• Overall survival (OS) [ Time Frame: From randomization to death due to any cause, or censored at date last known alive, assessed up to 15 years ]
  Will be estimated using the Kaplan-Meier (KM) method and compared using a stratified log-rank test. Stratified cox proportional hazards regression will produce a treatment hazard ratio estimate (ixazomib-lenalidomide/placebo-lenalidomide.
• Change in Functional Assessment of Cancer Therapy (FACT)/Gynecologic Oncology Group-Neurotoxicity (GOG-Ntx) Trial Outcome Index (TOI) score [ Time Frame: Baseline up to 12 cycles ]
  Descriptive statistics (mean, standard deviation [SD], median, range) will be used to evaluate the distribution of levels and changes for the set of health-related quality of life (QOL) evaluations. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.
• Change in FACT-Multiple Myeloma (MM) TOI score [ Time Frame: Baseline up to 24 cycles ]
  Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.

• Progression-free survival (PFS) [ Time Frame: From randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation, assessed up to 15 years ]
  Will be estimated using the KM method and compared using the stratified log-rank test. Only deaths that occur within 3 months of the last disease evaluation are considered events.
• Best response on treatment [ Time Frame: Up to 60 cycles post-randomization ]
  Will be based on standard International Myeloma Working Group (IMWG) criteria and tabulated by category. Response rates (stringent complete response [sCR], complete response [CR], very good partial response [VGPR]) will be compared using the chi-squared test for proportions.
• Minimal residual disease (MRD) conversion rate [ Time Frame: At 12 and 24 cycles post-randomization ]
• Incidence of adverse events [ Time Frame: Up to 15 years ]
  Will be assessed by worst grade and type determined using Common Terminology Criteria for Adverse Events. Will compare the rates of worst grade 3 or higher non-hematologic treatment-related events using the chi-squared test for proportions. Will plan to examine comprehensively adverse events experienced by study participants using the Tox-T method.
• Change in FACT- General (G) score [ Time Frame: Baseline up to 12 cycles ]
  Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. The t-test will be used to assess the change in FACT-G score between treatment arms. Also, FACT-G scores after 12 cycles of treatment will be compared between MRD positive and negative groups at that time point.
• Time to worsening of FACT/GOG-Ntx TOI [ Time Frame: Baseline to a decrease of 8 points (minimally important differences [MID]), respectively, or censored at the date of last assessment ]
  Will be analyzed with the KM method and compared using the log-rank test. Time to worsening of symptoms with PFS and OS will be assessed with Kendall's Tau adjusted for censored observations.
• Change in levels of all instruments [ Time Frame: Baseline up to 1 year after treatment discontinuation ]
  Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.
• FACT/GOG-Ntx TOI recovery rate [ Time Frame: Up to 1 year after treatment discontinuation ]
  The recovery rate will be estimated in the patients experiencing a MID decrease (the proportion of patients with the FACT/GOG-Ntx TOI score returning to baseline level). Will provide rates on each arm including exact binomial 95% confidence intervals.
• Time to improvement of the FACT-MM TOI [ Time Frame: Baseline to an increase of 10 points (MID), respectively, or censored at the date of last assessment ]
  Will be analyzed with the KM method and compared using the log-rank test.
• FACT-MM TOI response rate [ Time Frame: Up to 1 year after treatment discontinuation ]
  Will be defined as the proportion of patients experiencing a MID improvement since baseline at each assessment time point. Will provide rates on each arm including exact binomial 95% confidence intervals.

• Progression-free survival (PFS) [ Time Frame: From randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation, assessed up to 15 years ]
  Will be estimated using the KM method and compared using the stratified log-rank test.
• Best response on treatment [ Time Frame: Up to 60 cycles post-randomization ]
  Will be based on standard International Myeloma Working Group (IMWG) criteria and tabulated by category. Response rates (stringent complete response [sCR], complete response [CR], very good partial response [VGPR]) will be compared using the chi-squared test for proportions.
• Minimal residual disease (MRD) conversion rate [ Time Frame: At 12 cycles post-randomization ]
• MRD conversion rate [ Time Frame: At 24 cycles post-randomization ]
• Incidence of adverse events [ Time Frame: Up to 15 years ]
  Will be assessed by worst grade and type determined using Common Terminology Criteria for Adverse Events. Will compare the rates of worst grade 3 or higher non-hematologic treatment-related events using the chi-squared test for proportions. Will plan to examine comprehensively adverse events experienced by study participants using the Tox-T method.
• Change in FACT- General (G) score [ Time Frame: Baseline up to 12 cycles ]
  Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit. The t-test will be used to assess the change in FACT-G score between treatment arms. Also, FACT-G scores after 12 cycles of treatment will be compared between MRD positive and negative groups at that time point.
• Time to worsening of FACT/GOG-Ntx TOI [ Time Frame: Baseline to a decrease of 8 points (minimally important differences [MID]), respectively, or censored at the date of last assessment ]
  Will be analyzed with the KM method and compared using the log-rank test. Time to worsening of symptoms with PFS and OS will be assessed with Kendall's Tau adjusted for censored observations.
• Change in levels of all instruments [ Time Frame: Baseline up to 1 year after treatment discontinuation ]
  Descriptive statistics (mean, SD, median, range) will be used to evaluate the distribution of levels and changes for the set of health-related QOL evaluations. Levels and changes will also be assessed graphically. Linear mixed effects models will be used to perform repeated measured regression analysis with the assumed covariance matrix maximizing Akaike information criteria. Models with treatment, assessment time, and treatment by assessment time interaction with and without other predictors will be fit.
• FACT/GOG-Ntx TOI recovery rate [ Time Frame: Up to 1 year after treatment discontinuation ]
  The recovery rate will be estimated in the patients experiencing a MID decrease (the proportion of patients with the FACT/GOG-Ntx TOI score returning to baseline level). Will provide rates on each arm including exact binomial 95% confidence intervals.
• Time to improvement of the FACT-MM TOI [ Time Frame: Baseline to an increase of 10 points (MID), respectively, or censored at the date of last assessment ]
  Will be analyzed with the KM method and compared using the log-rank test.
• FACT-MM TOI response rate [ Time Frame: Up to 1 year after treatment discontinuation ]
  Will be defined as the proportion of patients experiencing a MID improvement since baseline at each assessment time point. Will provide rates on each arm including exact binomial 95% confidence intervals.

• Time to progression [ Time Frame: From randomization to progression, or censored at date of last disease evaluation, assessed up to 15 years ]
  Will be estimated in each arm using the Kaplan-Meier method.
• Duration of response [ Time Frame: From time of observed response (VGPR or better) to the time of progression in the respective group of responders, assessed up to 15 years ]
  Will be estimated in each arm using the Kaplan-Meier method.
• Treatment duration [ Time Frame: From randomization to date off treatment, or censored at the date of last treatment ]
  Will be estimated using the Kaplan-Meier method. Patients will be classified into dichotomous groups based on a 75% relative dose intensity cutoff (< 75% vs >= 75% represents poor vs good treatment adherence). The proportion of patients with poor lenalidomide treatment adherence will be compared between arms using the chi-squared test for proportions. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with calculated good treatment adherence.
• Cumulative dose [ Time Frame: Up to 15 years ]
  Will be calculated overall and by cycle. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
• Dose intensity [ Time Frame: Up to 15 years ]
  Will be calculated as cumulative dose received divided by treatment duration. Will be calculated overall and by cycle. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
• Relative dose intensity [ Time Frame: Up to 15 years ]
  Will be calculated as the dose intensity divided by planned dose intensity. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
• Presence, frequency, interference, amount, and/or severity of select Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Up to 1 year after treatment discontinuation ]
  Will be tabulated at each cycle
• Adherence Starts with Knowledge (ASK)-12 scores [ Time Frame: Up to 12 cycles ]
  Will be assessed at each assessment time point. Linear regression analysis at these 2 time points separately will be conducted with QOL score as outcome and treatment adherence group as the main effect adjusting for baseline QOL score along with other disease and demographic characteristics. Descriptive statistics will be used to summarize ASK-12 scores tabulated every 6 cycles on study therapy. The relationship between likelihood of medication adherence and calculated treatment adherence dichotomous groups will be evaluated in 2 x 2 tables. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with low likelihood of medication adherence over 12- and 24-cycles of treatment.
• ASK-12 scores [ Time Frame: Up to 24 cycles ]
  Will be assessed at each assessment time point. Linear regression analysis at these 2 time points separately will be conducted with QOL score as outcome and treatment adherence group as the main effect adjusting for baseline QOL score along with other disease and demographic characteristics. Descriptive statistics will be used to summarize ASK-12 scores tabulated every 6 cycles on study therapy. The relationship between likelihood of medication adherence and calculated treatment adherence dichotomous groups will be evaluated in 2 x 2 tables. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with low likelihood of medication adherence over 12- and 24-cycles of treatment.
• PRO compliance rate [ Time Frame: Up to 2 years ]
  Will be defined as the proportion of patients who submit the given PRO instrument among those eligible at each time point which excludes those missing by design (due to death or disease progression, early treatment discontinuation). Descriptive statistics will be used to summarize selected PRO-CTCAEs tabulated at each cycle overall and by arm. PRO-CTCAEs will be mapped with provider reported adverse events (AEs) and differences in incidence and worst severity will be evaluated. PRO-CTCAE ratings will further be evaluated in relation to patient bother by treatment side effects to identify the toxicities that are most highly associated with treatment tolerability issues.
• PRO completion rate [ Time Frame: Up to 2 years ]
  Will be defined as the proportion of patients who complete given PRO instrument based on the instrument's scoring system among those eligible at each time point. Descriptive statistics will be used to summarize selected PRO-CTCAEs tabulated at each cycle overall and by arm. PRO-CTCAEs will be mapped with provider reported AEs and differences in incidence and worst severity will be evaluated. PRO-CTCAE ratings will further be evaluated in relation to patient bother by treatment side effects to identify the toxicities that are most highly associated with treatment tolerability issues.

• Time to progression [ Time Frame: From randomization to progression, or censored at date of last disease evaluation, assessed up to 15 years ]
  Will be estimated in each arm using the Kaplan-Meier method.
• Duration of response [ Time Frame: From time of observed response (VGPR or better) to the time of progression in the respective group of responders, assessed up to 15 years ]
  Will be estimated in each arm using the Kaplan-Meier method.
• Treatment duration [ Time Frame: From randomization to date off treatment, or censored at the date of last treatment ]
  Will be estimated using the Kaplan-Meier method. Patients will be classified into dichotomous groups based on a 75% relative dose intensity cutoff (< 75% vs >= 75% represents poor vs good treatment adherence). The proportion of patients with poor lenalidomide treatment adherence will be compared between arms using the chi-squared test for proportions. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with calculated good treatment adherence.
• Cumulative dose [ Time Frame: Up to 15 years ]
  Will be calculated overall and by cycle. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
• Dose intensity [ Time Frame: Up to 15 years ]
  Will be calculated as cumulative dose receive divided by treatment duration. Will be calculated overall and by cycle. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
• Relative dose intensity [ Time Frame: Up to 15 years ]
  Will be calculated as the dose intensity divided by planned dose intensity. Data will be summarized by treatment arm with descriptive statistics and graphically over time.
• Presence, frequency, interference, amount, and/or severity of select Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE) [ Time Frame: Up to 1 year after treatment discontinuation ]
  Will be tabulated at each cycle
• Adherence Starts with Knowledge (ASK)-12 scores [ Time Frame: Up to 12 cycles ]
  Will be assessed at each assessment time point. Linear regression analysis at these 2 time points separately will be conducted with QOL score as outcome and treatment adherence group as the main effect adjusting for baseline QOL score along with other disease and demographic characteristics. Descriptive statistics will be used to summarize ASK-12 scores tabulated every 6 cycles on study therapy. The relationship between likelihood of medication adherence and calculated treatment adherence dichotomous groups will be evaluated in 2 x 2 tables. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with low likelihood of medication adherence over 12- and 24-cycles of treatment.
• ASK-12 scores [ Time Frame: Up to 24 cycles ]
  Will be assessed at each assessment time point. Linear regression analysis at these 2 time points separately will be conducted with QOL score as outcome and treatment adherence group as the main effect adjusting for baseline QOL score along with other disease and demographic characteristics. Descriptive statistics will be used to summarize ASK-12 scores tabulated every 6 cycles on study therapy. The relationship between likelihood of medication adherence and calculated treatment adherence dichotomous groups will be evaluated in 2 x 2 tables. In addition, multivariable logistic regression analysis will be conducted to identify the baseline factors associated with low likelihood of medication adherence over 12- and 24-cycles of treatment.
• PRO compliance rate [ Time Frame: Up to 2 years ]
  Will be defined as the proportion of patients who submit the given PRO instrument among those eligible at each time point which excludes those missing by design (due to death or disease progression, early treatment discontinuation). Descriptive statistics will be used to summarize selected PRO-CTCAEs tabulated at each cycle overall and by arm. PRO-CTCAEs will be mapped with provider reported adverse events (AEs) and evaluate differences in incidence and worst severity. PRO-CTCAE ratings will further be evaluated in relation to patient bother by treatment side effects to identify the toxicities that are most highly associated with treatment tolerability issues.
• PRO completion rate [ Time Frame: Up to 2 years ]
  Will be defined as the proportion of patients who complete given PRO instrument based on the instrument's scoring system among those eligible at each time point. Descriptive statistics will be used to summarize selected PRO-CTCAEs tabulated at each cycle overall and by arm. PRO-CTCAEs will be mapped with provider reported AEs and evaluate differences in incidence and worst severity. PRO-CTCAE ratings will further be evaluated in relation to patient bother by treatment side effects to identify the toxicities that are most highly associated with treatment tolerability issues.

PRIMARY OBJECTIVES:

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 1-21 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 1-21 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.

• Drug: Ixazomib
  Given PO
  Other Names:

  • MLN-2238
  • MLN2238
• Drug: Ixazomib Citrate
  Given PO
  Other Names:

  • MLN-9708
  • MLN9708
  • Ninlaro
• Drug: Lenalidomide
  Given PO
  Other Names:

  • CC-5013
  • CC5013
  • CDC 501
  • Revlimid
• Other: Placebo Administration
  Given PO
• Other: Quality-of-Life Assessment
  Ancillary studies
  Other Name: Quality of Life Assessment
• Other: Questionnaire Administration
  Ancillary studies

• Experimental: Arm A (lenalidomide, ixazomib citrate)
  Patients receive lenalidomide PO QD on days 1-21 and ixazomib citrate PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Ixazomib
  • Drug: Ixazomib Citrate
  • Drug: Lenalidomide
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration
• Active Comparator: Arm B (lenalidomide, placebo)
  Patients receive lenalidomide PO QD on days 1-21 and a placebo PO on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: Lenalidomide
  • Other: Placebo Administration
  • Other: Quality-of-Life Assessment
  • Other: Questionnaire Administration

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
• 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