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:
Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo
red staining with exhibition of an apple-green birefringence
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):
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.
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.
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.)
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
Must have recovered (ie, ≤ Grade 1 toxicity or participant's baseline status)
from the reversible effects of prior therapy
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):
Stage 1: both NT-proBNP and troponin T under threshold
Stage 2: either NT-proBNP or troponin T (but not both) over threshold;
Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP < 8000
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2.
Clinical laboratory values:
Absolute neutrophil count ≥ 1000/µL
Platelet count ≥ 75,000/µL
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
Alkaline phosphatase ≤ 5 x ULN
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN
Calculated creatinine clearance ≥ 30 mL/min
Female participants who:
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
Must also adhere to the guidelines of any treatment-specific pregnancy
prevention program, if applicable, OR
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
Male participants, even if surgically sterilized (ie, status post vasectomy), who:
Amyloidosis due to mutations of the transthyretin gene or presence of other non-AL
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:
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,
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
Known allergy to boron, MLN9708, any of the study treatments, their analogues, or
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 (5 years for sites 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