TerminatedNCT01659658Updated Sep 2, 2025Results posted

Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis

A Phase 3 interventional study of IXAZOMIB and Dexamethasone in Relapsed or Refractory Systemic Light Chain Amyloidosis, sponsored by Millennium Pharmaceuticals, Inc.. Terminated at 66 sites in 15 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-09-02.

Sponsored by Millennium Pharmaceuticals, Inc. · Phase 3, Interventional, and Treatment

Why this study was terminated

Sponsor's decision

Phase: Phase 3
Study type: Interventional
Enrollment: 177
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study summary

The purpose of this study is to provide continued access of ixazomib and/or other study medications and to continue collecting relevant safety data to monitor participant's safety, determine whether dexamethasone plus IXAZOMIB improves hematologic response, 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician's choice of a chemotherapy regimen in participants diagnosed with relapsed or refractory systemic light chain (AL) amyloidosis.

Read the detailed description

The drug being tested in this study is called IXAZOMIB. IXAZOMIB was being tested to treat people who have relapsed or Refractory Systemic Light Chain (AL) Amyloidosis.

The study will enroll approximately 177 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

IXAZOMIB 4 mg plus Dexamethasone 20 mg
Physician's choice: Participants will receive one of the following treatment options as selected by the physician:
1. Dexamethasone 20 mg
2. Dexamethasone 20 mg + Melphalan 0.22 mg/kg
3. Dexamethasone 20 mg + Cyclophosphamide 500 mg
4. Dexamethasone 20 mg + Thalidomide 200 mg
5. Dexamethasone 20 mg + Lenalidomide 15 mg
6. All participants will be asked to take oral formulation of the drugs. In both treatment arms, each participant will continue to receive sequential cycles of therapy until disease progression, unacceptable toxicity, or until the study is terminated, whichever occurs first. Participants in Arm B receiving melphalan and dexamethasone will be treated to best response plus 2 additional cycles.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 120 months (10 years), including 84 months of enrollment and 36 months of follow-up after the last participant is enrolled.

Conditions studied

Relapsed or Refractory Systemic Light Chain Amyloidosis

Browse trials for

Keywords

MLN9708
Amyloidosis
Light Chain
IXAZOMIB
Tourmaline AL1
Drug Therapy

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Male or female participants 18 years or older.
Biopsy-proven diagnosis of primary systemic light chain amyloidosis (AL amyloidosis) according to the following standard criteria:
1. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo red staining with exhibition of an apple-green birefringence
2. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in cases of doubt, amyloid typing may be necessary.
Measurable disease as defined by serum differential free light chain concentration (dFLC, difference between amyloid forming [involved] and nonamyloid forming [uninvolved] free light chain [FLC]) ≥ 50 mg/L.
Objective, measurable major (cardiac or renal) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required):
1. Cardiac involvement is defined as the presence of a mean left ventricular wall thickness on echocardiogram greater than 12 mm in the absence of other potential causes of left ventricular hypertrophy (controlled hypertension is allowed) with a noncardiac biopsy showing amyloid, or a positive cardiac biopsy in the presence of clinical or laboratory evidence of involvement. If there is isolated cardiac involvement, then typing of amyloid deposits is recommended.
2. Renal involvement is defined as proteinuria (predominantly albumin) >0.5 g/day in a 24-hour urine collection.
Note: Amyloid involvement of other organ systems is allowed, but not required.
Must be relapsed or refractory after 1 or 2 prior therapies. For this protocol, relapsed is defined as progressive disease (PD) documented more than 60 days after last dose; refractory is defined as documented absence of hematologic response or hematologic progression on or within 60 days after last dose of prior therapy.
1. Participant must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed participants in the future, at some time point after the first interim analysis (IA). In that case, the participant may not be refractory to proteasome inhibitor therapy.)
2. Given that the physician may select from an offered list of regimens to treat a specific participant, the participant may be refractory to an agent/s listed within the list of offered treatment choices
3. Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status) from the reversible effects of prior therapy
4. If a participant has received a transplant as his/her first-line therapy, he/she must be at least 3 months post transplantation and recovered from the side effects of the stem cell transplant.
Must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined by N-terminal proBNP [NT-proBNP] cut-off of \< 332 pg/mL and troponin T cut-off of 0.035 ng/mL as thresholds):
1. Stage 1: both NT-proBNP and troponin T under threshold
2. Stage 2: either NT-proBNP or troponin T (but not both) over threshold;
3. Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP \< 8000 pg/mL)
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
Clinical laboratory values:
1. Absolute neutrophil count ≥ 1000/µL
2. Platelet count ≥ 75,000/µL
3. Total bilirubin ≤ 1.5 upper limit of normal (ULN), except for participants with Gilbert's syndrome as defined by > 80% unconjugated bilirubin and total bilirubin ≤ 6 mg/dL
4. Alkaline phosphatase ≤ 5 x ULN
5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN
6. Calculated creatinine clearance ≥ 30 mL/min
Female participants who:
1. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study treatment, AND
2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
3. Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.).
Male participants, even if surgically sterilized (ie, status post vasectomy), who:
1. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, AND
2. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
3. Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion criteria

Exclusion Criteria:

Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL amyloidosis.
Female participants who are lactating, breast feeding, or pregnant.
Medically documented cardiac syncope, uncompensated New York Heart Association (NYHA) Class 3 or 4 congestive heart failure, myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.
Clinically overt multiple myeloma, according to the International Myeloma Working Group (IMWG) criteria with at least 1 of the following:
1. Bone lesions
2. Hypercalcemia, defined as a calcium of > 11 mg/dL
Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or gastrointestinal (GI) procedure that could interfere with the oral absorption or tolerance of treatment.
Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational or which would be considered as a treatment of AL amyloidosis. However, participants may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent) if they are being given for disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).
Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the participant inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active hepatitis B or C infection.
Psychiatric illness/social situations that would limit compliance with study requirements.
Known allergy to boron, MLN9708, any of the study treatments, their analogues, or excipients.
Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment.
Diagnosed or treated for another malignancy within 3 years (or 5 years for participants in France) before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

Study design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 177 participants (actual)

Study arms

Experimental
Arm A: Ixazomib + Dexamethasone
Ixazomib 4 mg, capsules, orally, once on Days 1, 8, and 15 and dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22 of each 28-day cycle for up to a maximum of 95.2 months. Dexamethasone was increased up to 40 mg/day after 4 weeks, if tolerated.
Drug: IXAZOMIB · Drug: Dexamethasone
Active comparator
Arm B: Dexamethasone + Melphalan
Participants received dexamethasone 20 mg, orally, and melphalan 0.22 mg/kg, orally once on Days 1 through 4 of each 28-day cycle, for up to a maximum of 72.4 months.
Drug: Dexamethasone · Drug: Melphalan
Active comparator
Arm B: Dexamethasone + Cyclophosphamide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15, and 22, and cyclophosphamide 500 mg, orally, on Days 1, 8 and 15 of each 28-day cycle for up to a maximum of 72.4 months.
Drug: Dexamethasone · Drug: Cyclophosphamide
Active comparator
Arm B: Dexamethasone + Thalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle, and thalidomide daily at a starting dose of 50 mg and increased, as tolerated, to a maximum of 200 mg, orally for up to a maximum of 72.4 months.
Drug: Dexamethasone · Drug: Thalidomide
Active comparator
Arm B: Dexamethasone + Lenalidomide
Participants received dexamethasone 20 mg, orally, once weekly on Days 1, 8, 15 and 22 of each 28-day cycle and lenalidomide 15 mg, orally, once on Days 1 through 21 every 28 days for up to a maximum of 72.4 months.
Drug: Dexamethasone · Drug: Lenalidomide

Interventions

DrugIXAZOMIB
IXAZOMIB capsules
Also known as: MLN9708
DrugDexamethasone
Dexamethasone tablets
DrugMelphalan
Melphalan tablets
DrugCyclophosphamide
Cyclophosphamide tablets
DrugThalidomide
Thalidomide capsules
DrugLenalidomide
Lenalidomide capsules

What researchers measure

Primary outcomes

Percentage of Participants With Overall Hematologic Response
Overall hematologic response was defined as the percentage of participants with complete response (CR), very good partial response (VGPR) and partial response (PR) based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as assessed by an adjudication committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of free light chain (FLC) ratio. VGPR: differential free light chain (difference between involved and uninvolved FLC levels; dFLC) \< 40 mg/L. PR: ≥50% reduction in dFLC. Percentages were rounded off to the nearest decimal.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
Cardiac (Heart) deterioration was defined as the need for hospitalization for heart failure. Kidney deterioration was defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration was evaluated by an adjudication committee. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: Up to 2 years

Secondary outcomes

Percentage of Participants With Complete Hematologic Response
Complete hematologic response was defined as the percentage of participants with CR based on central laboratory results and the 2010 ISA Consensus Criteria as assessed by the investigator. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of FLC ratio. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Overall Survival
Overall survival was defined as the time from the date of randomization to the date of death. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Progression Free Survival (PFS)
PFS was defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ (cardiac or renal) progression, or death due to any cause, whichever occurred first according to central laboratory results and ISA criteria as evaluated by the investigator. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Hematologic Disease Progression Free Survival
Hematologic disease PFS was defined as the time from the date of randomization to the date of first documentation of hematologic PD according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurred first. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
Time to vital organ deterioration or death was assessed by the investigator and defined as the time from randomization to vital organ (heart or kidney) deterioration or death, whichever occurs first. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to ESRD with the need for maintenance dialysis or renal transplantation. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From randomization to time of vital organ deterioration or death (up to 115 months)
Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response
Vital organ (heart and kidney) response rate was defined as the percentage of participants who achieved vital organ response according to central laboratory results and ISA criteria as evaluated by an adjudication committee. A vital organ response was defined as response of 1 or 2 of the involved vital organs with no change from Baseline in the rest of involved vital organs. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Vital Organ Progression Free Survival
Vital organ PFS is defined as the time from the date of randomization to the date of first documentation of progression of vital organ (heart or kidney) according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurs first. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Duration of Hematologic Response
Duration of hematologic response (DOR) was defined as the time from the date of first documentation of a hematologic response to the date of first documented hematologic disease progression as determined by the investigator. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From time of first documented response to disease progression (up to 115 months)
Number of Participants With Serious Adverse Events (SAEs)
A SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly/birth defect or medically important event.
Time frame: From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months)
Time To Treatment Failure (TTF)
TTF was defined as the time from randomization to the date of first documented treatment failure. Treatment failure was defined as: 1) death due to any cause; 2) hematologic progression or major organ progression according to central laboratory results and ISA criteria as evaluated by the investigator; 3) clinically morbid organ disease requiring additional therapy; or 4) withdrawn for any reason. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Time To Subsequent Anticancer Treatment
Time to subsequent anticancer therapy was defined as the time from randomization to the first date of subsequent anticancer therapy. Participants without subsequent anticancer therapy were censored at the date of death or last known to be alive. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until subsequent anticancer treatment (up to 115 months)
Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up
SF-36 Version 2 is a multipurpose, participant completed, short-form health survey with 36 questions that consists of an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Physical component summary (PCS) is mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and general health (GH). Mental component summary (MCS) is mostly contributed by mental health (MH), role emotional (RE), social function (SF), and vitality (VT). Each component on the SF-36 item health survey is scored from 0 (best) to 100 (worst). Total score ranges from 0-100, where higher scores are associated with less disability and better quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: Baseline, Week 28 of the PFS Follow-up
Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up
SF-36 Version 2 is a multipurpose, participant completed, short-form health survey with 36 questions that consists of an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Physical component summary (PCS) is mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and general health (GH). Mental component summary (MCS) is mostly contributed by mental health (MH), role emotional (RE), social function (SF), and vitality (VT). Each component on the SF-36 item health survey is scored from 0 (best) to 100 (worst). Total score ranges from 0-100, where higher scores are associated with less disability and better quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: Baseline, Week 28 of the PFS Follow-up
Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up
The FACT/GOG-Ntx is a participant completed questionnaire that comprises 11 individual items evaluating symptoms of neurotoxicity on a 5-point scale where: 0=not at all (best) to 4=very much for a total possible score of 0 to 44. Symptom scores are inverted so that higher scores of FACT/GOG-Ntx indicate higher quality of life or functioning. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: Baseline, Week 28 of the PFS Follow-up
Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up
The amyloidosis symptom scale questionnaire is a participant completed questionnaire that evaluates symptom severity of 3 symptoms: Swelling, Shortness of Breath and Dizziness, each rated on an 11-point scale where: 0=no symptoms to 10=very severe symptoms. Higher scores indicate worsening of symptoms. Total Score is the sum of all responses from the amyloidosis symptom scale ranging from 0 to 30. Higher scores represent higher levels of symptomatology or problems and a negative change from baseline indicates improvement. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: Baseline, Week 28 of the PFS Follow-up
Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score
The European Quality of Life (EuroQOL) 5-Dimensional (EQ-5D) is a patient completed questionnaire consisting of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 3 possible choices: no problems to extreme problems. Higher scores=worsening of the quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: At Week 28 of the OS follow-up
EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score
The EQ visual analogue scale (VAS) records the participant's self-rated health on a 20 centimeter vertical VAS that ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Baseline is defined as the value collected at the time closest to, but prior to, the start of study drug administration. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: At Week 28 of the OS follow-up
Plasma Concentration of Ixazomib
As prespecified in the protocol, data for this outcome measure was planned to be collected for ixazomib arm group only.
Time frame: Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days)
Number of Hospitalizations
A hospitalization was defined as at least one overnight stay in an intensive care unit and/or non-intensive care unit. If a single hospitalization included both an intensive care unit stay and a non-intensive care unit stay, the hospitalization was counted only once (as an intensive care unit stay). The mean number of hospitalizations is reported in this outcome measure. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.
Time frame: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)

Results

Posted Sep 21, 2023

Participant flow

Participants took part in the study at 66 investigative sites from 12 December 2012 to 11 July 2022. The study was prematurely terminated based on the Sponsor's decision following the first interim analysis.

Participant flow — Overall Study
Milestone	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide
Started	90	26	10	2	49
Completed	0	0	0	0	0
Not completed	90	26	10	2	49
Withdrew: Withdrawal by patient	18	4	2	0	11
Withdrew: Study terminated by sponsor	9	7	0	1	4
Withdrew: Reason not specified	61	15	8	1	34
Withdrew: Lost to follow-up	2	0	0	0	0

Outcome measures

PrimaryPercentage of Participants With Overall Hematologic Response

Overall hematologic response was defined as the percentage of participants with complete response (CR), very good partial response (VGPR) and partial response (PR) based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as assessed by an adjudication committee. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of free light chain (FLC) ratio. VGPR: differential free light chain (difference between involved and uninvolved FLC levels; dFLC) \< 40 mg/L. PR: ≥50% reduction in dFLC. Percentages were rounded off to the nearest decimal.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Number · percentage of participants

Percentage of Participants With Overall Hematologic Response
percentage of participants	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide
Percentage of Participants With Overall Hematologic Response	53 (41.8 to 63.9)	58 (36.6 to 77.9)	30 (6.7 to 65.2)	50 (1.3 to 98.7)	51 (36.1 to 65.9)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan vs Arm B: Dexamethasone + Cyclophosphamide vs Arm B: Dexamethasone + Thalidomide vs Arm B: Dexamethasone + Lenalidomide · Cochran-Mantel-Haenszel · p = =0.7623 (P-value was calculated from the unstratified Cochran-Mantel-Haenszel (CMH) test to compare hematologic response rate between the treatment arms.) · Odds ratio (or): 1.10 · 95% CI 0.60 to 2.01Odds ratio was derived from a logistic regression model with treatment and 95% confidence interval (CI) for the odds ratio was based on the Wald approximation.

Primary2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate

Cardiac (Heart) deterioration was defined as the need for hospitalization for heart failure. Kidney deterioration was defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. Vital organ deterioration was evaluated by an adjudication committee. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: Up to 2 years
Reported as:: Number · percentage of participants

2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
percentage of participants	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
2-Year Vital Organ (Heart or Kidney) Deterioration and Mortality Rate	47 (36.1 to 58.2)	54 (41.7 to 64.1)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Cochran-Mantel-Haenszel · p = =0.3510 (P-value was calculated from the unstratified CMH test to make comparisons between the 2 treatment arms.) · Odds ratio (or): 0.75 · 95% CI 0.41 to 1.38Odds ratio was derived from a logistic regression model with treatment and 95% CI for the odds ratio was based on the Wald approximation.

SecondaryPercentage of Participants With Complete Hematologic Response

Complete hematologic response was defined as the percentage of participants with CR based on central laboratory results and the 2010 ISA Consensus Criteria as assessed by the investigator. CR: Complete disappearance of M-protein from serum and urine on immunofixation, and normalization of FLC ratio. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Number · percentage of participants

Percentage of Participants With Complete Hematologic Response
percentage of participants	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Percentage of Participants With Complete Hematologic Response	30 (20.8 to 40.6)	17 (10.0 to 26.8)

SecondaryOverall Survival

Overall survival was defined as the time from the date of randomization to the date of death. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Median · months

Overall Survival
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Overall Survival	69.55 (0.8 to 95.5)	43.17 (0.0 to 82.4)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = =0.389 (P-value was calculated using log-rank test stratified by the stratification factors.) · Hazard ratio (hr): 0.82 · 95% CI 0.52 to 1.29

SecondaryProgression Free Survival (PFS)

PFS was defined as the time from the date of randomization to the date of first documentation of hematologic disease progression, or organ (cardiac or renal) progression, or death due to any cause, whichever occurred first according to central laboratory results and ISA criteria as evaluated by the investigator. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Median · months

Progression Free Survival (PFS)
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Progression Free Survival (PFS)	11.86 (0.8 to 72.0)	7.62 (0.0 to 71.1)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = =0.135 (P-value was calculated using stratified log-rank test with stratification factors.) · Hazard ratio (hr): 0.76 · 95% CI 0.52 to 1.09

SecondaryHematologic Disease Progression Free Survival

Hematologic disease PFS was defined as the time from the date of randomization to the date of first documentation of hematologic PD according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurred first. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Median · months

Hematologic Disease Progression Free Survival
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Hematologic Disease Progression Free Survival	29.50 (0.1 to 54.5)	27.73 (0.1 to 43.5)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = 0.2421 (P-value was calculated using log-rank test stratified by the stratification factors.) · Hazard ratio (hr): 0.76 · 95% CI 0.48 to 1.21

SecondaryTime to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate

Time to vital organ deterioration or death was assessed by the investigator and defined as the time from randomization to vital organ (heart or kidney) deterioration or death, whichever occurs first. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to ESRD with the need for maintenance dialysis or renal transplantation. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From randomization to time of vital organ deterioration or death (up to 115 months)
Reported as:: Median · months

Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Time to Vital Organ (Heart or Kidney) Deterioration and Mortality Rate	38.67 (0.0 to 70.5)	26.09 (0.0 to 71.1)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = =0.036 (P-value was calculated using log-rank test stratified by the stratification factors.) · Hazard ratio (hr): 0.62 · 95% CI 0.39 to 0.97

SecondaryPercentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response

Vital organ (heart and kidney) response rate was defined as the percentage of participants who achieved vital organ response according to central laboratory results and ISA criteria as evaluated by an adjudication committee. A vital organ response was defined as response of 1 or 2 of the involved vital organs with no change from Baseline in the rest of involved vital organs. Percentages were rounded off to the nearest decimal. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Number · percentage of participants

Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response
percentage of participants	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Percentage of Participants With Best Vital Organ (Cardiac and/or Kidney) Response	19 (11.2 to 28.8)	12 (5.9 to 21.0)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Cochran-Mantel-Haenszel · p = =0.2260 (P-value was calculated from the unstratified CMH test to compare vital organ response rate between the 2 treatment arms.) · Odds ratio (or): 1.69 · 95% CI 0.72 to 3.99Odds ratio was calculated from a logistic regression model with treatment and 95% CI for the odds ratio was based on the Wald approximation.

SecondaryVital Organ Progression Free Survival

Vital organ PFS is defined as the time from the date of randomization to the date of first documentation of progression of vital organ (heart or kidney) according to central laboratory results and ISA criteria as evaluated by an adjudication committee, or death due to any cause, whichever occurs first. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Median · months

Vital Organ Progression Free Survival
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Vital Organ Progression Free Survival	15.77 (0.0 to 72.0)	11.01 (0.0 to 71.1)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = =0.163 (P-value was calculated using stratified log-rank test with stratification factors.) · Hazard ratio (hr): 0.76 · 95% CI 0.52 to 1.12Unadjusted stratified Cox regression model was used to estimate the hazard ratio and its 95% CIs for the treatment effect using the stratification factors.

SecondaryDuration of Hematologic Response

Duration of hematologic response (DOR) was defined as the time from the date of first documentation of a hematologic response to the date of first documented hematologic disease progression as determined by the investigator. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From time of first documented response to disease progression (up to 115 months)
Reported as:: Median · months

Duration of Hematologic Response
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Duration of Hematologic Response	NA (1.8 to 71.1)	21.19 (0.0 to 69.0)

SecondaryNumber of Participants With Serious Adverse Events (SAEs)

A SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of an existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly/birth defect or medically important event.

Time frame:: From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months)
Reported as:: Count of participants · Participants

Number of Participants With Serious Adverse Events (SAEs)
Participants	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide
Number of Participants With Serious Adverse Events (SAEs)	44	11	2	0	17

SecondaryTime To Treatment Failure (TTF)

TTF was defined as the time from randomization to the date of first documented treatment failure. Treatment failure was defined as: 1) death due to any cause; 2) hematologic progression or major organ progression according to central laboratory results and ISA criteria as evaluated by the investigator; 3) clinically morbid organ disease requiring additional therapy; or 4) withdrawn for any reason. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Median · months

Time To Treatment Failure (TTF)
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Time To Treatment Failure (TTF)	10.32 (7.52 to 14.82)	5.32 (4.14 to 7.82)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = =0.025 (P-value was calculated using stratified log-rank test with stratification factors.) · Hazard ratio (hr): 0.68 · 95% CI 0.49 to 0.96

SecondaryTime To Subsequent Anticancer Treatment

Time to subsequent anticancer therapy was defined as the time from randomization to the first date of subsequent anticancer therapy. Participants without subsequent anticancer therapy were censored at the date of death or last known to be alive. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until subsequent anticancer treatment (up to 115 months)
Reported as:: Median · months

Time To Subsequent Anticancer Treatment
months	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Time To Subsequent Anticancer Treatment	26.48 (0.8 to 95.5)	12.45 (0.0 to 72.7)

Statistical analysis

Arm A: Ixazomib + Dexamethasone vs Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide · Log Rank · p = =0.010 (P-value was calculated using stratified log-rank test with stratification factors.) · Hazard ratio (hr): 0.58 · 95% CI 0.38 to 0.88

SecondaryChange From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up

SF-36 Version 2 is a multipurpose, participant completed, short-form health survey with 36 questions that consists of an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Physical component summary (PCS) is mostly contributed by physical function (PF), role physical (RP), bodily pain (BP), and general health (GH). Mental component summary (MCS) is mostly contributed by mental health (MH), role emotional (RE), social function (SF), and vitality (VT). Each component on the SF-36 item health survey is scored from 0 (best) to 100 (worst). Total score ranges from 0-100, where higher scores are associated with less disability and better quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: Baseline, Week 28 of the PFS Follow-up
Reported as:: Mean · score on a scale

Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up
score on a scale	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Change From Baseline in 36-item Short Form General Health Survey (SF-36) Mental Component Summary Score at Week 28 of the PFS Follow-up	—	2.0 ± NA

SecondaryChange From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up

Time frame:: Baseline, Week 28 of the PFS Follow-up
Reported as:: Mean · score on a scale

Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up
score on a scale	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Change From Baseline in SF-36 Physical Component Summary Score at Week 28 of the PFS Follow-up	—	10.3 ± NA

SecondaryChange From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up

The FACT/GOG-Ntx is a participant completed questionnaire that comprises 11 individual items evaluating symptoms of neurotoxicity on a 5-point scale where: 0=not at all (best) to 4=very much for a total possible score of 0 to 44. Symptom scores are inverted so that higher scores of FACT/GOG-Ntx indicate higher quality of life or functioning. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: Baseline, Week 28 of the PFS Follow-up
Reported as:: Mean · score on a scale

Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up
score on a scale	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Change From Baseline in Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) Score at Week 28 of the PFS Follow-up	—	0.0 ± NA

SecondaryChange From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up

The amyloidosis symptom scale questionnaire is a participant completed questionnaire that evaluates symptom severity of 3 symptoms: Swelling, Shortness of Breath and Dizziness, each rated on an 11-point scale where: 0=no symptoms to 10=very severe symptoms. Higher scores indicate worsening of symptoms. Total Score is the sum of all responses from the amyloidosis symptom scale ranging from 0 to 30. Higher scores represent higher levels of symptomatology or problems and a negative change from baseline indicates improvement. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: Baseline, Week 28 of the PFS Follow-up
Reported as:: Mean · score on a scale

Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up
score on a scale	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Change From Baseline in Amyloidosis Symptom Scale Total Score at Week 28 of the PFS Follow-up	—	-16.0 ± NA

SecondaryNumber of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score

The European Quality of Life (EuroQOL) 5-Dimensional (EQ-5D) is a patient completed questionnaire consisting of 2 pages: the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 3 possible choices: no problems to extreme problems. Higher scores=worsening of the quality of life. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: At Week 28 of the OS follow-up
Reported as:: Count of participants · Participants

Number of Participants in Each Category of the EuroQol 5-Dimensional (EQ-5D) Questionnaire Score
Participants	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Mobility: No Problems in Walking About	0	0
Mobility: Some Problem in Walking About	0	1
Mobility: Confined to Bed	0	0
Self-Care: No Problems With Self- Care	0	0
Self-Care: Some Problems Washing or Dressing	0	1
Self-Care: Unable to Wash or Dress	0	0
Usual Activities: No Problems With Performing Usual Activities	0	0
Usual Activities: Some Problem With Performing Usual Activities	0	1
Usual Activities: Unable to Performing Usual Activities	0	0
Pain/Discomfort: No Pain or Discomfort	0	0
Pain/Discomfort: Moderate Pain or Discomfort	0	1
Pain/Discomfort: Extreme Pain or Discomfort	0	0
Anxiety/Depression: Not Anxious or Depressed	0	0
Anxiety/Depression: Moderately Anxious or Depressed	0	0
Anxiety/Depression: Extremely Anxious or Depressed	0	1

SecondaryEuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score

The EQ visual analogue scale (VAS) records the participant's self-rated health on a 20 centimeter vertical VAS that ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). Baseline is defined as the value collected at the time closest to, but prior to, the start of study drug administration. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: At Week 28 of the OS follow-up
Reported as:: Mean · score on a scale

EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score
score on a scale	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
EuroQol 5-Dimension 3-Level (EQ-5D-3L) Visual Analogue Scale Score	—	23.0 ± NA

SecondaryPlasma Concentration of Ixazomib

As prespecified in the protocol, data for this outcome measure was planned to be collected for ixazomib arm group only.

Time frame:: Cycle 1, Day 1: 1, 4 hours postdose, Day 14: 144 hours postdose; Cycle 2, Day 1: predose, Day 14: 144 hours postdose; Cycles 3 to 10, Day 1: predose (cycle length=28 days)
Reported as:: Geometric mean · nanogram per milliliter (ng/mL)

Plasma Concentration of Ixazomib
nanogram per milliliter (ng/mL)	Arm A: Ixazomib + Dexamethasone
Cycle 1 Day 1: 1 Hour Post-dose	16.518 ± 97.0462
Cycle 1 Day 14: 4 Hours Post-dose	10.652 ± 121.7231
Cycle 1 Day 14: 144 Hours Post-dose	3.875 ± 100.3055
Cycle 2 Day 1: Pre-dose	2.000 ± 59.4061
Cycle 2 Day 14: 144 Hours Post-dose	4.726 ± 115.5653
Cycle 3 Day 1: Pre-dose	2.187 ± 59.1378
Cycle 4 Day 1 Pre-dose	2.276 ± 59.3690
Cycle 5 Day 1 Pre-dose	2.264 ± 54.8881
Cycle 6 Day 1: Pre-dose	2.235 ± 60.4723
Cycle 7 Day 1: Pre-dose	2.299 ± 53.7147
Cycle 8 Day 1: Pre-dose	2.038 ± 58.6811
Cycle 9 Day 1: Pre-dose	2.143 ± 55.0715
Cycle 10 Day 1: Pre-dose	2.232 ± 57.4067

SecondaryNumber of Hospitalizations

A hospitalization was defined as at least one overnight stay in an intensive care unit and/or non-intensive care unit. If a single hospitalization included both an intensive care unit stay and a non-intensive care unit stay, the hospitalization was counted only once (as an intensive care unit stay). The mean number of hospitalizations is reported in this outcome measure. As prespecified in the protocol, data was planned to be collected and analyzed in a combined way for non-ixazomib arm groups in this outcome measure.

Time frame:: From first dose of study drug until discontinuation of study drug due to disease progression or unacceptable toxicity, or death whichever occurs first (up to 115 months)
Reported as:: Mean · hospitalizations

Number of Hospitalizations
hospitalizations	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan/Cyclophosphamide/Thalidomide/Lenalidomide
Number of Hospitalizations	1.8 ± 1.34	1.4 ± 0.80

Adverse events

Collected over From first dose of study drug through 30 days after administration of the last dose of study drug (up to 115 months). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Arm A: Ixazomib + Dexamethasone	40/90 (44.4%)	44/90 (48.9%)	86/90 (95.6%)
Arm B: Dexamethasone + Melphalan	14/26 (53.8%)	11/26 (42.3%)	24/26 (92.3%)
Arm B: Dexamethasone + Cyclophosphamide	4/10 (40%)	2/10 (20%)	9/10 (90%)
Arm B: Dexamethasone + Thalidomide	0/2 (0%)	0/1 (0%)	1/1 (100%)
Arm B: Dexamethasone + Lenalidomide	22/49 (44.9%)	17/47 (36.2%)	46/47 (97.9%)

Most frequent serious events

Showing 10 of 85

Most frequent serious events
Event	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide
PneumoniaInfections and infestations	5/90	4/26	0/10	0/1	2/47
Acute kidney injuryRenal and urinary disorders	2/90	0/26	1/10	0/1	0/47
Cardiac failureCardiac disorders	4/90	0/26	1/10	0/1	1/47
CellulitisInfections and infestations	4/90	0/26	0/10	0/1	0/47
DyspnoeaRespiratory, thoracic and mediastinal disorders	4/90	0/26	0/10	0/1	1/47
Lower respiratory tract infectionInfections and infestations	0/90	1/26	0/10	0/1	2/47
Pulmonary embolismRespiratory, thoracic and mediastinal disorders	2/90	1/26	0/10	0/1	2/47
Septic shockInfections and infestations	0/90	0/26	0/10	0/1	2/47
Abscess limbInfections and infestations	0/90	1/26	0/10	0/1	0/47
Angina pectorisCardiac disorders	0/90	1/26	0/10	0/1	0/47

Most frequent other events

Showing 10 of 104

Most frequent other events
Event	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide
ConstipationGastrointestinal disorders	18/90	3/26	4/10	1/1	13/47
Dry skinSkin and subcutaneous tissue disorders	4/90	1/26	0/10	1/1	1/47
DyspnoeaRespiratory, thoracic and mediastinal disorders	19/90	3/26	0/10	1/1	12/47
FatigueGeneral disorders	40/90	7/26	3/10	1/1	24/47
InfluenzaInfections and infestations	7/90	1/26	1/10	1/1	3/47
InsomniaPsychiatric disorders	32/90	3/26	2/10	1/1	8/47
Muscle spasmsMusculoskeletal and connective tissue disorders	9/90	1/26	0/10	1/1	7/47
MyopiaEye disorders	0/90	0/26	0/10	1/1	0/47
Peripheral sensory neuropathyNervous system disorders	20/90	0/26	0/10	1/1	10/47
PneumoniaInfections and infestations	3/90	0/26	0/10	1/1	0/47

Baseline characteristics

Intent-to-Treat (ITT) Population included all participants who were randomized.

Age, Continuous
Age, Continuous(years)	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
Mean	63.4 ± 9.83	64.8 ± 8.73	60.0 ± 14.97	65.0 ± 2.83	64.9 ± 8.68	63.9 ± 9.65

Sex: Female, Male
Sex: Female, Male(Participants)	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
Female	35	11	4	2	22	74
Male	55	15	6	0	27	103

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
Hispanic or Latino	0	1	0	0	2	3
Not Hispanic or Latino	85	25	9	2	40	161
Unknown or Not Reported	5	0	1	0	7	13

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
American Indian or Alaska Native	0	0	0	0	0	0
Asian	16	9	5	1	1	32
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	1	0	0	0	0	1
White	70	17	5	1	48	141
More than one race	0	0	0	0	0	0
Unknown or Not Reported	3	0	0	0	0	3

Region of Enrollment
Region of Enrollment(Participants)	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
Canada	5	0	1	0	3	9
United States	24	2	3	0	13	42
Czechia	2	0	0	0	1	3
Denmark	0	0	0	1	2	3
France	3	1	0	0	1	5
Germany	8	5	0	0	3	16
United Kingdom	10	4	0	0	3	17
Greece	6	0	2	0	7	15
Italy	3	0	0	0	4	7
Netherlands	3	1	0	0	0	4
Spain	1	1	0	0	3	5
Turkey	1	0	0	0	0	1
Australia	8	0	0	0	6	14
Brazil	0	0	0	1	0	1
China	4	2	0	0	0	6
Israel	3	3	0	0	2	8
Japan	2	5	0	0	0	7
Korea, Republic of	7	2	4	0	1	14

Height
Height(centimeters (cm))	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
Mean	170.40 ± 10.507	167.07 ± 8.662	170.65 ± 13.274	160.50 ± 13.435	169.17 ± 10.532	169.48 ± 10.444

Weight
Weight(kilograms (kg))	Arm A: Ixazomib + Dexamethasone	Arm B: Dexamethasone + Melphalan	Arm B: Dexamethasone + Cyclophosphamide	Arm B: Dexamethasone + Thalidomide	Arm B: Dexamethasone + Lenalidomide	Total
Mean	77.33 ± 16.740	70.95 ± 12.476	70.20 ± 21.815	50.10 ± 15.415	75.35 ± 17.144	75.13 ± 16.830

Study locations

66 sites

Cedars Sinai Medical Center
Los Angeles, California 90048, United States
University of Chicago
Chicago, Illinois 60637, United States
Indiana University School of Medicine
Indianapolis, Indiana 46202, United States
Tufts Medical Center
Boston, Massachusetts 00211, United States
Boston Medical Center
Boston, Massachusetts 02118, United States
Karmanos Cancer Institute
Detroit, Michigan 48201, United States
Mayo Clinic
Rochester, Minnesota 05590, United States
Washington University
St Louis, Missouri 63110, United States
Columbia University Medical Center
New York, New York 10032, United States
Memorial Sloan Kettering Cancer Center
New York, New York 10065, United States
University of Cincinnati
Cincinnati, Ohio 45267, United States
Cleveland Clinic
Cleveland, Ohio 44195, United States
Vanderbilt University Medical Center
Nashville, Tennessee 37232, United States
University of Texas Southwestern Medical Center
Dallas, Texas 75390, United States
Froedtert and The Medical College of Wisconsin
Milwaukee, Wisconsin 53226, United States
Westmead Hospital
Westmead, New South Wales 214, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland 4102, Australia
Box Hill Hospital
Box Hill, Victoria 3128, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia 6009, Australia
Centro de Pesquisas Oncologicas
Florianópolis, Santa Catarina 88034-000, Brazil
Hospital Universitario Clementino Fraga Filho (UFRJ)
Rio de Janeiro, 21941-913, Brazil
Irmandade Da Santa Casa de Misericordia de Sao Paulo
São Paulo, 01223-001, Brazil
Hospital Israelita Albert Einstein
São Paulo, 05652-900, Brazil
Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo
São Paulo, 5403000, Brazil
Tom Baker Cancer Centre
Calgary, Alberta T2N 4N2, Canada
Cross Cancer Institute
Edmonton, Alberta T6G 1Z, Canada
Vancouver General Hospital
Vancouver, British Columbia V5Z 1M, Canada
Princess Margaret Hospital
Toronto, Ontario M5G2M9, Canada
Fakultni nemocnice Ostrava
Ostrava, Moravskoslezsk Kraj 708 52, Czechia
Vseobecna fakultni nemocnice v Praze
Prague, Praha, Hlavni Mesto 128 08, Czechia
Arhus Universitetshospital Arhus Sygehus
Aahus, 800, Denmark
Rigshospitalet
Copenhagen, 2100, Denmark
Hotel Dieu
Nantes, Loire-Atlantique 44093, France
Hopital Claude Huriez
Lille, 5903, France
Centre Hospitalier et Universitaire de Limoges
Limoges, 87042, France
Hopital Saint Louis
Paris, 75010, France
Hopital de Rangueil
Toulouse, 31059, France
Charite - Universitatsmedizin Berlin
Berlin, 12200, Germany
Universitatsklinikum Hamburg Eppendorf
Hamburg, 20246, Germany
Universitat Heidelberg
Heidelberg, 69120, Germany
University General Hospital of Patras
Pátrai, Achaia 26500, Greece
Alexandra Hospital
Athens, 11528, Greece
Rambam Health Corporation
Haifa, 31096, Israel
Hadasit Medical Research Services and Development Ltd
Jerusalem, 911, Israel
Meir Medical Center
Kfar Saba, 44281, Israel
Rabin Medical Center - PPDS
Petah Tikva, 49100, Israel
Chaim Sheba Medical Center
Ramat Gan, 52621, Israel
Institute of Hematology "Seragnoli" University of Bologna
Bologna, 40138, Italy
Fondazione IRCCS Policlinico San Matteo di Pavia
Pavia, 2710, Italy
VU Medisch Centrum
Amsterdam, North Holland 1081 HV, Netherlands
Maastricht University Medical Center
AZ Maastricht, 620, Netherlands
Universitair Medisch Centrum Utrecht
Utrecht, 3508, Netherlands
Gachon University Gil Medical Center
Incheon, 405-760, South Korea
Seoul National University Hospital
Seoul, 110744, South Korea
Severance Hospital at Yonsei University Health System - PPDS
Seoul, 120-752, South Korea
Samsung Medical Center - PPDS
Seoul, 135-710, South Korea
The Catholic University of Korea, Seoul St Mary's Hospital
Seoul, 137-70, South Korea
Clinica Universidad de Navarra
Pamplona, Navarre 31008, Spain
Hospital Clinic de Barcelona
Barcelona, 8036, Spain
Hospital Universitario de La Princesa
Madrid, 28006, Spain
Hospital Universitario Puerta de Hierro - Majadahonda
Majadahonda, 28222, Spain
Hospital Universitario de Salamanca
Salamanca, 37007, Spain
Queen Elizabeth Hospital
Birmingham, B152TH, United Kingdom
Royal Free and University College Medical School
London, NW3 2P, United Kingdom
Manchester Royal Infirmary
Manchester, MI3 9WL, United Kingdom
Oxford University Hospitals NHS Trust
Oxford, OX3 7L, United Kingdom

References and documents

Publications

Sanchorawala V, Wechalekar AD, Kim K, Schonland SO, Landau HJ, Kwok F, Suzuki K, Dispenzieri A, Merlini G, Comenzo RL, Cherepanov D, Hayden VC, Kumar A, Labotka R, Faller DV, Kastritis E. Quality of life and symptoms among patients with relapsed/refractory AL amyloidosis treated with ixazomib-dexamethasone versus physician's choice. Am J Hematol. 2023 May;98(5):720-729. doi: 10.1002/ajh.26866. Epub 2023 Feb 14. PubMed 36708469 ↗
Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schonland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. doi: 10.1182/blood-2017-03-771220. Epub 2017 May 26. PubMed 28550039 ↗

Study documents

Study protocol · Jan 14, 2020
Statistical analysis plan · Jul 15, 2015

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

Supporting information: Study protocol, Sap, Icf, Csr

Registry details

Key details

Study ID: NCT01659658
Lead sponsor: Millennium Pharmaceuticals, Inc.
Responsible party: Sponsor
First posted: Aug 8, 2012
Start date: Dec 26, 2012
Primary completion: Jul 11, 2022
Completion: Jul 11, 2022
Results posted: Sep 21, 2023
Last update: Sep 2, 2025

Study contacts

Medical Director

study director · Takeda

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in Aug 2025. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Recurrence→

Other studies from this sponsor

Millennium Pharmaceuticals, Inc.

Start the discussion

Study of Dexamethasone Plus IXAZOMIB (MLN9708) or Physicians Choice of Treatment in Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis

Study summary

Conditions studied

Browse trials for

Keywords

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Related links

Study documents

Individual participant data

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

Other studies from this sponsor

Inclusion criteria

Exclusion criteria