Multiple Myeloma

Primary  To determine the effect of ixazomib maintenance therapy on progression-free survival (PFS), defined as the time from randomization to progressive disease (PD) or death from any cause, compared with placebo, in patients with NDMM who have had a major responsedefined as complete response (CR), very good partial response (VGPR), or partial response (PR)to initial therapy and who have not undergone SCT Key Secondary  To determine the effect of ixazomib maintenance therapy on overall survival (OS) compared with placebo

Ixazomib (MLN9708)

Ixazomib

capsule

0.5, 2.3, 3.0, 4.0

Primary Outcome Measures :
1. Progression Free Survival (PFS) [ Time Frame: From the randomization until progressive disease (PD) or death or data cut-off date (12 Aug 2019) (Up to approximately 42 months) ]
PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an independent review committee (IRC) according to International Myeloma Working Group (IMWG) criteria, or death due to any cause, whichever occurs first. Per IMWG criteria, PD: serum M-component increase ≥0.5 g/dl or urine M-component increase ≥200 mg/24-hour/ difference between involved and uninvolved FLC levels increase >10 mg/dl or bone marrow plasma cell ≥10%/ development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma or development of hypercalcemia.


Secondary Outcome Measures :
1. Overall Survival (OS) [ Time Frame: From the date of randomization every 12 weeks after PD on next-line therapy until death (Up to approximately 76 to 104 months) ]
OS will be measured as the time from the date of randomization to the date of death.

2. Percentage of Participants Who Achieve or Maintain Any Best Response Category During the Treatment Period [ Time Frame: Up to 24 months ]
Response will be assessed according to IMWG criteria. Best response includes PR, VGPR and CR.

3. Time to Progression (TTP) [ Time Frame: From the date of randomization to the date of first documented PD (Up to approximately 76 to 104 months) ]
TTP is defined as the time from the date of randomization to the date of first documentation of PD, using IMWG criteria.

4. Progression Free Survival 2 (PFS2) [ Time Frame: From the date of randomization to every 12 weeks until 2nd PD or death (Up to approximately 76 to 104 months) ]
PFS2 is defined as the time from the date of randomization to objective PD on next-line treatment using IMWG criteria, or death due to any cause, whichever occurs first.

5. Time to Next Line Therapy (TTNT) [ Time Frame: From the date of randomization to the date of the first dose of the next-line of therapy (Up to approximately 76 to 104 months) ]
TTNT is defined as the time from the date of randomization to the date of the first dose of next-line antineoplastic therapy.

6. Time to End of the Next-line of Therapy After Study Treatment [ Time Frame: From the date of randomization to the date of last dose of the next-line of therapy (Up to approximately 76 to 104 months) ]
Time to end of the next line of therapy is defined as the time from the date of randomization to the date of last dose of the next line of antineoplastic therapy following study treatment.

7. Duration of Next-line Therapy [ Time Frame: From the date of the first dose of the line of antineoplastic therapy coming after study treatment to the date of the last dose (Up to approximately 76 to 104 months) ]
Duration of next-line therapy is defined as the time from the date of the first dose of the line of antineoplastic therapy coming after study treatment to the date of the last dose.

8. Percentage of Participants Who Develop A New Primary Malignancy [ Time Frame: From the randomization date till death or termination of the study (Up to approximately 76 to 104 months) ]
9. Percentage of Participants With Conversion From Minimal Residual Disease (MRD) Positive to MRD Negative, or the Maintenance of MRD Negativity [ Time Frame: Screening, Cycle 13, and Cycle 26 (Cycle length is equal to [=] 28 days) ]
Bone marrow aspirates and blood samples will be sent to a central laboratory and will be assessed for MRD using flow cytometry. MRD negativity is defined as absence of MRD and MRD positivity is defined as presence of MRD.

10. Correlation of MRD Status With PFS and OS [ Time Frame: Screening, Cycle 13, and Cycle 26 (Cycle length=28 days) ]
PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurs first. OS will be measured as the time from the date of randomization to the date of death.

11. OS in a High-risk Population [ Time Frame: From the date of randomization to every 12 weeks after PD on next-line therapy until death (Up to approximately 76 to 104 months) ]
High-risk population will include but not be limited to participants carrying deletion (del)17, t(4;14), t(14;16). OS will be measured as the time from the date of randomization to the date of death.

12. PFS in a High-risk Population [ Time Frame: From the date of randomization to every 4 weeks during follow-up until PD or death (Up to approximately 76 to 104 months) ]
High-risk population will include but not be limited to participants carrying del17, t(4;14), t(14;16). PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause.

13. Eastern Cooperative Oncology Group (ECOG) Performance Status [ Time Frame: Cycle 2 and every 28 days ( Up to 24 months) (Cycle length =28 days) ]
ECOG performance status assess participant's performance status on 5 point scale: 0=Fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity, ambulatory/able to carry out light or sedentary work; 2=ambulatory ( greater than [>] 50 percent [%] of waking hours), capable of all self-care, unable to carry out any work activities; 3=capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair; 5=dead.

14. Percentage of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) [ Time Frame: First dose of study drug through 30 days after last dose of study drug (Up to 25 months) ]
A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. AEs are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 30 days after the last dose of study drug.

15. Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) [ Time Frame: Baseline and every 28 days (Up to 24 months) ]
The EORTC QLQ-C30 is completed by the participant. The EORTC QLQ-30 contains 30 questions that incorporate 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), 1 global health status scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The participant answers questions about their health during the past week. There are 28 questions answered on a 4-point scale where 1 =Not at all (best) to 4 =Very Much (worst) and 2 questions answered on a 7-point scale where 1 =Very poor (worst) to 7 =Excellent (best).

16. Number of Participants With Any Markedly Abnormal Standard Safety Laboratory Values [ Time Frame: From First dose date of study drug through 30 days after the last dose of study drug (Up to 25 months) ]
Clinical laboratory evaluations will be performed by a central laboratory. The number of participants with any markedly abnormal standard safety laboratory values collected throughout study.

17. Correlation Between Frailty Status and PFS and OS [ Time Frame: Up to approximately 76 to 104 months ]
Participant's frailty status is classified as fit, unfit or frail on the bases of 4 components: age, the Charlson comorbidity scoring system without age weighting, the Katz index of independence in activities of daily living, and the Lawton instrumental activities of daily living scale. The sum of the 4 frailty scores equals the total frailty score. A total frailty score of 0 corresponds to a frailty status of fit; a total score of 1, to unfit; and a total score of 2 or more, to frail. PFS is defined as the time from the date of randomization to the date of first documentation of PD or death from any cause, as evaluated by an IRC according to IMWG criteria, or death due to any cause, whichever occurs first. OS will be measured as the time from the date of randomization to the date of death.

18. Pharmacokinetic Parameter: Plasma Concentration of Ixazomib [ Time Frame: Cycle 1 (1 and 4 hours post-dose Day 1, Days 8 and 15 pre-dose); Cycle 2 and 5 (Days 1 and 8 pre-dose) and Cycles 3, 4, 6-10 (Day 1 pre-dose) (Cycle length =28 days) ]
Plasma concentrations of the complete hydrolysis product of ixazomib citrate (ixazomib) will be measured using a validated Liquid Chromatography-tandem Mass Spectrometry (LC/MS/MS) assay.

19. Time to Resolution of Peripheral Neuropathy (PN) Events [ Time Frame: From the initial onset date of PN up to the resolution date for resolved events (Up to 25 Months) ]
PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies not elsewhere classified (NEC) according to the Medical Dictionary for Regulatory Activities (MedDRA). A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the resolution date or the day before and after. Time to resolution is defined as the time from the initial onset date (inclusive) to the resolution date for resolved events.

20. Time to Improvement of PN Events [ Time Frame: From the initial onset date of PN up to the improvement of event (Up to 25 Months) ]
PN is defined as the treatment-emergent adverse event in the high-level term of peripheral neuropathies NEC according to the MedDRA. A PN event is considered as resolved if its final outcome is resolved with no subsequent PN event of the same preferred term occurring on the improvement date or the day before and after. Time to improvement is defined as the time from the initial onset date (inclusive) to the improvement of event.

Inclusion Criteria
Each patient must meet all the following inclusion criteria to be randomized to treatment:
1. Adult male or female patients aged 18 years or older with a confirmed diagnosis of
symptomatic NDMM according to standard criteria (see Section 15.1).
2. Completed 6 to 12 months ( 2 weeks) of initial therapy, during which the patient
was treated to best response, defined as the best response maintained for 2 cycles
after the M-protein nadir is reached.
3. Documented major response (PR, VGPR, CR) according to the IMWG uniform
response criteria, version 2011, after this initial therapy.
4. Female patients who:
 Are postmenopausal for at least 1 year before the screening visit, OR
 Are surgically sterile, OR
 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 drug, or
 Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation,
symptothermal, postovulation methods] and withdrawal are not acceptable
methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
 Agree to practice effective barrier contraception during the entire study
Treatment period and through 90 days after the last dose of study drug, or
 Agree to practice true abstinence, when this is in line with the preferred and usual
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods for the female partner] and withdrawal
are not acceptable methods of contraception.)
5. 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 patient at any time without prejudice to future medical care.
6. Complete documentation of the details of the initial therapy before randomization
including cytogenetics and ISS is available.
7. Eastern Cooperative Oncology Group Performance Status of 0 to 2 (see Section
15.2).
8. Suitable venous access for the study-required blood sampling and consent for the
specific amounts that will be taken.
9. Patient is willing and able to adhere to the study visit schedule and other protocol
requirements including blood sampling and bone marrow aspiration.
10. Patients must meet the following clinical laboratory criteria at study entry:
 Absolute neutrophil count (ANC)  1,000/mm3 without growth factor support
and platelet count  75,000/mm3
. Platelet transfusions to help patients meet
eligibility criteria are not allowed within 3 days before randomization.
 Total bilirubin  1.5  the upper limit of the normal range (ULN).
 Alanine aminotransferase and aspartate aminotransferase  3  ULN.
 Calculated creatinine clearance  30 mL/min (using the Cockroft-Gault equation

Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be randomized to
treatment:
1. Multiple myeloma that has relapsed after, or was not responsive to, initial therapy.
2. Prior SCT.
3. Radiotherapy within 14 days before randomization.
4. Diagnosed or treated for another malignancy within 5 years before randomization or
previous diagnosis with another malignancy. Patients with nonmelanoma skin
cancer or carcinoma in situ of any type are not excluded if they have undergone
complete resection.
5. Female patients who are lactating and breastfeeding or have a positive serum
pregnancy test during the Screening period.
6. Major surgery within 14 days before randomization.
7. Central nervous system involvement.
8. Infection requiring IV antibiotic therapy or other serious infection within 14 days
before randomization.
9. Diagnosis of Waldenstrom’s macroglobulinemia, POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)
syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or
myeloproliferative syndrome.
10. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, uncontrolled congestive heart
failure, unstable angina, or myocardial infarction within the past 6 months.
11. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin,
ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin,
itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole), or strong
CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin,
phenobarbital) or use of Ginkgo biloba or St. John’s wort within 14 days before
randomization.
12. Ongoing or active infection, known human immunodeficiency virus positive, active
hepatitis B or C infection.
13. Comorbid systemic illnesses or other severe concurrent disease that, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens (eg, PN that is Grade 1 with pain or Grade 2 or higher of any
cause).
14. Psychiatric illness/social situation that would limit compliance with study
requirements.
15. Known allergy to any of the study medications, their analogues, or excipients in the
various formulations of any agent.
16. Inability to swallow oral medication, inability or unwillingness to comply with the
drug administration requirements, or GI procedure that could interfere with the oral
absorption or tolerance of treatment.
17. Treatment with any investigational products within 30 days before randomization.