PRIMARY OBJECTIVE:
I. To determine whether escalating maintenance therapy with the addition of ixazomib citrate
(ixazomib) to lenalidomide improves overall survival among patients who are MRD positive
after approximately 1 year of lenalidomide maintenance following an early stem cell
transplant (=< 12 months from diagnosis).
SECONDARY OBJECTIVES:
I. To establish whether progression-free survival is superior with the addition of ixazomib
to lenalidomide maintenance.
II. To evaluate best response on treatment and compare response rates between arms.
III. To evaluate the safety profile of ixazomib added to lenalidomide and compare toxicity
rates between arms.
EXPLORATORY CLINICAL OBJECTIVES:
I. To measure treatment exposure and adherence. II. To estimate treatment duration, duration
of response and time to progression.
PATIENT-REPORTED OUTCOMES OBJECTIVES:
I. To determine the extent and timing of neuropathy associated with the addition of ixazomib
to lenalidomide maintenance on patient reported health-related quality of life outcomes.
II. To assess the impact and timing of disease control with the addition of ixazomib to
lenalidomide maintenance on patient reported health-related quality of life outcomes.
III. To evaluate attributes of select patient reported treatment-emergent symptomatic adverse
events (Patient-Reported Outcomes - Common Terminology Criteria for Adverse Events
[PRO-CTCAE]) longitudinally and compare responses with provider-reported adverse events.
IV. To measure the likelihood of medication adherence and examine the relationship with
treatment exposure.
V. To assess correlation among patient reported outcome measures and association with
clinical outcomes.
VI. To tabulate PRO compliance and completion rates.
IMAGING OBJECTIVES:
I. To evaluate the association between baseline fludeoxyglucose F-18 (FDG)-positron emission
tomography (PET)/computed tomography (CT) and patient outcomes.
II. To compare overall survival with the addition of ixazomib to lenalidomide among baseline
FDG-PET/CT-positive and FDG-PET/CT-negative subgroups.
III. To compare the change in quantitative FDG-PET/CT parameters over time with the addition
of ixazomib to lenalidomide.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-28 and ixazomib
citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease
progression or unacceptable toxicity.
ARM B: Patients receive lenalidomide PO QD on days 1-28 and a placebo PO on days 1, 8, and
15. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 3 months if < 2 years
from study entry, every 6 months if 2-5 years from study entry, then every 12 months for up
to 15 years from study entry.
Inclusion Criteria:
- STEP 0: PRE-REGISTRATION
- Patients must be previously diagnosed with multiple myeloma and be on lenalidomide
maintenance with >= 10 mg daily dose for at least 10 months and no more than 15 months
after an early autologous stem cell transplantation (SCT =< 12 months of diagnosis).
Patients should not be off lenalidomide maintenance therapy for more than 30 days
prior to start of treatment on protocol
- Patients must be able to undergo a diagnostic bone marrow aspirate following
registration to step 0
- NOTE: A bone marrow aspirate specimen must be submitted to Mayo Clinic Hematology
Laboratory for central assessment of minimal residual disease (MRD) status to
confirm patient's eligibility for step 1 randomization. Mayo Clinic will forward
results =< within three (3) business days of receipt of the bone marrow specimen
to the submitting institution
- Patients must not have primary refractory or progressive disease on a proteasome
inhibitor-based regimen during induction therapy prior to stem cell transplant
- Patients must not be on other concurrent chemotherapy, or any ancillary therapy
considered investigational
- NOTE: Bisphosphonates are considered to be supportive care rather than therapy
and are allowed while on protocol treatment
- Patients must not have uncontrolled psychiatric illness or social situations that
would limit compliance with study requirements
- Patients must not have another malignancy requiring treatment or have received
treatment within 2 years before pre-registration or previously diagnosed with another
malignancy and have any evidence of residual disease. Patients with non-melanoma skin
cancer or carcinoma in situ of any type are not excluded if they have undergone
complete resection
- Patients must have been able to maintain at least 10 mg dose of lenalidomide without
growth factor support
- Patients must not have known gastrointestinal (GI) disease or GI procedure that could
interfere with the oral absorption or tolerance of ixazomib or lenalidomide including
difficulty swallowing
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- Patients must not have known hepatitis B surface antigen-positive status or known or
suspected active hepatitis C infection, but testing specifically for the trial is not
required
- STEP 1 RANDOMIZATION
- Patient must meet Step 0 eligibility criteria at the time of Step 1 randomization
- Patients must not be off lenalidomide maintenance therapy for more than 30 days prior
to start of treatment on protocol
- Patients must have evidence of residual disease by central MRD testing or by presence
of monoclonal protein in serum or urine
- Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum
free light chain (FLC) are required to be performed =< 28 days prior to randomization
- NOTE: UPEP (on a 24-hour collection) is required, no substitute method is
acceptable. Urine must be followed monthly if the baseline urine M-spike is >=
200 mg/24 hour (hr). Please note that if both serum and urine M-components are
present, both must be followed in order to evaluate response
- Hemoglobin >= 8 g/dL (obtained =< 14 days prior to randomization)
- Untransfused platelet count >= 75,000 cells/mm^3 (obtained =< 14 days prior to
randomization)
- Absolute neutrophil count >= 1000 cells/mm^3 (obtained =< 14 days prior to
randomization)
- Calculated creatinine clearance >= 30 mL/min (obtained =< 14 days prior to
randomization)
- Total bilirubin =< 1.5 times the upper limit of normal (obtained =< 14 days prior to
randomization)
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and
serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3
times the upper limit of normal (obtained =< 14 days prior to randomization)
- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status 0,
1, or 2
- Patients must not have grade 2 or higher peripheral neuropathy or grade 1 peripheral
neuropathy with pain per CTCAE
- Patients must not have uncontrolled intercurrent illness
- Patients must not have grade 2 or higher diarrhea per CTCAE in the absence of
antidiarrheals
- Patients must not have been on systemic treatment, within 14 days before the first
dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin,
carbamazepine, phenytoin, phenobarbital), or use of St. John's wort
- Patients must agree to register into the mandatory Risk Evaluation and Mitigation
Strategies (REMS) program and be willing and able to comply with the requirements of
REMS
- Women must not be pregnant due to potential harm to the fetus from ixazomib and
lenalidomide. All females of childbearing potential (FCBP) must have a blood test or
urine study with a sensitivity of at least 25 mIU/mL within 10-14 days prior to the
first dose of lenalidomide and again within 24 hours prior to the first dose of
lenalidomide. FCBP must also agree to ongoing pregnancy testing while on treatment. A
female of childbearing potential is any woman, regardless of sexual orientation or
whether they have undergone tubal ligation, who meets the following criteria: 1) has
achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer
therapy does not rule out childbearing potential) for at least 24 consecutive months
(i.e., has had menses at any time in the preceding 24 consecutive months)
- Females of childbearing potential (FCBP) must either abstain from sexual intercourse
for the duration of their participation in the study or agree to use TWO acceptable
methods of birth control, one highly effective method and one additional effective
method AT THE SAME TIME for 1) at least 28 days before starting study treatment; 2)
while participating in the study; 3) during dose interruptions; and 4) for at least 90
days after the last dose of protocol treatment. Women must also agree to not
breastfeed during this same time period. Men must agree to either abstain from sexual
intercourse for the duration of their participation in the study or use a latex condom
during sexual contact with a FCBP while participating in the study and for 90 days
after the last dose of protocol treatment even if they have had a successful
vasectomy. Men must also agree to abstain from donating sperm while on study treatment
and for 28 days after the last dose of protocol treatment even if they have had a
successful vasectomy. Both women and men must both agree to abstain from donating
blood during study participation and for at least 28 days after the last dose of
protocol treatment
