	27 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1 Participants n=5 Participants	35 Participants n=7 Participants	1 Participants n=5 Participants	37 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 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	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	3 Participants n=7 Participants	0 Participants n=5 Participants	3 Participants n=4 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	33 Participants n=7 Participants	1 Participants n=5 Participants	35 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants